NON-ODONTOGENIC FACIAL BONE TUMOR IN CHILDREN (OSTEOMA, OSTEOIDOSTOMA, OSTEOBLASTOKLASTOMA).ODONTOGENOUS JAW TUMORS IN CHILDREN (AMELOBLASTOMA,EPULID, ODONTOMA, TSEMENTOMA). DIAGNOSIS, DIFFERENTIAL DIAGNOSIS, CLINICAL FEATURES, TREATMENT.
TUMOR-LIKE GROWTHS OF BONE MAXILLOFACIAL AREA (FOLLICULAR, RADICULAR CYSTS, RETROMOLYARNAYA, PRIMARYODONTOGENIC CYST). THE ETIOLOGY, CLINICAL FEATURES, TREATMENT.
FIBROUS DYSPLASIA, CHERUBISM, HYPEROSTOSIS,EXOSTOSIS, EPULID. MALIGNANT TUMORS OF THE FACIAL SOFT TISSUES. CLASSIFICATION, CLINICAL MANIFESTATIONS, DIAGNOSIS, DIFFERENTIAL DIAGNOSIS AND TREATMENT.
A spectrum of benign and malignant bone tumors may be seen in the maxillofacial region. Knowledge of the pathologic features of these tumors and how these features are reflected in their imaging appearance is essential for diagnosis. Familiarity with the imaging appearance, common location, age and gender of bone tumors of the maxillofacial region facilitates the diagnosis and helps radiologists to narrow the list of differential diagnoses and allows for definitive diagnosis in some cases. Early diagnosis of bone tumors is crucial in promoting aggressive treatment, often allowing complications to be avoided.
Computed tomography (CT) is commonly used for imaging the maxillofacial region. A bone window algorithm better delineates the details of a bony lesion. CT scanning is sensitive for detecting calcified tumor matrix, bone changes and cortical destruction. Magnetic resonance (MR) imaging is not frequently used for the diagnosis of bony maxillofacial lesions. Routine T2- and T1-weighted images and a post-contrast study may be used for the diagnosis of soft tissue lesions with bony tumors.
Bone tumors of the maxillofacial region may arise from osteogenic, chondrogenic, fibrogenic, vascular, hematopoietic and other elements of the bone. Table Table11 shows the World Health Organization classification of benign and malignant bone tumors of the maxillofacial region. Table Table22 shows the imaging appearance of bone tumors of the maxillofacial region.
BENIGN TUMOR
Osteoma
Osteoma is the most common osseous tumor in the maxillofacial region. Osteoma is most commonly seen in the 5th to 6th decades of life and the male-to-female ratio is 1.3:1. Osteoma occurs more commonly in the fronto-ethmoidal sinus and is rarely seen in the maxillary and sphenoid sinuses. All osteomas contain three main components: compact bone (ivory), cancellous bone (trabeculae), and fibrous (spongy) tissue. Osteomas are named according to the dominant component. Compact osteomas most often involve the frontal sinus and grow gradually. Cancellous osteomas are located mostly in the maxillary and ethmoid sinuses and grow relatively quickly. Osteomas are slow growing benign tumors. Multiple craniofacial osteomas may be a part of Gardner syndrome. It is usually asymptomatic but may be associated with facial swelling, deformity, mucocele, proptosis, ocular disturbances and pneumocephalus[2,7]. Osteoma appears as a characteristic sharp, well delineated sclerotic lesion attached by a broad base or pedicle to the bone. Osteoma composed exclusively of compact bone is radiodense (Figure (Figure1),1), while those containing cancellous bone show evidence of internal trabecular structure. CT multiplanar reconstructions allow the precise identification of the site of origin of the lesion, to fully depict course and patency of all sinus paths, and to correctly assess the integrity of thin bony walls such as the lamina papyracea or the cribriform plate. Compact osteomas produce a complete signal void on all MR sequences, so they are often indistinguishable from the surrounding air in the paranasal sinuses and are thus overlooked. Fibrous osteomas have low to absent signal intensity on all MR sequences.
Compact Osteoma. Axial computed tomography scan of the paranasal sinus shows a pathognomonic dense sclerotic mass (arrow) in the frontal sinus.
Osteoid osteoma
Osteoid osteoma is a rare tumor in maxillofacial regions (with a few case reports in the ethmoid region) that affects young males in the 2nd to 3rd decades of life. It is a benign osteoblastic lesion characterized by varying intermixtures of osteoid, newly formed bone, and highly vascular supporting osseous tissue (nidus) surrounded by a distinctive surrounding zone of reactive bone formation. Osteoid osteoma appears on CT scan as a characteristic radio-opaque lesion with a nidus (less than 1.5 cm in diameter) which has a radiolucent center surrounded by dense sclerosis. Occasionally, the nidus may have a radio-opaque calcified center with a surrounding radiolucent area. The osteoid osteoma may even be completely sclerotic. MR appearance of osteoid osteoma depends upon the amount of calcification within the nidus, the size of the fibrovascular zone and reactive sclerosis; so it may not be diagnostic. The mass demonstrates patchy enhancement.
Osteoblastoma
Osteoblastoma is typically seen in male patients during the 2nd decade of life. It may be seen in the maxilla, ethmoid, nasal cavity and orbit. It shows a marked amount of osteoid tissue produced by osteoblasts. The osteoclasts are numerous and the background is highly vascular. Histologically, osteoblastoma show some similarity to osteoid osteoma, but they are larger without nidus or zonal architecture and show a stronger, more progressive, occasionally even destructive growth; thus, they are sometimes called aggressive osteoblastoma. The patient presents with pain, facial swelling and asymmetry of the face. It is commonly seen as an expansile lytic lesion with cortical shell (Figure (Figure2A),2A), or it may show as mixed lytic and sclerotic or predominately sclerotic bone forming a lesion. Ossification foci with ground glass appearance, cloudy confluent mineralization in the central part of the lesion (75%) may be seen. It exhibits intermediate to low signal intensity on T1-weighted images and high to low signal intensity on T2-weighted images depending upon the amount of ossification. Areas of mineralization appear as zones of low signal intensity on T2-weighted images. It shows variable patterns of contrast enhancement (Figure(Figure2B2B and C).
Osteoblastoma. A: Coronal computed tomography shows a nonspecific expansile lesion (arrows) seen in the the right frontoethmoid air cells with extension into the right orbit. It shows ossific foci; B: Coronal T2-weighted image shows a well-defined mass …
Chondroblastoma
Chondroblastoma is an extremely rare tumor of the maxillofacial region with few case reports. Eighty-three percent of patients with skull chondroblastoma are more than 30 years of age, whereas 92% of patients with chondroblastomas in long bones are less than 30 years of age[12]. It is more commonly seen in the sphenoid and ethmoid and rarely in the maxilla. The tumor is a locally aggressive, well-demarcated expansile lesion. The matrix of the tumor revealed chondroblast and areas of calcification. CT scan confirms the lytic nature of the lesion and shows areas of calcifications in the center and the periphery of the tumor. Areas of low signal intensity on T2-weighted images are secondary to chondroid matrix mineralization. Chondroblastoma of the peripheral skeleton appears to show a different age predilection and characteristically is surrounded by striking peritumoral edema.
Chondromyxoid fibroma
Chondromyxoid fibroma of the maxillofacial region is typically seen in patients in the 2nd-3rd decade of life with slight female predominance. It is more commonly seen in the maxilla and is unusual in the sphenoid and ethmoid sinuses. The tumor is composed of hypocellular chondroid or myxochondroid tissue with multinucleated giant cells. The CT findings of chondromyxoid fibroma are non specific and almost always suggest a benign lesion. They typically have a lobulated outline with sharp margins, and the majority has a sclerotic rim. The cortex of the bone is usually thinned and expanded. In approximately 50% of cases, a portion of the cortex may be absent. Up to one-third of cases show radiographic evidence of soft tissue extension. The majority of tumors have purely lucent matrix. However, approximately 13% of tumors show some discrete areas of calcification (Figure (Figure3).3). It exhibits low signal intensity on T2-weighted images due to chondroid and myxoid tissue with an inhomogeneous pattern of enhancement[14,15].
Chondromyxoid fibroma. Coronal computed tomography shows expanded mass in the sphenoid sinus with pathognomonic discrete areas of calcification (arrows).
Chondroma
Chondroma occurs in patients less than 50 years old of either gender. The most frequent sites of occurrence are the nasal cavity (septum) and ethmoid air cells. It is a polypoid firm, smooth surface nodule measuring from 0-5 to 2 cm and rarely greater than 3 cm. Histologically, it is a lobulated tumor composed of chondrocytes, resembling the normal histology of the hyaline cartilage. The differentiation of chondroma from a well-differentiated chondrosarcoma may at times be difficult if not impossible. It may be differentiated from chondrosarcoma by pathology. It shows discrete areas of calcification on CT scan.
Osteochondroma
Osteochondroma is an extremely rare tumor of the maxillofacial region. The age of incidence ranges between 10 and 40 years, with most patients presenting in the 3rd decade. The male to female ratio ranges from 1:1 to 2:1. It is located in the facial bones, nasal septum, sphenoid sinus, ethmoid cells and zygomatic arch. The reason for the rare occurrence of osteochodroma in the maxillofacial skeleton is the intramembranous development of these bones. It is a benign cartilage-capped osseous growth composed of compact and cancellous bone. Osteochondromas are characterized by the presence of a cartilage cap on top of the tumor; with time, cartilage tissues gradually undergo endochondral ossification and are replaced by bone. It may be multiple in patients with hereditary multiple exostoses[4]. Osteochondroma usually has a pathognomonic pedunculated mushroom shaped bony outgrowth with peripheral cortex and central cancellous bone that arises from the surface of the bone. The cartilaginous cap may or may not be focally calcified. On MR imaging, it shows a peripheral rim of low signal intensity of the cortical bone and central high signal intensity within the cancellous region. A thin hyperintense cartilagenous cap on T2-weighted images may be seen[4,17].
Fibrous dysplasia
Fibrous dysplasia (FD) represents 2.5% of all osseous and 7% of all benign osseous neoplasms. The craniofacial bones are the affected sites in 10%-25% of patients with monostotic FD and in 50% of patients with polyostotic FD[18]. In addition, the craniofacial region may be affected by a form of FD that is not restricted to a single bone, but may be confined to a single anatomical site. This type of the disease has been termed craniofacial FD. In addition, FD may be a component of McCune-Albright syndrome or it may exhibit cherubism phenotype. The monostotic and polyostotic types are known to be related to mutations in the guanine nucleotide-binding protein gene located on chromosome 20q and the craniofacial subtype has not been localized to this chromosome. It is more commonly seen at the 1st to 2nd decade of life at the floor of the anterior cranial fossa[5,19]. It is located in the frontal bone (82%), sphenoid (71%), ethmoid (68%), and maxillary (28%) bones. Histologically, FD consists of varying amounts of spindle cell bundles and trabeculae of immature woven bone. There is replacement of normal spongiosa and filling of the medullary cavity of affected bones by an abnormal fibrous tissue that contains trabeculae of poorly calcified primitive bone formed by osseous metaplasia. It may be associated with aneurysmal bone cyst. Spontaneous malignant transformation of FD is estimated to occur in less than 1% of cases, and osteosarcoma is the most common histological type, followed by fibrosarcoma, chondrosarcoma and malignant fibrohistiocytoma. These malignancies are most commonly found in the maxilla. Most reported cases of malignant degeneration in FD have occurred after radiation therapy.
The imaging appearance of FD depends upon the amount of fibrous and bony element. CT remains the ‘‘gold-standard’’ imaging modality for FD, allowing characterization of the three main imaging patterns of expanded bone. The cortical bone tends to remain intact, with the FD changes most often found in the medullary bone. The CT findings include: pathognomonic ground glass appearance with bone expansion and alternative radiolucent and radiodensity areas (56%), sclerotic pattern with homogenous radiodensity (23%) and lytic appearance with solitary round or oval, well-defined radiolucent with sclerotic margins (21%) (Figure (Figure4).4). Sclerotic lesions are homogeneously dense, whereas cyst degeneration is the least common finding and is characterized by a spherical or ovoid lucency surrounded by a dense bony shell. On T1-weighted images, the signal intensity is usually low to intermediate depending on the ratio of fibrous tissue to mineralized matrix. On T2-weighted images, lesions with a highly mineralized matrix show low signal intensities, whereas lesions with high fibrous tissue content and cystic spaces return high signal intensities. The lesion may enhance after contrast administration[5,18–21].
Fibrous dysplasia. Coronal computed tomography scan shows a well-defined expansile bony lesion involving the left maxilla with characteristic ground glass appearance.
Cherubism is a rare autosomal-dominant disorder resulting from different mutations to FD and is therefore a distinct entity at the molecular level. It occurs in children (2-5 years) and is more common in males. It commonly appears as a bilateral and symmetrical multilocular cystic swelling of the mandible with expansion of the maxilla and involvement of the maxillary sinuses. The signal characteristics on MR imaging of cherubism are non-specific. Cherubism has been reported in association with neurofibromatosis type 1 and Noonan-like/multiple giant-cell lesion syndrome.
Giant cell tumor
Giant cell tumors occur more commonly during the 3rd and 4th decades of life and are more commonly located in the sphenoid but rarely in the ethmoid bones and the maxilla. It is a benign, locally aggressive tumor characterized by osteoclast-like giant cells. Multicentric tumors with an aggressive course or malignant giant cell tumor with metastasis have been reported. There is a high recurrence rate (40%-60%) after resection[24]. Classically, the tumor destroys the bone and appears as a non-specific rarified area, being a lytic lesion. Although fairly well circumscribed, some cystic changes, ballooning and perforation of the bony cortex may be noted. The area of destruction has a “soap bubble” appearance, with normal trabeculae and little reactive bone at the margin. On MR imaging, it shows fairly low signal intensity on all pulse sequences, and shows moderate to marked contrast enhancement.
Aneurysmal bone cyst
Aneurysmal bone cyst occurs more commonly in the 2nd decade of life and may be seen in the maxilla, ethmoid, sphenoid bone and periorbital region. These cysts are composed of blood-filled, anastomosing cavernous spaces, separated by cyst-like walls. The precise nature and histogenesis of the aneurysmal bone cyst remains unclear. A primary type has to be differentiated from a secondary form; the latter develops on a preexisting bone lesion such as giant cell tumor, osteoblastoma, or chondroblastoma in 1/3 of patients. It appears as an expansile, multi-locular “soap bubble” (honey comb) radio-lucency, causing expansion of the bony cortex. It is surrounded by a marginal thin shell. MR imaging commonly shows cystic spaces with internal septa (Figure (Figure5)5) and septal contrast enhancement. Fluid-fluid levels of varying intensities might be present and should not be considered diagnostic, as this finding might be present in giant cell tumor, telangiectatic osteosarcoma, and chondroblastoma[26,27].
Aneurysmal bone cyst. Axial T2-weighted image shows an expans
Intraosseous (central) hemangioma
Intraosseous hemangioma can occur at any age with the peak incidence being in the 2nd decade of life. An estimated 2:1 female to male ratio has been documented. These tumors occur more commonly in the maxilla and nasal bones and may be found in the orbit. It is a hamartoma with anomalous proliferation of endothelial-lined vascular channels. Hemangiomas are classified into capillary, cavernous and mixed sub-types, depending on the predominant type of vascular channel. It is usually asymptomatic. The characteristic “spoke-wheel”, “wagon-wheel”, “corduroy” or “sunburst” appearance on CT scan arises from thickening of pre-existing trabeculae, secondary to intramembranous bone affected by the vascular channels. T1-weighted images characteristically show hypointensity of the lesion. T2-weighted images reveal heterogeneous hyperintensity within the lesion. A stippled appearance is seen in the tumor matrix. The tumor enhances, intensely or heterogeneously, after the administration of contrast material.
Intraosseous (central) meningioma
Intra-osseous meningioma forms 1% of all meningiomas that typically occur in the 4th decade of life with female predominance. It is more commonly seen in the orbit and sphenoid ridge and rarely involved in the paranasal sinuses. It is more commonly seen as an osteoblastic or mixed sclerotic lesion. It shows a hyperostotic form that may be associated with inward bulging of the inner table and surface irregularity of the hyperostotic bone. CT is the investigation of choice to detect the tumor, cortical destruction and both intra- and extra-osseous extension. At MR imaging, there is bone thickening that exhibits low signal intensity on all pulse sequences with intense contrast enhancemen.
MALIGNANT TUMOR
Osteosarcoma
Fewer than 10% of osteosarcomas arise in the craniofacial bones with most such tumors developing in the mandible and maxilla. Typically, the tumor affects males in the 3rd decade and one or two decades later in the appendicular skeleton. Osteosarcomas may involve the mandible or maxilla and rarely the ethmoid region. The most common sites of involvement are the body of the mandible and the alveolar ridge or the antral area of the maxilla. The majority of tumors arise within the medullary cavity of the affected bone with rare examples developing on the bony surfaces. It may be secondary to radiation, fibrous dysplasia, Paget disease, trauma, osteomyelitis, ossifying fibroma and giant cell tumor. Osteosarcoma after radiation typically develops after a latency period of 5-10 years after doses in excess of 3000 Gy. These tumors characteristically occur at the edge of the radiation field because the administered radiation is unable to cause cell death but is sufficient to induce malignant transformation. Osteosarcoma can be classified on location into intramedullary, intracortical, periosteal and parosteal (surface) and extraosseous. It can be further categorized according to the prominent type of matrix tissue observed microscopically such as osteoblastic, chondroblastic, fibroblastic, telengectatic and osteoclast-rich types. On CT, the tumor displays a spectrum of bone changes from well demarcated borders, notably the low grade osteosarcoma (uncommon), to lytic bone destruction with indefinite margin and variable cortical bone erosion, to the ostoeblastic form, where the bone is sclerotic. The majority of osteosarcomas have matrix mineralization, calcifications of the osteoid or osteoid-Iike substance within the tumor and some tumors show a sunburst effect caused by radiating mineralized tumor spiculae. Cortical breakthrough and interruption of alveolar margin is common in advanced cases. On MR imaging, osteosarcoma is of low to intermediate signal intensity on T1-weighted images and is of high signal intensity on T2-weighted images. Calcifications and new bone formations appear as signal void regions within the lesion that show inhomogeneous patterns of contrast enhancement (Figure (Figure66).
Osteosarcoma. A: Axial computed tomography shows a rather irregular characteristic spiculated mass in the left alveolar margin of the maxilla adjacent to the lateral pterygoid plate; B: Axial contrast T1-weighted image shows inhomogeneous enhancement …
Chondrosarcoma
Craniofacial chondrosarcoma accounts for 2% of all chondrosarcomas with a peak incidence during the 4th to 5th decades of life and a male to female ratio of 2.4:1. It is seen in the skull base (common), maxilla and orbit (less common), and cartilage of the nasal septum (rarely). Chrondosarcoma has been reported to develop in association with malignant conditions, such as osteosarcoma, fibrosarcoma, and leukemia, as well as benign conditions, such as Paget disease and fibrous dysplasia[35]. Histologically, chondrosarcoma of the craniofacial region can be divided into subtypes: the conventional subtype with myxoid and/or hyaline components, the aggressive mesenchymal and dedifferentiated subtype and the extremely rare clear cell subtype. The conventional type, which is the most common form, is slow growing, and rarely metastatic. On the other hand, mesenchymal chondrosarcoma is more aggressive and tends to metastasize. They slowly increase in size, and the majority of them are already extensive at the time of diagnosis[36]. On CT scan, chondrosarcoma shows a soft tissue mass with characteristic multiple stippled and amorphous areas of calcifications that may be associated with bone destruction and an inhomogeneous pattern of contrast enhancement (Figure (Figure7).7). The signal intensity of the chondroid matrix is lower than bone matrix on T1-weighted images. There are hyperintense areas (chondroid tissue) and hypointense areas (calcified regions) on T2-weighted images. The tumor may show characteristic curvilinear septal enhancement of fibrovascular tissue and non-ossified cartilage. The development of metastases varies among studies and ratios of metastases are between 14% and 90%, with the lungs being the preferred site. Regional cervical lymph node metastases are reported iot more than 5% of all cases.
Chondrosarcoma. Axial computed tomography shows bulky mass in the nasal cavity and left maxillary sinus with characteristic stippled and amorphous areas of calcification (arrows).
Ewing sarcoma
Craniofacial Ewing sarcoma accounts for 1%-4% of all Ewing sarcomas with peak incidence between 5 and
20 years old in either sex, although it does have a predication for whites[38]. It may be seen in the orbital wall, sphenoid and maxilla. It is an aggressive, malignant, small round cell tumor of bone. Because of the intense vascularity of the tumor, hemorrhage and necrosis are common. Marked tumor necrosis is considered a poor prognostic factor. The commonest sites of metastases are the lungs and the skeleton that occur in the early course of the disease. Ewing sarcomas appear as a destructive aggressive mass with mottled irregular lucent areas interposed with some sclerosis. The margin is diffuse with unsharp edges and extensive cortical destruction. It may be associated with perpendicular bony spicules and shows the characteristic onion peel appearance of periosteal reaction, and less often with a sunburst type of periosteal reaction. The tumor tends to metastasize early, often to multiple other bony sites and the lungs. On MR imaging, the tumor is heterogeneously hypointense on T1-weighted and heterogeneously hyperintense on T2-weighted scans. On post-contrast T1-weighted images, the lesion shows heterogeneous signal increase with internal hypointense necrotic areas (Figure (Figure88).
Ewing Sarcoma. Axial contrast T1-weighted image shows a large destructive mass occupying the entire left maxillary sinus. The mass shows inhomogeneous non-specific pattern of contrast enhancement.
Fibrosarcoma
Craniofacial fibrosarcoma is very rare and is seen in the 3rd to 6th decades of life with a slight male predominance. The infantile variant that is seen in patients less than 5 years has a better prognosis. It is rarely seen in the maxilla. It may be central (medullary) or peripheral (periosteal). It is a malignant tumor with variable fibrous intracellular substances devoid of bone or cartilage formation. On CT, fibrosarcoma is a destructive lesion of variable size, frequently associated with extra osseous soft tissue mass. On MR imaging, the tumor shows low or intermediate signal intensity on both T1- and T2-weighted images with an inhomogeneous pattern of contrast enhancement.
Hemangioendothelioma
Hemangioendothelioma of the maxillofacial region is a low-grade, malignant vascular tumor. Hemangioendotheliomas account for only 0.5% to 1.0% of malignant primary bone tumors. Most of them arise in the third decade and they are prone to occur in the maxillary sinus. Multifocality is present in 9%-14% of cases. The tumor is often large and aggressive. Multifocal lytic lesions (honeycomb appearance), aggressive bony destruction with expansion, dense sclerotic lesion and soft-tissue mass are seen on CT scan (Figure (Figure9).9). There is a low to intermediate signal intensity on T1-weighted images and slightly high signal intensity on T2-weighted images. Tubular signal-void regions represent blood vessels that may be seen within the lesion. It shows moderate to marked contrast enhancement[42].
Hemangioendothelioma. Axial computed tomography shows a non-specific sclerotic enhanced lesion related to the posterior part of the nasal septum on the right side (Courtesy of Castillo M).
Chordoma
Chordoma forms 1% of all intracranial tumors that are typically seen in male patients during the 4th decade of life. It is commonly located in the clivus and may extend into the sphenoid and maxillary sinus. It is a benign, locally invasive tumor. It appears as a hypodense mass with irregular intratumoral calcifications (30%-50%) that are associated with variable contrast enhancement and bone destruction. The tumor shows intermediate signal intensity with areas of high signal representing hemorrhage or high protein cystic areas on T1-weighted images. The lesion has relatively high signal intensity associated with areas of low signal intensity that may be seen in the lesion that represents residual fragments or sequestrations of bone on T2-weighted images. After contrast administration, it shows inhomogeneous patterns of enhancement.
Lymphoma
Lymphoma of the maxillofacial region occurs over a broad age range (4th-7th decades) with slight male predominance. The vast majority are large B cell non-Hodgkin lymphomas. On CT scan, lymphoma can produce lytic, sclerotic or mixed lesions that may be associated with soft tissue mass. It appears as isointense to muscles on both T1- and T2-weighted images that are associated with soft tissue mass. The mass shows intense patterns of contrast enhancement. Burkitt’s lymphoma is a special type that may be seen in Africans during the 1st decade of life. It appears as an osteolytic lesion with periosteal reaction and perpendicular spicules of new bone in the maxilla. An extra-osseous soft tissue mass may develop parallel with bone destruction.
Solitary intramedullary plasmacytoma
Plasma cell disorders are characterized by the accumulation of monoclonal plasma cells that produce the same immunoglobulin. Plasmacytomas are plasma cell tumors. They can occur as solitary tumors outside the bone marrow (solitary medullary (bone) plasmacytomas, solitary extramedullary plasmacytomas, but can also be associated with multiple myeloma. Solitary medullary plasmacytoma occurs more commonly in male patients between the 4th and 7th decades of life. It may be seen in the sphenoid sinus and the maxilla. It is a fairly well defined expansile lesion with contrast enhancement. It exhibits low signal intensity on T1-weighted images and high or mixed signal intensity on T2-weighted images with marked contrast enhancement that may simulate meningioma.
Metastasis
Metastasis is uncommon in the maxillofacial region. The maxillary sinus is most frequently involved (33%) followed by the sphenoid (22%), ethmoid (14%) and frontal (9%) sinuses. In 22% of cases, multiple sinuses are involved. The most common tumor sites to disseminate to this region are the kidney (40%), lung (9%), breast (8%), thyroid (8%) and prostate (7%). The remaining 28% of cases include multiple miscellaneous sites. In 10-15% of cases, the metastases are limited to the nasal cavity. Although the eventual outcome is usually poor, prognosis depends, in part, on whether the sinonasal metastasis is isolated or part of widespread disseminated disease. Metastasis may appear as a localized, well-defined radiolucent lesion in a slow growing lesion, or it may be associated with cortical destruction in a highly aggressive lesion, osteoblastic in breast cancer or mixed lytic or sclerosis in patients with prostate cancer. The tumor exhibits low signal intensity on T1-weighted images and high signal intensity on T2-weighted images that may be associated with an enhancing soft tissue mass.
DEFINITION AND PROPERTIES OF TUMORS
Willis ( 1960) proposed a workable definition for distinguishing true tumors from inflammatory and reparative proliferations, hyperplasias, and malformations with excess of tissue. A tumor “is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues, and persists in the same excessive manner after cessation of the stimuli which evoked the change.” Every pathologist can think of exceptions but these do not invalidate the general applicability of the definition.
Classification of tumors
The commonly used and most useful classification of tumors is histogenetic, that is, the tumors are named according to the tissues from which they arise and of which they consist. In most tumors the neoplastic tissue consists of cells of a single type and, with experience, one can readily classify them. The types of histological differentiation found in tumors appear to be inherent in the parent tissues. Foulds ( 1940) concluded that most adult normal cells have a greater capacity for divergent differentiation than was formerly supposed and that it is unlikely that tumor cells acquire new capacities. The few kinds of tumors in which there is uncertainty regarding the precise tissue of origin require further histopathological research. Meanwhile in these cases we must settle for noncommittal identifying names.
Willis ( 1960) illustrated the application of histogenetic classification to both human and animal tumors. Cloudman ( 1941) presented a histological classification of mouse tumors. Dunham and Stewart ( 1953) gave a classification of transplantable and transmissible animal tumors.
Benign or malignant
In addition to histogenetic classification, it is of practical value in human oncology to attempt to predict the behavior of a tumor from its morphology. The tumors of any given cell type may show a wide range of difference in structure, mode of growth, rate of growth, and danger to the host. Some, called benign, are well differentiated, grow only by expansion with the formation of a capsule, grow slowly, and are dangerous only in terms of position, accidental complication, or excessive hormone production. Others, often less well differentiated, grow rapidly, invade adjacent tissues, spread by metastasis, and unless extirpated at an early stage will kill the host; these are malignant tumors. Between these extremes there may be tumors of intermediate behavior. Thus, the terms benign and malignant are relative and arbitrary.
Criteria for diagnosing malignancy include imperfect differentiation and variation in the size, shape, and staining quality of the cell and the nucleus, invasion of adjacent tissues, and metastasis. In general the degree of malignancy is roughly proportional to the degree to which tumors fail to attain histological differentiation; the most anaplastic tumors are the most malignant. Metastasis depends on the invasion of blood vessels, lymphatics, or serous and other cavities, with the detachment of tumor cells or cell clusters and the establishment of distant secondary deposits. Lymphatic metastasis is less common in mice than in man. When tumors occur in inbred animals, there is available an additional criterion of malignancy: successful transplantation with progressive growth ( Chapter 28).
Stages of development
The fact that tumors develop in a series of stages was first clearly recognized by Rous and Beard ( 1935), in studies on virus-induced skin tumors in rabbits, and by Greene ( 1940), in studies on the development of spontaneous mammary and uterine tumors in rabbits. Foulds ( 1954, 1958) has generalized under the termprogression the concept of the development of a tumor by irreversible, qualitative changes in one or more of its characters. The concept includes the early “precancerous” and neoplastic changes and the extended development of neoplastic characters that occurs during serial transplantation. A tumor may change, often abruptly, in growth rate, histological structure, invasiveness, or responsiveness to extraneous stimuli such as hormones or chemotherapeutic agents. These characters tend to be independently variable and subject to independent progression. Progression is independent of the duration or size of a tumor. Some tumors pass through, or bypass, all the theoretically possible developmental stages before they are grossly or even histologically recognizable. Others may become stabilized at any stage for the lifetime of the host. Continued serial transplantation, however, almost inevitably results in continued progression toward an endpoint of rapid growth rate, loss of functional and histological differentiation, and loss of responsiveness to extraneous stimuli.
In mice, Berenblum and Shubik ( 1947) demonstrated stages of initiation and promotion in the induction of skin tumors by a carcinogenic hydrocarbon. Foulds (1956) carried out detailed studies on mammary tumors developing from plaques which grow in response to pregnancy and regress after parturition. Many tumors of endocrine glands and their target organs go through a dependent or conditional phase in which removal of the causative stimulus is followed by regression ( Furth, 1953). In such tumors, some cells ultimately become altered if not during residence in the primary host then after transplantation and give rise to autonomous growth, which continues even when the causative stimulus is eliminated.
Genetic factors
Heston ( 1963) stated that the development of inbred strains has constituted probably the greatest advance in all cancer research. Genetic factors are immediately apparent in the different incidences of spontaneous tumor types among inbred strains and in the differing susceptibilities of these strains to the effects of carcinogens. The process of inbreeding fixes genes concerned with susceptibility to tumor formation ( Chapter 2) at the same time, transmitted oncogenic viruses may be carried along as in the case of the mammary tumor agent. Additional environmental factors, bacterial, viral, nutritional, and other, may be perpetuated by laboratory conditions (Chapters 4, 30). In general, the susceptibility of inbred strains and their hybrids to specific tumor induction is related to the frequency of spontaneous tumors of the same type. Potent carcinogens in high doses can induce subcutaneous sarcomas in mice of any strain, but graded doses reveal strain differences. Susceptibility to the development of most tumors appears to be inherited as a multiple-factor character with alternative expression ( Heston, 1963). The character appears when the combined action of the genetic and nongenetic factors surpasses a threshold ( Chapter 9). The nongenetic factors include physical and chemical carcinogens, hormones, nutritional factors, and viruses.
CHARACTERISTIC TUMORS
The most common tumors of inbred strains of mice are mammary tumors (in breeding females), lymphocytic leukemia, primary lung tumor, hepatoma (in males), and reticulum cell sarcoma (in older animals). Andervont and Dunn ( 1962) showed that wild mice maintained under laboratory conditions have a similar predominance of these tumor types, except for lymphocytic leukemia. Mammary tumors occur in high incidence in breeding females of strains C3H, DBA, A, and DD. In virgin females the incidence is high in C3H and DD, intermediate in DBA, and low in A. Tumors of high incidence tend to occur during the latter half of the first year of life and in the early part of the second year. Tumors of low incidence tend to occur during the latter half of the second year and the first half of the third year. Characteristic tumors of inbred strains are listed in Table 27-1. The spectrum of tumors observed in some longer-lived sublines and in wild mice is shown in Table 27-2.
MAMMARY TUMORS
The “mammary tumor of the mouse has probably been the most completely studied of all tumors” ( Dunn, 1959). Accessibility to palpitation, predictable frequency in a number of inbred strains, and ready transplantability have made the mammary tumor an invaluable tool for investigations in genetic, viral, hormonal, chemotherapeutic, nutritional, and other facets of cancer research. The discovery of the milk agent ( Staff, Jackson Memorial Laboratory, 1933) greatly stimulated research on mammary tumors. the agent has the characteristics of a virus and is transmitted by the milk of high mammary tumor strain females to the young. It appears to modify the responsiveness of the mammary gland tissue so that with a favorable genetic constitution and the proper hormonal stimulation, tumors develop at a comparatively early age. A usually much lower incidence of mammary tumors of variable morphology occurs in older mice in the absence of the milk agent ( Table 27-2). Mammary tumors have been induced by estrogenic hormones ( Lacassagne, 1932; Gardner et al., 1959), implantation of pituitary glands ( Mühlbock and Boot, 1959; Heston, 1964), chemical carcinogens ( Andervont and Dunn, 1953), and by polyoma virus ( Dawe et al., 1959).
Classification
Many classifications of mammary tumors have been proposed. Apolant ( 1906) made the first detailed histological study of mammary tumors of the mouse. His classification was standard for many years. The histological classification of Dunn ( 1959) has the advantage of simplicity and has been extensively applied to the analysis of histological types in a number of inbred strains, with and without the milk agent. Dunn’s classification appears in Table 27-3 and an application in Table 27-2.
Gross appearance
Because of the extent of the mammary tissue in the female mouse, from the cervical region to the vulva on the ventral surface and almost to the midline in the back, the tumors may be found at almost any subcutaneous site in the body. In gross appearance, tumors may be round, oval, or coarsely nodular, and well circumscribed. The tumor tissue is usually grayish white and soft and often contains blood-filled cysts and central areas of necrosis.
Adenocarcinoma, Type A
The tumor is composed of uniform small acini, or tubules lined by a single layer of small cuboidal epithelial cells ( Figure 27-1). The tissue appears well differentiated and may show foci of secretory activity. Type A is the characteristic tumor of strain C3H with the mammary tumor agent and together with Type B represents the “typical” adenocarcinomas in mice with the agent.
Adenocarcinoma, Type B
The category represents a diversified group of glandular epithelial patterns, several of which may appear in a single tumor. Areas similar to Type A may be found as well as cysts filled with blood or clear fluid, intracystic papillary projections, irregular cords and tubes, and solid sheets of cells ( Figure 27-2). The amount of stroma may vary.
Adenocarcinoma, Type C
The tumor is composed of multiple cysts of varying size, lined by a single layer of cuboidal epithelial cells, which are closely surrounded by a spindle cell layer ( Figure 27-3). The connective tissue stroma usually appears edematous. Type C has nearly always been found in very old mice that lacked the agent.
Adenoacanthoma
Although foci of stratified squamous epithelium may occur in any type of mammary tumor, the term adenoacanthoma is restricted to tumors in which at least one-fourth of the section shows epidermoid differentiation ( Figure 27-4). The glandular elements of the tumors resemble Types A and B.
Carcinosarcoma
In these tumors there are irregular nests of epithelial cells closely intermixed with spindle cells resembling fibroblasts. Both elements may show numerous mitotic figures. The type occurs frequently among tumors induced by carcinogenic hydrocarbons. On repeated transplantation, purely glandular tumors may undergo a stage of carcinosarcoma and finally become pure sarcomas.
Sarcomas of the subcutaneous tissue must be distinguished from mammary tumors. However, some sarcomas may be derived from the stroma of the mammary gland and may appear in increased number after experimental procedures that increase the incidence of epithelial tumors. Cloudman ( 1941) presented a list of tumors and other lesions, arising in the area of the mammary gland, that may be mistaken for mammary tumors. For the sake of completeness, salivary gland tumors, lymphocytic and reticulum cell neoplasms, and squamous cell carcinoma of the skin should be added. These lesions can be distinguished by histological study.
Miscellaneous mammary tumors
These tumors that fit none of the other categories include a peculiar giant-type cell, epithelial tumors bearing no resemblance to the structure of mammary tissue, and tumors with abundant fibrous stroma resembling the characteristic human “Scirrhous” carcinoma. Organoid tumors composed of ducts and acini radiating from a central area have been described ( Dunn, 1959). The central area is keratinized in the mulluscoid type.
Preneoplastic and early neoplastic change
The preneoplastic and early neoplastic changes in the mammary gland of high-tumor strains have often been studied. The most important precancerous change in high-tumor strains with the milk agent appears to be the “hyperplastic nodule,” composed of a localized proliferation of acini. These areas are well demonstrated in whole mounts of the mammary glands ( Chapter 13). The nodules also occur in old female mice without the agent. Foulds ( 1956) has described an early neoplastic “plaque” which grew only during pregnancy and regressed after parturition. The plaques consisted of radially arranged branching tubules. These growths were dependent on the hormonal stimulation of pregnancy.
TUMORS OF THE HEMATOPOIETIC STYSTEM
The classification of tumors of the hematopoietic system in the mouse is adapted from Dunn ( 1954a) and appears in Table 27-4. Only the more common types will be described here. See Dunn’s monograph for a description of variants and rarer types.
Lymphocytic neoplasms
The generalized form of lymphocytic neoplasm, lymphocytic leukemia, is the most frequent and most extensively studied form of leukemia in mice. The incidence is high in relatively young mice of high leukemia strains, such as AKR and C58, but the tumor appears sporadically in mice of other strains, usually at a more advanced age. The incidence was low ioninbred mice reviewed by Horn and Stewart ( 1952). Dunn and Andervont ( 1963) found only two lymphocytic neoplasms among 225 wild mice maintained under laboratory conditions. Lymphocytic neoplasms have been induced by a number of viruses ( Moloney, 1960; Lieberman and Kaplan, 1959), by X-irradiation ( Furth and Furth, 1936; Kaplan, 1964), by carcinogenic hydrocarbons ( Law, 1941), and by estrogenic hormones ( Gardner et al., 1959).
A characteristic case shows general enlargement of the lymph nodes, thymus, and spleen. The involved organs are soft and white and often show hemorrhagic areas. The kidney and the liver may be enlarged and pale and contaiodules of soft white tissue. Ascites may occur in advanced cases. Microscopically ( Figure 27-5), the leukemic cell infiltrates the internal organs and may be found in blood smears. Two types of leukemic cells occur. One closely resembles a normal lymphocyte, with a deep basophilic small round nucleus and a thin rim of clear basophilic cytoplasm. In other cases, the cell is larger than the normal adult lymphocyte, with amore vesicular nucleus which may be round or slightly indented and with more abundant cytoplasm.
Reticulum cell neoplasms
The solitary fixed cells of the reticular framework of lymphatic and hematopoietic organs give rise to several distinctive tumors in the mouse. These reticulum cell sarcomas occur in older mice of a variety of inbred strains, particularly in their long-lived hybrids, and are less well known than the tumors of younger mice. Since they involve lymph nodes, spleen, and other organs, in many studies they tend to be lumped grossly with the leukemias. However, they are readily separated histologically.
Reticulum cell neoplasm, Type A. This tumor of unusually well-differentiated reticulum cells has been described in the literature as histiocytoma, monocytoma, reticuloendothelioma, and reticuloendotheliosis. The process may be localized or generalized and tumor cells may be found in the peripheral blood. Gorer ( 1946) reported an incidence of 15 to 20 per cent in strain C57BL mice over 18 months of age (see also Table 27-2). The tumors occur sporadically in old animals of other inbred strains.
At autopsy, enlargement of the liver and ascites are usually found. Involvement of the uterus is common in females. Spleen, lungs, kidneys, thymus, mesenteric, and other lymph nodes may be involved. The tumor tissue is firm, usually white, often shows hemorrhagic foci, and may have a distinctive orange color due to hematoidin. The tumor cell has eosinophilic cytoplasm and a heavily stained basophilic nucleus, and shows great variation in the size and shape of the cell and the nucleus ( Figure 27-6). Differentiation is indicated by erythrophagia and hemosiderin within the tumor cells. Multinucleated cells are frequent and may resemble Langhans-type giant cells. A common variant contains sheets of small spindle cells, with heavily basophilic ovoid nuclei and scanty cytoplasm, resembling fibrosarcoma. Both patterns may appear in the same animal, either intermixed or in separate deposits. An angiomatous pattern is occasionally seen in the tumor in the liver.
Transplantation to mice of the same strain is usually successful but growth is slow and may extend for 10 to 12 months. The Type A neoplasm may be compared with the more differentiated types of reticulum cell sarcoma in man, such as the clasmatocytic lymphoma described by Gall and Mallory ( 1942). The tumor induce by the Friend virus ( Friend, 1957) has been derived by Buffet and Furth ( 1959) from the reticulum cell. It resembles some of the leukemic forms of Type A.
Reticulum cell neoplasm, Type B. This multicellular tumor is more common than Type A and may be the most common tumor in older mice of otherwise low-tumor strains and of long-lived hybrids. Jobling ( 1910) and other early investigators used the term Hodgkin’s disease; later investigators, Hodgkin’s-like. The tumor occurs in 25 per cent of strain C57L/He mice, 18months of age ( Heston, 1963). It is a characteristic tumor of old age in mice of many inbred strains and in wild mice maintained under laboratory conditions ( Dunn and Andervont, 1963). Murphy ( 1963) has reported an incidence of more than 90 per cent at an average age of 13 months in a new inbred strain, SJL/J. Stansly and Soule ( 1962) presented evidence for a filterable agent that can induce Type B reticulum cell neoplasms.
At autopsy the mesenteric node is usually greatly enlarged. Peyer’s patches are frequently involved and the tumor appears to spread to the pancreatic and renal nodes. Nodular involvement of the white pulp of the spleen is common and discrete nodules may be found in the liver. Advanced cases may involve kidney, lungs, mediastinal, and peripheral nodes. A minority of cases may be primary in some other node or the spleen. The tumor tissue is firm and white, with little hemorrhage. The process develops slowly; therefore localized cases may readily be found. Transplantation has been successful in a limited percentage of trials.
Microscopically, there is a background of large, pale reticulum cells intermixed with lymphocytes and plasma cells ( Figure 27-7). Tumor giant cells and multinucleated cells resembling foreign-body giant cells and Langhans’ giant cells may be found. In strain SJL/J eosinophils may be prominent along with fibrosis (Figure 27-8), and in several cases tumor giant cells were observed which duplicate the classic features of the Sternberg-Reed cells described in human Hodgkin’s disease ( Murphy, 1963).
Granulocytic leukemia
Granulocytic leukemia is rare in comparison with lymphocytic leukemia in the mouse. It can be induced in strain RF mice by ionizing radiation ( Upton, 1961). Graffi (1957) described granulocytic leukemias in mice isolated from five different tumors. Grossly, the distribution and appearance of the tumors are usually indistinguishable from those of lymphocytic leukemia, unless the green color of chloroleukemia is present. A high granulocyte count with many undifferentiated cells is found in the peripheral blood. In the tissues, collections of relatively immature granulocytic cells are found ( Figure 27-9). Invasion of the capsule of lymph nodes and infiltration of fatty tissue are helpful in distinguishing this leukemia from extramedullary hematopoiesis.
Plasma cell neoplasm
Rask-Nielsen and Gormsen ( 1956) have reported a low incidence of plasma cell leukemia in several inbred strains. Plasma cell neoplasms have been induced by Plexiglas fragments ( Merwin and Redmon, 1963) and mineral oil ( Potter and Boyce, 1963) introduced into the peritoneal cavity of BALB/c mice. The inducing agents appear to exert their effect by their physical rather than their chemical properties ( Potter and MacCardle, 1964). Transplantable plasma cell tumors secrete a variety of proteins related to γ- and β-immunoglobulins and their subunits in the form of Bence-Jones proteins ( Fahey, 1961).
Dunn ( 1954a) has described both localized and generalized forms of plasma cell neoplasm. The localized type begins in the ileocecal area of old strain C3H mice, and the neoplastic cells extend through all coats of the intestine, through the mesenteric fat, and involve the medullary sinuses of the mesenteric node. One of these tumors has been successfully transplanted and shows heavy infiltration of the gonads and the kidneys. The generalized type ( Figure 27-10) involves lymph nodes, spleen, and perivascular tissue in the kidneys and lungs. The tumor cell has an eccentric nucleus, with a clear area in the cytoplasm, and the Giemsa stain shows the violet-colored cytoplasm of the plasma cell. Russell bodies may occur in the tumor cells. These tumors must be distinguished from plasma cell hyperplasia of lymph nodes (especially frequent in old mice), from inflammatory plasma cell infiltrations, and from other neoplasms.
Mast cell neoplasm
True neoplasms of mast cells are rare in mice. They may be localized and termed mastocytoma or more generalized and termed mast cell leukemia. Dunn ( 1954a) observed several of these tumors at autopsy. They were usually localized masses in lymphatic or connective tissue. Rarely, the neoplasm was widely distributed, involving lymph nodes, spleen, liver, lungs, and kidneys. Microscopically, the neoplastic mast cell is larger than the normal, it is less heavily and uniformly granulated, and the granules generally do not stain so intensely. Transplantable mast cell tumors have been reported ( Dunn and Potter, 1957; Rask-Nielsen and Christensen, 1963). These tumors are of particular interest because they may secrete heparin, histamine, and serotonin.
Stem cell leukemia
In human pathology this term refers to cases of acute leukemia in which the neoplastic cell is undifferentiated. Such tumors are not commonly distinguished in the mouse, but are probably included with the lymphocytic leukemias. Because of the preponderance of lymphocytic over granulocytic and other leukemias in the mouse, the undifferentiated forms are probably related to lymphocytic leukemia.
Misleading nonneoplastic lesions
Pathologists trained in human pathology are frequently misled by interstitial infiltrates of lymphocytes which occur with increasing frequency in the kidney, liver, and other organs of aging mice. The question of leukemic infiltration is often raised. The cell collections are usually perivascular, and on closer examination usually show a mixed population of reticulum cells, lymphocytes, and plasma cells.
A possible error is the misdiagnosis of extramedullary hematopoiesis as granulocytic leukemia. Extramedullary hematopoiesis in the spleen is physiological in the mouse. It requires little stimulus for the liver, lymph modes, and other organs to respond with tumorlike infiltrates, with predominance of the granulocytic series. The spleen may be as large as in many cases of leukemia, but the numerous intermixed megakaryocytes usually rule out granulocytic leukemia. Barnes and Sisman ( 1939) have described and tabulated the important points for differentiating extramedullary hematopoiesis from the rare granulocytic leukemia in the mouse.
Simonds ( 1925) described an enlargement of the mesenteric lymph node in five mice of the Slye stock. The node was enlarged by wide blood-filled spaces, which disrupted the normal histology of the node. The process is not neoplastic but appears to be due to venous congestion. It is frequent in strain C3H and its hybrids and occurs in old C57BL mice.
PULMONARY TUMORS
Spontaneous pulmonary tumors are known to be frequent in only two species, man and mouse ( Stewart, 1959b). Although the characteristic human tumor is bronchogenic in origin, the characteristic tumor of the mouse is alveologenic.
Alveologenic tumors
Alveologenic tumors occur spontaneously in high incidence is strains A, SWR, and BALB/c and can be induced in these and other susceptible strains by a variety of agents including urethan, carcinogenic hydrocarbons, nitrogen mustard, and γ-radiation ( Shimkin, 1955). Even though these tumors have been variously diagnosed as adenoma, papillary cystadenoma, and adenocarcinoma, they may all be morphological variants of a single malignant neoplastic process. The pulmonary tumor of the mouse is a malignant neoplasm, as judged from its lack of encapsulation, local invasiveness, transplantability, and ability to metastasize.
In gross appearance, the tumors are rounded, pearly white nodules, often situated just below the pleura, and projecting slightly. The spontaneous tumors are frequently solitary and usually do not exceed two to four per animal. The induced tumors are almost invariably multiple. Microscopically, most of the tumors present a uniform pattern of closely packed columns of cuboidal columnar cells ( Figure 27-11). The cells are rather uniform in size and shape, with acidophilic cytoplasm and round or oval nuclei. The sparse stroma is composed of mature fibrous tissue. Papillary formation is frequent in larger tumors. Spontaneous and induced tumors are indistinguishable microscopically. The common metastatic tumors in the lungs of mice can usually be suspected from the presence of a primary tumor in another site and distinguished microscopically.
Bronchogenic tumors
Squamous cell carcinomas arising in bronchi have been induced by local application of radioactive substances ( Gates and Warren, 1960) and by a combination of influenza virus and aerosols of hydrocarbons ( Kotin and Wiseley, 1963).
HEPATIC TUMORS
Hepatomas (liver cell carcinoma, hepatocellular carcinoma) occur spontaneously in low incidence in a number of inbred strains, but are common in older males of strains C3H and CBA ( Burns and Schenken, 1940; Gorer, 1940; Andervont, 1950b). Heston et al. ( 1960a) found an incidence of 85 per cent in C3H/He males. Deringer ( 1959) reported 91 per cent in C3HeB males and 58 per cent in virgin females. The tumors are usually solitary but may be multiple. They are usually elevated round or ovoid masses on the surface or margins of the lobes; some may be pedunculated. They may be gray or yellow or the same color as the liver. The histology is usually remarkably uniform and rather closely resembles normal liver ( Figure 27-12). Cords of cells are separated by sinusoids lined by flattened endothelial cells. However, a true lobular architecture is absent and bile ducts occur only at the periphery of the tumor. The size of the hepatoma cells and their nuclei shows a wide range of variation ( Miyagi, 1952). Cytoplasmic hyaline inclusion bodies are frequently observed. The nontumorous portions of the liver appear normal, without evidence of cirrhosis or inflammatory processes. Cholangioma has not been observed in untreated mice.
Metastasis of hepatomas has been described and, although not all spontaneous tumors were successfully transplanted, Andervont and Dunn ( 1952) could not demonstrate a consistent histological difference between those that grew and those that failed to grow. Therefore, the spontaneous tumors of the liver must be considered malignant. It is unlikely that an attempt to distinguish between adenoma and carcinoma would be useful. The incidence of spontaneous hepatoma has been influenced by diet ( Tannenbaum and Silverstone, 1949) and by castration ( Andervont, 1950b). Hepatomas have been induced in the mouse by azo dyes, other chemical carcinogens, radioactive compounds, carbon tetrachloride, chloroform, and urethan ( Heston et al., 1960a). Andervont and Dunn ( 1952) could find no identifiable qualitative histological difference between spontaneous and induced hepatomas.
TUMORS OF THE FEMALE REPRODUCTIVE TRACT
Ovarian tumors
Ovarian tumors occur only sporadically in most inbred strains, although nonneoplastic cysts are common. However, incidences of 34 per cent have been reported in CE females ( Dickie, 1954) and 47 per cent in C3HeB/De virgin females ( Deringer, 1959). The incidence in C3HeB/FeJ is 64 per cent after 19 months of age, and in RIII/J, 60 per cent after 17 months of age (Hummel, 1965, personal communication).
The most common types are granulosa cell tumors and tubular adenomas. A simple classification of spontaneous and induce ovarian tumors includes tubular adenoma, granulosa cell tumor, luteoma, papillary cystadenocarcinoma, and teratoma. Except for the latter two, these types have been induced by X-irradiation (Furth and Butterworth, 1936), by transplantation of ovaries to the spleen ( Li and Gardner, 1949), by transplantation of ovaries to other sites in strain DBA mice (Hummel, 1954a), by remotely applied chemical carcinogens ( Howell et al., 1954), and by genic deletion of ova ( Murphy and Russell, 1963).
Tubular adenoma. Downgrowth of the so-called “germinal” epithelium is a common aging change in the ovaries of mice ( Thung, 1961). It may be so extensive that the ovary is replaced by interlacing clefts and tubules lined by cuboidal to columnar epithelium resembling the germinal epithelium ( Figure 27-13). Only arbitrary morphological distinctions can me made between tubular adenomatous change and tubular adenoma, perhaps best at the point where the entire ovary is involved. Bali and Furth ( 1949) found that tubular adenomas could be transplanted and grew slowly, particularly in gonadectomized hosts.
Tubular adenoma is usually a prominent precursor in the formation of granulosa cell tumors and luteomas following genic deletion of ova, X-irradiation, and transplantation to the spleen. Gardner ( 1955) postulated that the germinal epithelium is the source of granulosa cell tumors. Bali and Furth ( 1949) have observed tubules in a tubular adenoma lined partly by germinal epithelium and partly by granulosa cells. At an intermediate stage in ovarian tumorigenesis there is frequently a proliferation of interstitial cells, which can undergo luteinization ( Figure 27-14). The term complex tubular adenoma has been applied to these tumors ( Bali and Furth, 1949). It is possible that some of these lipid-containing tumors have been called luteomas in the literature. Current opinion derives granulosa cell tumors and luteomas from the “interstitial” cells, that in turn are derived from theca cells ( Guthrie, 1957; Mody, 1960). Thung ( 1959) has stressed the tremendous plasticity of the cells of the ovary and has suggested that the various tumors may arise from more than one original cell type.
Granulosa cell tumor. Estrogen-secreting tumors composed of cells resembling the characteristic cells of the membrana granulosa constitute the most common induced type of ovarian tumor in mice. The cells frequently show an elongated nucleus, with densely stippled chromatin especially around the nuclear membrane, and may be organized into sheets, cords, or pseudo-follicles ( Figure 27-15). As in the case of human granulosa cell tumors, there can be so many patterns that the diagnosis is not always certain on morphological grounds alone. Besides estrogen secretion the tumors may also produce hypervolemia by secretion of a substance termed “plethorin” ( Furth and Sobel, 1946). Many of the cells of granulosa cell tumors may undergo a fatty change which is not true luteinization. However, true luteinization may occur and mixed tumors have been described ( Bali and Furth, 1949). The spontaneous tumors of strain CE and its hybrids are frequently granulosa cell in type. They appear to develop from proliferations of peripheral stromal cells, forming cortical plaques and grossly observable mushroom-like caps ( Figure 27-16). Sertoli cell differentiation is common ( Figure 27-17).
Luteoma. Progesterone-secreting tumors composed of cells resembling those of the corpus luteum occur rarely spontaneously but have been induced by X-irradiation, transplantation to the spleen, and genic deletion of ova. The tumors are yellow, and the cells are polygonal, have abundant acidophilic cytoplasm, and are arranged iodules separated by thin strands of reticular and collagenous fibers ( Figure 27-18). Furth and Sobel ( 1947) have described studies on a transplantable luteoma.
Teratoma or teratocarcinoma. Ovarian teratomas, derived from pluripotent cells, occur very rarely in mice. However, several have been observed in strain C3H mice at The Jackson Laboratory, and Fekete and Ferrigno ( 1952) have reported a transplantable ovarian teratoma that maintained its pleomorphic character through nine transplant generations. A further discussion of this important tumor type is given under the heading Testicular Teratoma.
Other ovarian tumors. Papillary cystadenocarcinomas have been reported ( Cloudman, 1941; Dunn, 1954b). A transplantable mucin-producing tumor has been described by Dunn ( 1954b). Nonspecific tumors of the ovary such as leukemias, reticulum cell sarcomas, hemangioendotheliomas, and fibrosarcomas have been described.
Tumors of the uterine horns
Spontaneous tumors of the uterine horns are infrequent. The sporadic tumors are usually sarcomas, either fibrosarcomas or leiomyosarcomas. Spontaneous adenocarcinomas are rare in most inbred strains, however Dunn (1965, personal communication) has observed a number of transplantable adenocarcinomas is strain BALB/c and some similar tumors in C3H x C57BL hybrids ( Dunn, 1954b; Heston, 1963). Glandular tumors appear to be less readily induced by carcinogens than sarcomas. Fibrosarcomas and leiomyosarcomas have been induced by methylcholanthrene-coated threads ( Murphy, 1961). Rare leiomyomas resembling the common benign human uterine tumor have been reported ( Table 27-2). Endometrial stromal sarcomas occur.
Tumors of the cervix and vagina
Spontaneous carcinomas of the cervix and vagina are extremely rare in mice, as in other laboratory animals, and in fact in all animals studied other than man. However, the mouse has become the laboratory animal of choice in the induction of these tumors by estrogenic hormones ( Gardner et al., 1959; Dunn and Green, 1963), chemical carcinogens, and the combination of these agents ( Murphy, 1961). There is one report of a strain of mice in which a high spontaneous incidence of cervical and vaginal carcinoma was observed ( Gardner and Pan, 1948). Unfortunately, the strain was lost because of associated sterility ( Gardner et al., 1959).
Both the rare spontaneous carcinomas and the induced tumors range from well-differentiated squamous cell (epidermoid) carcinomas with extensive keratinization to anaplastic carcinomas with little or no evidence of differentiation. Most of the induced tumors, however, tend to be well differentiated and show much more keratin formation than occurs in human cervical carcinomas. A type of differentiation that occurs in rodents is the formation of mucin by the stratified squamous epithelium of the vagina and cervix. Mucin formation has been demonstrated is some of the tumors induced by methylcholanthrene ( Murphy, 1961). The tumors metastasize to the lungs and are transplantable.
Tumors of the vulva
Papillomas and squamous cell carcinomas of the vulva have been observed in strain 129 females at The Jackson Laboratory.
TUMORS OF THE MALE REPRODUCTIVE TRACT
Interstitial cell tumors of the testis
Sporadically occurring spontaneous interstitial cell tumors have been reported in hybrids of strain A ( Gardner, 1943), and in strains C ( Hooker et al., 1946), BALB/c ( Hummel, 1954b), and RF ( Clifton et al., 1956). Andervont et al. ( 1960) have established the incidence of spontaneous hyperplasias and tumors in BALB/c as probably under 1 per cent. Interstitial cell hypertrophy, hyperplasia, and tumor formation have been reported in a high mammary tumor strain, designated strain H, in which the males also develop mammary tumors ( Athias, 1945; Furtado Dias, 1958). Interstitial cell tumors have been induced by the administration of estrogens, particularly in strains A and BALB/c. Wide differences in susceptibility of inbred strains have been reported by Bonser ( 1944), Gardner et al. ( 1959), and Andervont et al. ( 1960). Experimentally produced cryptorchid testes of BALB/c mice developed a high incidence of interstitial cell hyperplasia and tumor formation ( Huseby, 1958).
The tumors are yellowish brown and consist of masses of large polygonal or irregularly shaped cells with granular or vacuolated cytoplasm and nuclei varying in size (Figure 27-19). The cells may contain a light brown pigment. Lymphatic metastasis is common. The induced tumors can be transplanted to animals of the same strain if estrogen is present. After serial transplantation the tumors lose their dependency on estrogen. The tumors produce androgen, losing this ability as they become more autonomous ( Gardner et al., 1959).
Testicular teratoma
These tumors, derived from pluripotent cells, are extremely rare in male mice except for strain 129 in which approximately1 per cent develop congenital tumors spontaneously ( Stevens, 1959). It has been possible to raise the incidence as high as 10 per cent by introducing the steel gene (Sl) into strain 129 and by selecting males from second and later litters ( Stevens and Mackensen, 1961). The transplantation of male gonadal ridges from strain 129 fetuses to adult testes has resulted in an 82 per cent incidence of teratoma ( Stevens, 1964).
Grossly, larger tumors are hemorrhagic and the smaller ones appear as solid masses occupying one-fourth to three-fourths of the testicular volume. Usually the masses contain cysts filled with clear or bloody fluid. many of the teratomas contain palpable nodules of bone and cartilage. Histologically ( Figure 27-20), the most common components are nervous tissue, epithelia of various types, cartilage, bone with well-differentiated marrow, muscle, fat, and glandular tissue ( Stevens and Little, 1954). Undifferentiated embryonic cells may be observed. The tumors are transplantable, but only a minority grow progressively. The grafts that merely survive are composed entirely of adult-type tissues. Those that grow progressively may consist purely of embryonal cells, mainly of undifferentiated cells, or principally of differentiated tissues ( Stevens, 1958). Serial section study of testes in 15- to 19-day fetuses has demonstrated the origin of the teratomas within the seminiferous tubules and provided evidence of origin from the primordial germ cells ( Stevens, 1962).
TUMORS OF OTHER ENDOCRINE GLANDS
Adrenal cortical tumors
Adrenal cortical tumors are rare ioninbred mice ( Slye et al., 1921). They are readily induced by gonadectomy in strain CE ( Woolley and Little, 1945a) and in (DBA x CE)F1 hybrids ( Woolley et al., 1952). They have been similarly induced in strains BALB/c, NH, CBA, C3H, and A ( Frantz and Kirschbaum, 1949). Strain differences were noted in the secretion of androgen, estrogen, or both hormones by the tumors. The response of the adrenal gland to castration is influenced by genetic factors. Strain DBA responds with nodular hyperplasia ( Fekete et al., 1941), while strains C57BR and C57BL show only slight increase in width of the cortex.
Fekete and Little ( 1945) have described the tumors arising in the adrenal cortex of gonadectomized mice of the CE strain. In most of the large tumors the predominant cells were polygonal and diffusely arranged ( Figure 27-21). Rows and cords of cuboidal cells tended to be more prominent at the periphery of the tumors. In some cases a syncytial type of cell resembling Sertoli cells of the testis formed a component of the tumor. Giant cells with yellow pigmented cytoplasm and often with multiple blood nuclei were found in many tumors. Blood vessels were numerous and consisted mainly of capillaries and sinusoids between groups of tumor cells. The larger tumors showed capsular invasion. Stewart et al. ( 1959) presented excellent illustrations of such a tumor and its transplants.
Adrenal medullary tumors
Tumors of the adrenal medulla in mice have been described by Smith et al. ( 1949) and as occasional findings by other investigators. Jones and Woodward ( 1954) reported these tumors in untreated (C3H x I)F1 virgin females. The tumors closely reproduce the cell type and arrangement of the normal adrenal medulla of the mouse ( Figure 27-22). It is for this reason that the tumors are commonly termed “pheochromocytomas,” not because of demonstrated chromaffin staining or endocrine properties.
Pituitary tumors
Spontaneous pituitary tumors have been considered rare in mice. Slye et al. ( 1931) and Gardner et al. ( 1936) have described single cases. Cloudman ( 1941) reported two adenocarcinomas in hybrids between C57BL and C57BR. Furth et al. ( 1960) found an increase of 3.5 per cent in C57L and 1 per cent in LAF1hybrids. Pituitary tumors have been observed at The Jackson Laboratory in approximately one-third of retired female breeders of strains C57L/J and C57BR/cdJ (Russell, 1965, personal communication). These tumors are associated with mammary duct hyperplasia and, in more differentiated specimens, the cell type is acidophilic ( Figure 27-23).
Pituitary tumors have been induced in mice by chronic administration of estrogen, ionizing irradiation, goitrogenic drugs, surgical thyroidectomy, radiothyroidectomy, and gonadectomy ( Gorbman, 1956). The tumors induced by gonadectomy in strain CE and its hybrids are associated with adrenal cortical tumors ( Dickie and Woolley, 1949). Subcutaneous isografts of pituitaries develop into chromophobe adenomas ( Mühlbock and Boot, 1959).
The classic cellular classification of pituitary tumors as acidophilic, basophilic, or chromophobic has been of limited value in mice. Most of the tumors have been described as “chromophobe,” or lacking in stainable granules. In human pathology this designation usually signifies lack of hormonal function. In mice these tumors show a number of hormonal effects. They are best classified as mammotropic, thyrotropic, adrenotropic, somatotropic, or gonadotropic ( Clifton, 1959). Functional characterization usually requires the study of transplants, since the inductive processes often produce masking hormonal responses in the diagnostic target organs.
Mammotropic activity has been demonstrated in spontaneous tumors and those induced by estrogens and by irradiation. Transplanted mammotropic tumors cause hyperplasia of all elements of the mammary glands with milk secretion, body growth, and disproportionate increase in weight of the viscera ( Furth et al., 1956). The cell type, although usually described as chromophobic, may show acidophilic granules.
Thyrotropic tumors, induced by procedures which eliminate or suppress thyroid function, arise from the aldehyde fuchsin-positive beta basophils ( Halmi and Gude, 1954). Transplanted tumors cause massive thyroid hyperplasia with formation of dependent thyroid adenomas ( Furth and Clifton, 1957).
Adrenotropic tumors were the first type to be described in irradiated mice ( Furth et al., 1952). They were “chromophobic” by the usual staining methods. The tumors induced by gonadectomy have been described as “basophilic” and postulated to be gonadotropic ( Dickie and Woolley, 1949).
The cranial cavity is ofteot routinely examined at autopsy; therefore pituitary tumors can be overlooked. Careful removal of the calvarium and brain may be tedious, but it is a simple matter to slice off the upper part of the skull and brain with a razor blade in order to examine the pituitary gland and the brain for tumors.
Thyroid tumors
Spontaneous tumors of the thyroid gland are rare in mice. Slye et al. ( 1926) reported several malignant epithelial and mesodermal tumors. Adenomas and adenocarcinomas are readily induced by goitrogens ( Morris, 1955) and by thyrotropin-secreting pituitary tumors ( Furth, 1954). Figure 27-24 illustrates such a tumor. Adenomatous tumors have been induced by polyoma virus ( Stanton et al., 1959; Dawe et al., 1959).
TUMORS OF SKIN AND SKIN APPENDAGES
Spontaneous tumors of the skin have rarely been reported since creosoted wooden cages have been discarded. A low percentage of papillomas and squamous cell carcinomas occurs in both haired and hairless genotypes of strain HR/De (Deringer, 1951, 1956; Table 27-2). Extensive studies have been carried out on the induction of skin tumors in mice by painting with tars and pure carcinogenic hydrocarbons and by exposure to ultraviolet radiation ( Stewart, 1959a; Boutwell, 1964). Hair-follicle tumors have been induced by polyoma virus ( Dawe et al., 1959).
Papilloma and squamous cell carcinoma
The initial sequence of events during the induction of skin tumors in mice by painting with methylcholanthrene induces: epilation, hyperemia, appearance of areas of ulceration which may heal, and swelling due to edema of the dermis ( Stewart, 1959a). Hyperplasia of the hair follicles in the marginal areas and epithelial hyperplasia with hyperkeratosis occur. Keratinized cysts, which may open on the surface, occur, and broad-based and pedunculated papillomas follow. The epithelial component of the papillomas is hyperplastic with frequent downgrowths of papillae into the stroma, but the cells are well oriented. Foci of carcinomatous change may develop anywhere in the hyperplastic epithelium, not necessarily in the papilloma. The pedunculated papillomas may even regress. In the carcinomatous foci the epithelial cells show increased variability in size, shape, and staining quality, show loss of orientation, frequently form epithelial pearls and keratin, and frequently invade the stroma (Figure 27-25). As the tumors grow larger and invade more extensively, they eventually ulcerate. They may metastasize to the regional lymph nodes and the lungs. Extremely anaplastic tumors with little evidence of differentiation occur. Forms with spindle-shaped epithelial cells are seen. Spontaneous basal cell tumors have rarely been reported. They have been induced by repeated applications of polyoxyethylene sorbitan monostearate (Tween 60) alone or after a single dose of a carcinogenic hydrocarbon ( Della Porta et al., 1960).
Sebaceous gland tumors
Large round cells with pale foamy cytoplasm and relatively small, pale, oval central nuclei may occur in induced and in spontaneous tumors. The most rapidly growing parts of the tumor may contain small, round, deeply staining cells resembling the small undifferentiated cells of epidermoid carcinomas. Stratified squamous cells may also be found. In the mouse, the preputial and clitoral glands are specialized large sebaceous glands with large alveoli lined by pale sebaceous cells, and ducts lined by stratified squamous epithelium. Tumors of the clitoral and preputial glands have been observed. They may be remarkably organoid in structure. At The Jackson Laboratory a transplantable preputial gland tumor, ESR586, has been established and has maintained a highly differentiated form through over 150 transplant generations ( Figure 27-26). It has been found to contain large amounts of provitamin D and vitamin D. The tumor is a convenient sterol “factory” and has enabled Kandutsch and Russell ( 1960) to find a new pathway in intermediate sterol metabolism.
Melanoma
These highly pigmented tumors have occurred infrequently in strain DBA mice at The Jackson Laboratory ( Cloudman, 1941). The commonest primary site has been on or near the tail, but the ear and other sites have been involved. The tumors are brown to black, smooth and rounded, and visible through the skin of the living animals. The microscopic architecture and cellular detail are heavily masked by the intense pigmentation ( Figure 27-27). The tumor cells may be spindle-shaped or large and oval, and they may be arranged in sheets, whorls, and interlacing bundles. The cytoplasm may be filled with small brown granules of melanin pigment. The tumors metastasize widely, particularly to lymph nodes and lungs. The transplantable Cloudman melanoma, S91, which arose in a DBA mouse, has been extensively studied. An amelanotic variant has been obtained by selection of less pigmented portions during the course of transplantation in albino strain BALB/c mice ( Loustalotet al., 1952).
TUMORS OF THE ALIMENTARY TRACT
Induced tumors
The high incidence of tumors of the alimentary tract in man contrasts with the rarity of such tumors in mice. Spontaneous adenocarcinomas of the stomach, rectum, and colon and squamous cell carcinomas of the upper alimentary tract have only rarely been reported in mice. Adenocarcinomas of the small intestine and squamous cell carcinomas of the forestomach are readily induced by feeding chemical carcinogens ( Stewart, 1953a). Adenocarcinomas of the stomach have been induced by intramural injection of methylcholanthrene ( Stewart et al., 1953). Hyperplastic adenomatous gastritis, which occurs in strain I and DBA, has been mistaken for a malignant process ( Stewart, 1953a).
Salivary gland tumors
Myoepithelioma. A spontaneous tumor of the parotid gland, which closely resembles the myoepithelioma of the parotid gland in man, has been observed repeatedly in strains A and BALB/c and twice in C58 ( Law et al., 1955). The tumors characteristically form large central cysts containing a glairy mucoid substance. The microscopic pattern is that of sheets and cords of cells indistinctly separated into small alveoli by bands of connective tissue ( Figure 27-28). The cells are pleomorphic, a basal rounded cell lying adjacent to the connective tissue stroma. The cells become progressively more flattened and fusiform. Myoglia and fibroglia have been demonstrated in association with the fusiform cells ( Lippincott et al., 1942). A pseudoglandular pattern suggesting acinar structures may appear. Focal keratinization occurs. The tumors, both primary and transplanted, may be associated with a granulocytic leukemoid reaction in the host ( Bateman, 1951). Myoepitheliomas have been found rarely in subcutaneous areas where they may originate from mammary gland elements ( Andervont and Dunn, 1950). Adenocacanthomas of the salivary glands have been induced by carcinogenic hydrocarbons ( Bauer and Byrne, 1950).
Pleomorphic tumors.
Gross ( 1953) and Stewart ( 1955) described the induction of a new type of salivary gland tumor following inoculation of newborn mice with cell-free filtrates of leukemic mouse tissues. The tumors are most prominent in the parotid and exorbital lacrymal glands ( Law et al., 1955). They are usually bilateral. They are multinodular, the nodules varying from grayish white to pearly white, often resembling a bunch of grapes. When they become cystic, the contents are serous rather than mucoid. Histologically, both an epithelial and a mesenchymal of fibroblastic component can usually be distinguished ( Figure 27-29). The epithelial component consists of small tubules or minute cysts lined by a cuboidal epithelium. The connective tissue component can range from a poorly differentiated mesenchymal type of tissue, with basophilic fusiform cells separated by a loose network of fibers, to a well-differentiated tissue composed of fibroblasts with eosinophilic cytoplasm and intercellular collagen. The tumors are clearly multicentric in origin, undoubtedly reflecting their induction by the polyoma virus. On transplantation the mesenchymal component frequently outgrows the epithelial component ( Law et al., 1955).
Similar tumors occur in the submaxillary, sublingual, and accessory salivary glands of the oropharynx, and the submucosal glands of the nasal passages and trachea (Dawe et al., 1959). Polyoma virus also induces tumors of thymus, bone, thyroid gland, hair follicles, mammary glands, subcutaneous connective tissue, renal medulla, adrenal medulla, and other sites ( Dawe et al., 1959). Almost all of these tumors differ in many respects from the characteristic tumors of these tissues in the mouse (Dawe, 1960), except for the subcutaneous sarcomas ( Law et al., 1955).
Intramandibular tumors
Carcinomas of the alveolar socket associated with exogenous hairs have been reported iearly 1 per cent of old mice related to strain O20 ( Van Rijssel and Mühlbock, 1955). Experimental introduction of nylon threads, whisker hairs, and stainless steel wire into the alveolar socket induced many more of these tumors (Hollander and van Rijssel, 1963).
TUMORS OF THE MESODERMAL TISSUES
“A sarcoma is a malignant tumor arising from any nonepithelial mesodermal tissue—fibrous, mucoid, fatty, osseus, cartilaginous, synovial, lymphoid, hemopoietic, vascular, muscular or meningeal. The simplest nomenclature specifies each form of sarcoma by an appropriate prefix, fibro-, myxo-, lipo-, osteo-, etc.” ( Willis, 1960). There are benign forms for each of these tumors, but they are rarely reported for the mouse. The classification of some of these tumors requires special stains such as Mallory’s phosphotungstic acid hematoxylin.
Fibrosarcoma
Fibrosarcoma is often used as a term for any tumor composed of spindle-shaped cells whose properties have not been further characterized. Under these circumstances the noncommittal term sarcoma or the descriptive term spindle cell sarcoma should be used. Statistically, the guess is more often right than wrong, but a number of more specialized mesodermal tumors are missed.
Fibrosarcomas occur spontaneously in the subcutaneous connective tissue and also in the internal organs. Dunn et al. ( 1956) have reported 106 subcutaneous sarcomas, probably derived from fibroblasts, among 4049 female mice of strains C3H, C3Hf, C57BL, and the F1 and backcross hybrids. None of the tumors occurred in C57BL or C57BL backcross females. Fibrosarcomas have been induced by a number of subcutaneously injected carcinogens ( Stewart, 1953b), by long-term tissue culture ( Sanford et al., 1950), and by subcutaneously implanted plastic films ( Oppenheimer et al., 1959).
Fibrosarcomas are usually smooth, rounded, white, and often firm in texture. Microscopically, they are composed of elongated spindle-shaped cells arranged in bundles running in different directions ( Figure 27-30). The cytoplasm is pale, acidophilic, and usually scanty. Collagen fibers are present and fine, branching fibroglial fibrils can be demonstrated by the phosphotungstic acid hematoxylin stain. Reticulum fibers usually form a network embracing single cells. In poorly differentiated tumors, the spindle-shaped cells may be in the minority. The predominant cell is large and polyhedral. Multinucleated tumor giant cells may be formed.
Leiomyosarcoma
Tumors of smooth muscle cells occur spontaneously in the uterus and have been induced by chemical carcinogens in this organ ( Murphy, 1961) and in the alimentary tract ( Saxén and Stewart, 1952). The tumors are composed of interlacing bundles of rather large spindle-shaped cells with abundant acidophilic cytoplasm ( Figure 27-31). Stroma is scanty and collagenous material minimal. Characteristic coarse, short, myoglial fibrils can be demonstrated by the phosphotungstic acid hematoxylin stain. Giant cells with one to several large nuclei may be present.
Rhabdomyosarcoma
Tumors of striated muscle have been observed in several strains of mice at The Jackson Laboratory. Stewart et al. ( 1959) gave a well-illustrated account of transplantable rhabdomyosarcoma H6668 that arose spontaneously in a BALB/c mouse. The most striking cell type is a large cell which may be round, sometimes oval, racquet-shaped, or straplike ( Figure 27-32). The nuclei are large, generally round, and centrally located. Giant cells with multiple nuclei are common. The cytoplasm is abundant and acidophilic. A number of the cells may contain longitudinal myofibrils which, in a few cells, may be arranged to show cross striations. Cross striations are not demonstrable in all tumors. There is also a small tumor cell which may be round, oval, or spindle-shaped.
Granular myoblastoma
This tumor of disputed histogenesis has been considered peculiar to man. It has been induced in the uterine cervix of mice by estrogen treatment ( Murphy, 1961;Dunn and Green, 1963). The tumors are composed of large round cells packed with faintly eosinophilic granules of varying size. Dunn and Green ( 1965) have reported a transplantable tumor in strain C3H.
Liposarcoma
Malignant tumors of fatty tissue are extremely rare in the mouse. A transplantable liposarcoma has been established at The Jackson Laboratory in strain WB/Re mice.
Osteogenic sarcoma
Malignant tumors usually originating in bone and forming sporadically in mice. Most of the spontaneous osteogenic sarcomas reported fro inbred strains have occurred in sublines of C3H and its hybrids ( Dunn and Andervont, 1963; Hilberg, 1954). The incidence is below 1 per cent. Females are affected more frequently than males. Pybus and Miller ( 1938) derived sublines of the Simpson stock that developed a high incidence of bone tumors. The group of tumors showed the wide range of differentiation of the osteoblast: osseus, fibrous, cartilaginous, and osteoclastic. The most common type consisted principally of cancellous bone and osteoid tissue and ranged in structure from benign-appearing osteomas to osteogenic sarcomas with no sharp dividing line ( Pybus and Miller, 1940). Next most common were fibrosarcomatous tumors. Several tumors were classified as giant-celled tumor, chondro-osteosarcoma, and osteoma of the compact type. Unfortunately, descendants of these mice no longer develop bone tumors.
Spontaneous osteogenic sarcomas have been transplanted but rarely maintain their bone-forming property for more than several generations ( Stewart et al., 1959;Hilberg, 1956). Transplantable chondrosarcomas have been described ( Ehrlich, 1906; Swarm, 1963). Osteogenic sarcomas have been induced in mice by X-irradiation and by bone-seeking radioactive substances ( Glucksmann et al., 1957; Finkel et al., 1964), chemical carcinogens ( Brunschwig and Bissell, 1938), and by polyoma virus. The majority of bone tumors induced by polyoma virus lacked the usual histological and cytological criteria of malignancy ( Dawe et al., 1959), but metastasizing tumors have been described ( Sjögren and Ringertz, 1962; Stanton et al., 1959).
An osteogenic sarcoma may be bony-hard or may be composed of softer tissue that is gritty when cut. Microscopically, the tumor can usually be identified by trabeculae of osteoid or partially ossified tissue ( Figure 27-33). More cellular portions are composed of interlacing bundles of spindle-shaped cells, resembling fibrosarcoma. In the trabeculae, cells are isolated in a matrix of hyaline material and may be rounded, resembling osteocytes, or may be spindle-shaped. The tumor cells may be palisaded along the borders of osteoid tissue, in the pattern of osteoblasts. There may be multinucleated giant cells having the appearance of osteoclasts. Foci of cartilage may be found.
Hemangioendothelioma
Malignant tumors of the vascular endothelium occur in low frequency in many inbred strains and in wild mice ( Table 27-2). Deringer ( 1962b) found an incidence of 24 per cent in strain HR/De. Hemangioendotheliomas have been induced by carcinogenic hydrocarbons, ultraviolet radiation, 4-o-tolylazo-o-toluidine ( Andervont, 1950a), and urethan ( Deringer, 1962b). The spontaneous tumors occur in various sites, such as subcutaneous tissues, liver, spleen, ovaries, and mesentery.
The tumors form extremely vascular soft red masses. A collagenous fiber capsule and its extensions separate the masses into coarse and fine nodules. These fibers also form the supporting stroma for the neoplastic cells and blood vessels. The tumors are composed predominantly of blood vascular channels and sheets of neoplastic cells ( Figure 27-34). The tumor cells may be flat, round, polygonal, or spindle-shaped. Many of the tumor cells lining blood vessels resemble hyperplastic endothelial cells. More benign-appearing forms resembling cavernous hemangioma occur in the liver. Stewart et al. ( 1959) described and illustrated transplantable hemangioendothelioma H6221, which arose in the epididymus of a BALB/c mouse at The Jackson Laboratory.
LESS COMMON SITES OF SPONTANEOUS TUMORS
Brain and spinal cord
Spontaneous tumors of the brain and spinal cord are extremely rare in mice. The widely used transplantable tumor C1300 arose in the region of the spinal cord in an A/J mouse. Gorer ( 1947) identified it as a “round cell tumor” and added that it might possibly be a neuroblastoma. Ioninbred mice, Horn and Stewart ( 1952) found reports of an ependymoma and an endothelioma of the brain and a “spindle cell” sarcoma of the spinal cord. Cloudman ( 1941) reported a medulloblastoma and a glioma in C57BL females. Stewart et al. ( 1950) reported two cases of primary tumors involving spinal nerve roots and meninges in strain NHO mice. Dickie (1965, personal communication) found a transplantable meningeal sarcoma in backcross DED2F1 x DBA/2WyDi. A glioblastoma multiforme has been reported by Andervont et al. ( 1958) in a (BALB/c x C3H)F1 mouse.
Direct implantation of carcinogenic hydrocarbons in the brain has induced glioblastoma multiforme, medulloblastoma, medulloepithelioma, astrocytoma, oligodendroglioma, spongioblastoma polare, ependymoma, pinealoma, and meningeal sarcoma ( Stewart, 1953c; Peers, 1940; Zimmerman and Arnold, 1941).
Kidney
Rare adenomas and adenocarcinomas of the renal cortex have been reported by Tyzzer ( 1909), Haaland ( 1911), Slye et al. ( 1921), and Cloudman ( 1941).Figure 27-35 illustrates and adenocarcinoma. Claude ( 1958) reported the occurrence of bilateral renal adenocarcinomas in over 40 per cent of adults of a subline of BALB/c. Papillary cystadenomas have been induced by X-irradiation ( Berdjis, 1959; Rosen and Cole, 1962). Berdjis ( 1959) illustrated a clear cell adenocarcinoma (hypernephroma). Stevenson and von Haam ( 1962) reported that methylcholanthrene induced a renal cell adenocarcinoma and a number of tumors derived from the transitional epithelium of the pelvis. Transitional cell papillomas and carcinomas of the renal pelvis have been reported by Cloudman ( 1941).
Bladder
Spontaneous tumors of the urinary bladder are extremely rare. Cloudman ( 1941) mentioned papillomas and one transitional cell carcinoma. Heston and Deringer (1952) recorded a papilloma in strain C3Hf. Papillomas and transitional cell carcinomas have been induced by 2-acetylaminofluorene ( Armstrong and Bonser, 1944), other aromatic amines ( Bonser et al., 1956), and directly applied methylcholanthrene ( Jull, 1951). Bonser and Jull ( 1956) described the histogenesis of the induced tumors.
Pancreas
Cloudman ( 1941) reported three adenocarcinomas and two islet cell tumors. Hueper ( 1936) reported a case of islet adenoma. Additional islet cell tumors have been recorded ( Table 27-2). A high incidence of ö-cell hyperplasias and tumors has been reported in (C3Hf x I)F1 hybrids ( Jones, 1964).
Harderian gland
The Harderian gland is a retro-orbital lachrymal gland ( Chapter 13). Spontaneous tumors are commonly reported as incidental findings in various inbred strains and hybrids ( Table 27-2). Harderian gland tumors have been induced by X-irradiation ( Furth et al., 1960) and by urethan ( Tannenbaum and Silverstone, 1958). Large tumors cause protrusion of the eye. Microscopically, they are usually papillary and may be cystic or have solid adenomatous areas. Many of the cells closely resemble those typical of the normal gland, with foamy cytoplasm and basally located nuclei ( Figure 27-36). Harderian gland tumors may be invasive, metastasize to regional lymph nodes and lung, and be transplantable ( Upton et al., 1960).
DEVELOPMENT OF NEW TUMOR TYPES
Manipulation of environmental factors
By refinement of techniques, most human tumor types can be duplicated in the mouse by direct application of chemical carcinogens to the comparable tissues. The small size of the mouse is no great hindrance. An increasing variety of tumor types is being produced by hormonal imbalance, irradiation, and oncogenic viruses. Combinations of genetic and environmental factors can be highly selective in the production of specific tumors.
Manipulation of genetic factors
More physiological models of human tumors can be expected from the development of new inbred strains and their hybrids and from the introduction of mutant genes into existing strains. The development of the SJL/J strain revealed a high incidence of reticulum cell sarcoma including close replicas of human Hodgkin’s disease (Murphy, 1963). It has been shown that alleles at the W locus which limit the migration of primordial germ cells produce ovarian tumor adenomas in C57BL/6J mice (Russell and Fekete, 1958). By placing these genes on a hybrid background, it was possible to induce the characteristic range of ovarian tumors ( Murphy and Russell, 1963). Dickie ( 1954) reported a wide variety of tumors in F1 hybrids and backcross generations, involving strains CE, DBA, and DE, that were not characteristic of the parent strains. Adenocarcinomas of the uterus closely resembling the common human tumor have been found in C3H x C57BL hybrids ( Heston, 1963; Dunn, 1954b). Spontaneous carcinomas of the cervix occurred in high incidence in the PM stock ( Gardner and Pan, 1948), which has been lost because of sterility factors. These animals were derived from the stock in which Pybus and Miller ( 1938, 1940) described a high incidence of osteogenic sarcomas.
It is likely that many other analogues of important human tumor types can be developed by hybridizing our present strains. Selection of underlying genetic factors by the use of proper doses of carcinogens applied to segregating generations may be as effective as Snell’s use of transplanted tumors to isolate the genetic factors concerned with tissue transplantation ( Chapter 24).
SUMMARY
The characteristic spontaneous tumors of the mouse are described and illustrated. The five common tumors of the major inbred strains are mammary tumors, lymphocytic leukemias, primary lung tumors, hepatomas, and reticulum cell sarcomas. Ovarian tumors are frequent in several inbred strains, and hemangioendotheliomas in one. Additional spontaneous and some induced tumors, characteristic of the mouse, are described. The definition, classification, and biological properties of tumors are discussed briefly. Possibilities of manipulation of environmental and genetic factors in the development of experimental models for human tumor types are presented.
1. General points, age and some clinical peculiarities, classification.
The unfavorable and worsening ecologic situation in Ukraine, connected considerably with Chornobyl disaster, is one of the main reasons of acute increase of oncologic diseases among population. Recently the malignant tumors in Ukraine grow from year to year, more than in 150 thousand of patients and children make more than 1 % of them, and at present this index is being increased (L.V.Kharkov, and coauthors, 2003). The situation is not better in the pre-boundary regions (e.g. in Moscow approximately 9 mln. of population are ill) and every 10 days approximately 6 children are being revealed with malignant tumors (L.S. Durnov,1993).
The mortality in oncologic diseases is higher, than from other diseases, what one may explain by great malignancy of their course, rapid growth and multiplication of tumors. Oral cancer is one of the few forms of cancer that has not experienced a significantly deceased mortality rate in the last 30 years. Deaths from oral cancer are higher than from cervical, testicular or thyroid cancer.
In the past 20 years, there has been an increasing interest in human papillomaviruses (HPV) because of their potential role in the pathogenesis of malignant tumors. In 1983, it was published the first evidence that HPV might be involved in oral squamous cell carcinomas. In a recent meta-analysis, HPV was indeed confirmed as an independent risk factor for oral carcinoma. To date, totally more than 100 types of HPV have been identified. As in anogenital cancers, HPV type 16 is the most prevalent type in oral carcinomas. The benign oral lesions, associated with HPV infection, include squamous cell papilloma, condyloma acuminatum, verrucca vulgaris and focal epithelial hyperplasia (FEH). Papillomas and condylomas are mostly caused by HPV type 6 or 11, while oral verrucas are associated with the skin types 2 or
We think it is purposeful to remind the row of some main points of oncology. By definitions of Abrykosov and Strukov, the tumor is the reactive growth of the tissue, which is different from physiological growth; namely, it is a pathologic manifestation of growth and development of tissue, and of cells, which is caused by malignancy of their flow, disturbance of physiologic mechanisms, regulating the development of tissues, their structure and function.
The real tumors have their peculiarities, which differ them from the similar by external signs, new formations (tumor-like) namely:
1. With removal of the reason of tumor formation, its growth is not stopped.
2. Pathologic peculiarities of tumor cells and pathologically changed metabolism of substances inside them –lead to the cell’s unlikeness and polymorphism and these signs are inherited by their ancestors. Many new peculiarities appear in them –the ability to germinate into other tissues and organs.
The pathologic signs of tumor growth are:
• atypicality of their multiplication – non-regulated and non-limited mitosis;
• atypicality of metabolism- in particular, oncoproteins’ synthesis;
•antigenic atypicality –which means the simplification of antigen composition;
•morphological atypicality –cell and tissue atypicity (cataplasia);
•functional atypicality;
•physico-chemical atypicity-in particular the saturation of tumor cells of hydrogen is increased, and this facilitates the diffusion of their substrates’ metabolism, and, along with this, the saturation by Calcium ions is decreased, what leads to worsening of inter- cell adhesion.
The benign or mature tumors consist of cells, by means of which one may determine, what tissue they originate from. They are called homological tumors.
The malignant or no mature tumors consist of slightly or no differentiated cells, which loose similarity to tissue, they have been formed from. The less the tissue is differentiated, the more malignant is its course.
Children make more than 15 % among patients with oral-facial area neoplasia. The frequency of malignant neoplasm of maxillo-facial area in children grew from 5 to 16% (L.M.Kliachkina) and it makes, according to recent data-12 cases per 100 thousand of children. Unfortunately, this growth is being continued. In averaged, the malignant tumors of head and neck make approximately 8% of all malignant tumors in child age (by data of oncologic institute in Paris, 1975), or 10% of all neoplasm of maxillo-facial area.
The necessity of knowledge of oncologic aspects of pedodontics-is stipulated by causes, independent from age, and also stipulated by peculiarities of children’ organism development, namely:
1. The tumors of maxillo-facial area are located close to the brain and to main vessels and nerves of head and neck. The pointed out tumors may considerably worsen the process of food intake, breathing, eye functions, ear and nose functions, and also manifest visible cosmetic defects.
2. The age aspect means, that it is more difficult to determine in children, than in grown-ups, by
way of morphologic investigation, whether the cells are regarded to no mature, non-differentiated tissues, where these are the cells of malignant tumor, and that is why, in child’s age it almost impossible to establish exactly whether the tissue is benign or malignant (O.O.Kolesov,1991). This is also a case of fact, that 70% of children with malignant tumors of maxillo-facial area attend doctors with tumor processes, which have started much earlier, and now being in such degree, that is almost impossible to cure.
As Kharkov and co-authors note, tissues of maxillo-facial area (MFA) are favorable for development of tumor processes, as all 3 germ-layers take place in formation of these tissues. The major part of tumors of MFA in children doctors consider as the pathologic formations of disonthogenetic origin, which have appeared on the ground of violations of genetic programs of intra-cell division; or the process of development and differentiation of germ, which is most sensitive to external risk factors action, such as radiation, chemisation, drugs. That’s why, doctors observe “young” oncologic diseases and growth of specific weight of oncologic patients among children. The majority of tumors are formed before 5 years of age of a child and they are often combined with malformations. Prevailingly, they are mesenchymal, but not epithelial.
It’s necessary to mention, that a row of tumors in children, being congenital ones, may be combined with other defects, e.g. lymphangioma- with a row of defects, beginning from congenital cataract of eyes and tongue bifurcation, to congenital heart defects and lower extremities pathology.
Neoplasms of jaw bones are more often to happen in children 7-12 years old and it is connected with their increased growth, and more rarely –in children 12- 16 years old(endocrine re-formation), and very rarely –in children, aging 1 year. And concerning soft tissues of mouth cavity –the majority of diseases is observed at the age of 1, and in children 12-16 years old.
So, the tumor processes in small children are caused by disonthogenetic origin, but in 7-12 years old are caused by endocrine reformation and the abundant grows. Doctors observe the connection of children development acceleration with increase of specific weight of osteogenic sarcomas. When a person becomes older, the frequency of malignant tumors increases, what may be partly explained by larger durability of different oncogenic factors of influence (ecologic, harmful manners, chronic injuries, etc.).
According to growth character and clinics, all tumors are divided into benign and malignant ones.
Benign tumors grow slowly, as a rule, they are surrounded by capsule, and don’t grow, but only move apart the neighboring tissues or organs. They don’t form metastases and don’t relapse after radical removal. But keep in mind, that benign tumors may press on the neighboring organs, causing disturbance of their function, atrophia; they may tighten vessels and nerves, with different consequences. Sometimes they may threaten the life of a child, disturbing lively important functions.
The malignant tumors of MFA are most often diagnosed in children 3-4 and 7-10 years old, 80% of them are sarcomas. Malignant tumors grow rapidly and don’t have a capsule. They grow into other tissues and organs, ruining them. The cells of such tumors, growing into blood-carrying and lymphatic vessels, flowing with liquid stream, may be sometimes carried away to further located organs, causing the development of new tumors in them, called metastases. Such tumors cause disturbance of metabolism in the organism, its intoxication by products of life-activity, and at later stages of self decay-the self exhaustion (cohesion). Their infiltration growth hampers the determination of tumor borders. The infiltration growth leads to vessels destruction and bleedings, which sometimes may be mortal.
To make a correct diagnosis and for optimal organization of medical-prophylactic work concerning oncologic diseases of maxillo-facial area in children the doctors must know how to classify these diseases.
All tumors are classified into benign and malignant. They are divided into groups, depending on their origin, from the certain tissue, or from the certain organ. These groups take into account the known morphologic types of neoplasm.
BENIGN MALIGNANT
1. Epithelial tumors
2. Tumors of soft tissues.
3. Tumors of bones and cartilage.
4. Tumors of lymphoid and blood-forming tissue.
5. Tumors of mixed genesis.
6. Secondary tumors.
7. Tumors, which are not classified.
8. Tumor-like conditions.
As has been mentioned above, it is difficult to establish in children the distinct borders between benign and malignant tumors and that’s why such concept as neoplasm of transitional group –are applied (O.I.Paches, 1983).
At present, for theoretical and clinical application, the convenient classification of tumor processes in MFA in childhood is absent. The transfer of general oncologic schemes into pedodontics doesn’t give the needed result. Taking into consideration some remarks, one may accept the tumors’ division into benign and malignant ones, distribution according to histo-genesis and localization.
O.O. Kolesov classified tumors of jaw-facial area basing on clinico-morphological features, depicting 3 main groups:
1. Soft tissue tumors (55%)
2. Salivary glands’ tumors (5%)
3. Tumors and tumor-like neoplasm of jaw bones (40%).
The International histological classification of the head and neck tumors, accepted by IOHP, looks in the following way:
1. Skin tumors
2. Tumors and tumor-like neoplasm of the mouth cavity and pharynx, formed of many-layer flat epithelium
3. Salivary glands tumors and tumor-like neoplasm
4. Soft tissue tumors
5. Primary bone tumors and tumor-like neoplasm
6. Odontogenic tumors, tumor-like neoplasm and cysts of the jaw bones.
3 signs of anatomic spreading of neoplasm are put into the basis of International classification: spread of primary focus (T04-tumor); regional metastasing (N0x-bundle); remote metastasing (N0x-metastas).
According to E.Simanovska classification (1968), the benign tumors of soft tissues are divided into 3 main groups:
1. Tumors of mucous membrane and soft tissues:
• formed of epithelium (e.g. papiloma);
• formed of connective tissue and its derivatives (fibrome, hondrome, lipome);
• formed from muscle tissue (mioma);
• formed from nervous tissue (nervenome, neurofibrome, neurofibromatosis);
• formed from pigment tissue (pigment nevus);
• of vessel origin ( hemangioma, lymphangioma).
2. Salivary glands tumors:
• formed of epithelium (adenomas, mixed tumors);
• of connective tissue, vessels, nerves.
The tumor-like retention cysts are also included into this classification.
3. The tumors of skin and soft tissues under skin, and also tumor-like cysts –epidermoidal, dermoidal, atheromas.
The most often on children faces benign tumors of soft tissue appear. Further on, according to frequency, neoplasms of the bones appear. In the mouth cavity neoplasms of epithelial tissues prevail, the tumors of connective tissue origin-happen more rarely.
Basing on ICT principles, such benign tumors of soft tissues of mouth and pharynx are distinguished:-papiloma, fibroma, lipoma, rhabdomioma (from striped muscle tissue), hemangioma (capillary, cavernous, branchy, bunch-like, combined), lymphangioma( cavernous, branchy,combined), mixoma, myoblastoma.
Among neoplasms of skin and soft tissues of face in children-one may distinguish hemangiomas( capillary, venous, cavernous, cyst-like and arterial, venous, arterial-venous), lymphangiomas, neurofibromatosis.
Papilomatosis (nipple hyperplasia of mucous membrane), gum fibromatosis, giant-cell epulisis, dermoidal cyst, cysts of the salivary glands and ducts, adenomas-are related to tumor-like neoplasms. The epithelial tumors of salivary glands in children may be observed very rarely.
The benign tumors and tumor-like neoplasms of jaws are divided into:osteogenic, odontogenic and other origin. Such tumors as: osteoma, osteoblastoclastoma and tumor-like neoplasms: fibrous dysplasia, heruvism, hyperostosis, esinofilic granuloma, deformating ostosis- belong to osteogenic tumors. Among odontogenic tumors doctors may meet odontomas (hard and soft),adamantinomas, odontogenic fibromas; and from tumor-like neoplasm –cementoma, usual gigantic cell epulis and cysts-radicular, follicular, retromolar and primary odontogenic are distinguished.
The osteoma, chondroma, osteoblastoclastoma, desmoplastic and ossificated fibroma are related to benign bone tumors.
Among tumor-like neoplasms of jaw bones-one may distinguish their fibrous dysplasia and its special form-heruvism.
Fibrous Dysplasia is an uncommon benign fibro-osseous lesion disease, of unknown aetiology. It causes bone thinning and growths or lesions in one or more bones, and leads to bone weakness and scar formation within the bones.These lesions are tumor-like growths that consist of replacement of the medullary bone with fibrous tissue, causing the expansion and weakening of the areas of bone involved. The lesions can cause externally visible deformities.
Fibrous dysplasia usually occurs in children ages 3 to 15, but it sometimes is not diagnosed until adulthood. It is found equally between males and females.
Causes:
There are two types of fibrous dysplasia:
1. Monostotic (Involving a single bone, 70-80%),
2. Polyostotic (Involving many bones). The most severe form of polystotic fibrous dysplasia is known as Albright Syndrome. It was defined by the triad of polyostotic fibrous dysplasia of bone , skin pigmentation, and precocious puberty.
Symptoms may include
– bone pain (as a consequence of the expanding fibrous tissue in the bone)
– bone deformity
– bone fractures
Diagnostic procedures for fibrous dysplasia may include the following:
-x-ray
–biopsy
-computed tomography scan (Also called a CT or CAT scan). The radiograph shows the typical “ground glass” appearance replacing normal trabecular architecture.
– blood tests
Treatment for fibrous dysplasia:
may include:
- surgery, including the following:
- removal of affected bone, followed by bone grafting
- removal of bone wedge
- placement of a rod down the shaft of the bone
- medication
- pain management
- physical therapy.
Cherubism (familial fibrous dysplasia) is a rare genetic disorder (an autosomal dominant trait) characterized by abnormal bone tissue in the lower part of the face. Beginning in early childhood, both the mandible and the maxilla become enlarged as bone is replaced by fibrous tissue that is less dense, leading to swollen looking cheeks. Enlargement of the jaw usually continues throughout childhood and stabilizes during puberty.
The incidence of cherubism is unknown. At least 250 cases have been reported worldwide. It presents particularly in males, usually after the age of 4-5 years.
Mutations in the SH3BP2 gene have been identified in about 80 percent of people with cherubism.
Common clinical features of cherubism include:
- Bilateral swelling of the jaw (on both sides in the same area, although not necessarily to the same degree)
- More common in mandible than maxilla
- Upturned eyes (rim of sclera – the white of the eye – visible beneath the iris)
- Inverted V-shaped palate arches (the curved rear portion of the roof of the mouth)
- Enlarged submandibular lymphnodes
- Painless
- Premature loss of primary teeth
- Failure of permanent teeth to erupt or random distribution on eruption.
- Rapid development in childhood, slowing during puberty, later stabilization with possible regression.
- Sometimes, cherubism is associated with Noonan syndrome, which includes a typical facial appearance with low set ears, sunken chest, low platlets, generalized mild low bone density, and subtle (usually) heart malformations.
Diagnosis of cherubism is usually based on the above symptoms through a physical examination, family history, and imaging (panoramic X-rays and CT scans). Biopsies can be conducted to establish the presence of cell patterns typical of cherubism in the lesions.
Treatment options depend on the symptoms.
- Children with cherubism should be monitored by their physician and their dentist. If lesions are in the orbits an ophthalmologist should also monitor the optic nerve.
- If appearance causes serious image problems, surgery can be performed to remove the fibrous tissue. However, the potential for spontaneous regression of the disease suggests that surgical interventions should be delayed until after puberty.
- Malplaced teeth that hinder chewing and or cause serious image problems can be adjusted through orthodontia or extracted.
- Missing teeth can be replaced with prostheses.
- Radiation is NEVER recommended!
- To date, there is no established medical intervention into the growth phase although several scientific investigations have been conducted.
- Parents of affected childreeed to ensure that they have an opportunity to talk about their feelings about the condition, especially during the teen years.
- Parents should educate caregivers and teachers about the disease to decrease the possibility of teasing.
Fibro-osseous Dysplasia is a developmental, non familial, benign anomaly of bone development occurring in single or multiple bones, characterised by the replacement of normal bone by fibro-osseous tissue.
Eosinophilic granuloma ( Langerhans cell histiocytosis of bone) is a slowly-progressing benign tumor like condition characterized by an expanding proliferation of Langerhans cells in bones. Peak incidence is between the ages of 5 and 10 years and 75% of cases occur in persons under 20 years of age. Solitary painful bone lesions are the most common presentation, although they may be disseminated and polyostotic. Eosinophilic granuloma is one of the diseases that may have an associated sequestrum. The skull is usually involved, but lesions may be seen in any bone. Prognosis is excellent.
Etiology:
– occurs as a result of metabolic defects in the reticuloendothelia system;
– it is sometimes non painful, unless of course a fracture occurs;
– hallmark is presence of an osseous lesion (70-90%) most frequently arising in skull
– osseous lesions may produce rapidly destructive bone lesions.
Pathology:
Eosinophilic granuloma, which is classified with tumors of histiocytic origin, may be an isolated bony lesion or parenchymal (usually located in the cranium), or may be part of systemic disease (e.g. Letterer- Siwe disease or Hand-Schuller-Christian disease). Grossly, the tumor usually has ill-defined borders and a yellow-tan appearance. Microscopically, it is composed of large multinucleated giant cells with a polymorphous, eosinophil-rich inflammatory infiltrate. Special studies, including electron microscopy, may be necessary to resolve this differential. Electron microscopy shows distinctive structures called langerhans or Birbeck granules. These are rod like structures, with a striated core that may have a dilated end, giving them a tennis racket appearance
The differential diagnosis includes:
– Osteomyelitis:
– Ewing’s sarcoma: unlike EOG, Ewing’s sarcoma typically has a soft tissue extension arising from the bony lesion;
– Lymphoma
– Leukemia
– Hodgkin’s disease
– Myeloma:
– Intraosseous hemangioma
– Fibrous dysplasia.
Tests in children may also include:
- Biopsy of skin to check for the presence of Langerhans cells
- Bone marrow biopsy to check for the presence of Langerhans cells
- Complete blood count
- X-rays of all the bones in the body (skeletal survey)
Treatment:
– bone lesions often resolve spontaneously and do not require treatment unless they cause symptoms (less than 10% of lesions);
– curettage provides diagnostic biopsy material and is curative;
– with large lesions, bone grafts may be needed;
– injection of high dose steroids is another option and tends to result in rapid resolution of the lesion (often within 2 weeks);
– typical dose of steroid is 125 mg of methylprednisolone;
– chemotherapy or radiation therapy is usually not indicated
– XRT is indicated. The dose of XRT is usually between 500 to 1000 rads.
The pecularity of tumors and tumor-like neoplasm is that a row of them have odontogenic origin: adamantinoma (epithelial tumor; the structure of which is similar to the structure of enamel organ of dental germ); odontoma (soft and hard); cementoma, odontogenic fibroma, mixoma of jaw bones.
Cysts of jaw bones are divided into 3 groups: no epithelial, epithelial, and inflammatory. The simple and aneurismatic bone cysts belong to no epithelial cyst. The follicular, incisive and middle palatal cysts belong to epithelial ones. The inflammatory root cysts of jaws are also distinguished.
The tumors of jaw bones are frequently met in children 10-15 years old, and they are as of osteogenic origin, just so- of odontogenic origin (Paches, 1983). By the way, malignant tumors are observed to 10 times more rarely. And the most frequent of them is the odontogenic, the osteogenic and non-osteogenic sarcomas.
The neoplasms of salivary glands in children are met most frequently in large salivary glands, and very rarely –in small ones. In paired glands they, as a rule, are developed only on one side. The girls of 12-15 years old fall ill more often. The most frequent tumors of salivary glands in children are hemangioma, lymphangioma, and out of malignant tumors –no differentiated cancer and different sarcomas. At the same time when grown-ups have polymorphic adenomas around ear glands, children have prevailingly mucoepidermoid carcinomas and mixed tumors. In the sub-jaw gland in children- polymorphic adenomas develop prevailingly.
The clinic of large salivary glands in children is similar to that in grown-up persons. The main sign of benign tumors is a tight movable growth. The signs of malignant tumors are the mimic muscle paresis, when the tumor is localisated in the in the pre-ear gland; the trismus, metastases.
The sizes of neoplasms are observed in limits 2-
The tumor injury of lymphatic nodes of the head and neck in children make 50-60% of all tumor pathology. There are lymphogranulematos, hematosarcomas and metastases. It’s not easy to diagnose the tumor of lymphatic system as the main part of children diseases is connected with the enlargement of the lymphatic nodes. The tumor injury of lymphatic nodes, especially on the initial stages, reminds the usual lymphadenitis. That’s why, in their durable enlargement- the doctor must carry out a cytological investigation. The correct differential diagnostics with leucosis depends on the detailed hematologic observation.
The skin tumors in children are rather frequent and have prevailingly a benign character. The epithelial malignant tumors in children, comparing to grown-up persons, are rare. Among benign tumors most often there are the vessel neoplasms, which in 2/3 of cases are localisated on the haired part of the head. They are revealed in 90-95% of newborn children. When they have been revealed in children, after some months of birth, it’s important to find out whether they are congenital. From the moment of their appearance one must observe, because in 60-70% hemangiomas become smaller or disappear when a child is 1 year old, especially on haired part of head. But it’s good to remember, that some increase of hemangioma may be observed before this. At the same time, the tumor may give a sudden very rapid growth and proliferate into the mouth cavity, nose or pharynx and it may lead to complex of functional disturbances.
Among unfrequented malignant tumors of skin in children melanomas prevail. The benigevus is not, as a rule, dangerous, concerning melanomas.
Other malignant tumors of skin and soft tissues (sarcomas of different origin) are very rear and very aggressive. Also neuroblastomas are very malignant and unfortunately their first signs are metastases into the bones, liver, lungs. That’s why when there is a suspicion of neuroblastoma, the doctor must carry out a roentgenologic investigation of bones and lungs, USD of liver, and also, as L. Durnov recommended (1979), to study the cateholamines’ metabolism, which has the tendency to change.
Among malignant tumors of maxillo-facial area in children there are:
• osteogenic sarcoma
• fibrosarcoma
• Ewing sarcoma
• reticular sarcoma
• lymphogranulomatosis
• lymphosarcoma.
The doctors also observe the cancerogenic injuries of different localization: of lips, cheeks, tongue, jaw bones. The malignant tumors in children are prevailingly primary tumors of connective-tissue origin: fibrosarcoma, angiosarcoma and reticulosarcoma.
Prior to tumor are tumor-like neoplasms, dysplasias, hyperplasias. For example, in development of malignant epithelial tumor-cancer, a considerable role plays the disturbance of mutual relation between epithelium and the connective-tissue, lying under it, as the epithelium growth is determined by structural-functional condition of this connective tissue. In case of pathology, the epithelium grows into it (germinates) and this is the first step to the tumor development.
This concerns tissue changes. And what is about cells? Where do the malignant tumors come from in organism? Each of them begins from 1 cell, which looses the mechanism of its growth regulation. Throughout a man’s life, many healthy cells are reborn in such way, but the tumor doesn’t appear in each of them. The cancerogenic factors favor it. And then from 1 typical cell the other similar cells develop. The development of many cells from 1 cell is called cloning. So, the tumor is a clone. It’s necessary to note that in a person only one tumor may develop, but not several ones, as in other diseases.
The majority of atypical cells, appearing in the organism, may die rapidly, because of limited blood supply, and a low metabolism level. The accumulation of milk acid stimulates the germination of vessels and mitosis of atypical cells. If more than 600 thousand of such cells have been formed, than the intensive growth of capillaries in them may happen and then this new foundation becomes a clinical tumor.
The group of pre-cancer conditions of face skin, red edges of lips and mucous mouth membrane is worth of attention, because their diagnostics and treatment are first of all the prevention of cancer and its discovery on early stages.
Pre-cancers are unstable proliferates, which have not yet become tumors. Their development may be reverse and they may be treated. Durable inflammatory processes, chronic traumas, tumor-like neoplasm and benign tumors may be named as pre-tumor conditions.
Doctors may distinguish a concept “pre-cancer” in its wide meaning. They mean all benigeoplasms, chronic inflammations, hormonal disturbances. And in a narrow meaning- the pre-cancer- is characterized by presence of specific morphologic changes in the epithelium, which may appear under the influence of chronic trauma, e.g. harmful habits. Here may happen the hyper- or diskeratosis of epithelium. According to Mashkileison classification, there are 2 main forms of cancer: obligate and facultative. The obligate pre-cancer is transformed into cancer and the facultative one-never. The latent period is only in obligant pre-cancers- it may last to 30-40 years.
The pre-cancer conditions of face skin are: obligant -Boyen disease and pigment xeroderm; facultative- radiational dermatosis, melanosis, keratosis of mucous mouth cavity-erythroplakia (obligant form), leucoplakia, red vovchak, flat lichen (facultative form); and also pre-cancer of red edge of lips as the facultative (on mucous membrane), just so- the obligant one- a wart-like pre-cancer, Manghanotti cheilitis, hyperkeratosis. Besides the pathologic conditions the so-called pre-cancer background diseases exist: chronic ulcers, cracks, scars after burns.
So, the neoplasm in jaw-facial area in children are characterized by a special clinical course and morphology, which must be taken into account in diagnostics and treatment, and be tightly connected with questions of organization of oncologic help, the most important of which is the early reveal of tumors and their timely treatment.
2. Diagnostics and organization of treatment of children with tumors of maxillo-facial area.
The comparatively high illness of children with tumor processes of tooth-jaw area demands the special attention concerning questions of organization of help to this group of patients. This is stipulated by low affectivity and not enough prophylactics of neoplasm, because their etiology and pathogenesis are not completely studied. That’s why only a timely diagnostics, in cases with malignant tumors – allows curing the patient and saving his /her life. It’s a pity, that the treatment of neoplasm, especially of malignant nature, and old ones – is not quite effective. The matter is, that in case of too late reveal and untimely treatment of benign tumors – the large sizes of post-operational defects and disturbance of a row of functions may be quite negatively marked on health and life activity of a sick child.
The success in achievement of positive result in oncologic patients depends first of all on the primary diagnosis, put by the first doctor. That’s why the organizational basis of oncologic help must be known by every doctor, because in this very case– the district dentists decide the question of early diagnostics of the disease.
In the basis of giving aid to children with oncologic dental pathology is the dispensary method of initiative character. It allows timely revealing and recognizing the true disease
during planned professional examinations, to give a timely specialized help, and also to reveal as early as possible the recurrences and metastases.
The children are not habitual to complain of pain, even in cases of large tumor sizes. At the same time, the grown-ups may notice some changes in the child’s behavior (irritability, weakness, tiredness, loss of appetite, disturbance of sleep).
The first clinical symptoms of tumors most often is a jaw deformation , which is revealed in asymmetry of face, irregular form of a tooth row, displacement of certain teeth, thickening of alveolar sprout, difficulty during opening the mouth or chewing, in swallowing. Some of teeth
may be movable or get loosen. The skin above a large tumor, as a rule, is not changed, and later on – it may be strained, revealing the picture of vessels. In presence of a malignant process, the tumor grows into skin layers and it is connected with them. The metastases on early stages are quite rare. The rapidity of tumor growth depends on its sizes – the larger the tumor, the more rapid is its growth.
Ieoplasm diagnostics – great role plays the study of life anamnesis, including the antenatal period, and the anamnesis of disease, the questions about the earliest symptoms of the disease. It could be complains on the swell of the face, neck, protrusion of the tongue, difficulty during chewing food, swallowing or pronunciation of words, change of a bite or position of separate teeth, defects of a bite or position of separate teeth, their movement, bleeding, appearance of ulcers, which don’t heal for a long time (during 2-3 weeks or more). The doctor must remember about the possibility of tumors development, in presence of some congenital defects.
During examination a doctor may reveal changes of skin color, or the color of mucosa, changes in the face configuration, swelling, incorrect position of some teeth, defects of occlusion (bite), mobility of teeth, thickening of alveolar sprout. Depending on the tumor localization, the doctor may guess about the type of a tumor.
The defects in correct placement of teeth – may be observed as in soft tissues tumors, just so in jaw bones tumors. (hemangiomas, fibromas, reticular sarcomas). The salivary glands tumors may occur as in the thickness of large salivary glands, just so– on the edge of hard and soft palates. Fibromas and papilomas may occur on the mucosal cover of cheeks, along the line of teeth occlusion. Lipomas are in thickness of cheeks; the retention cysts, hemangiomas, papilomas may occur on the mucus of lips. The fibro- and hemangiosarcomas may develop in the tongue thickness, and rhabdomiomas – may appear in muscles of sides of the tongue. Fibromas and fibroadenomas may occur near the tongue root. In babies – mioblastoma may appear under the gums cover.
Face configuration may change in case of hemangiomas, lymphangiomas, neurofibromatosis, cysts of large salivary glands. The limitation of jaw mobility, pain during opening of mouth –may be the sign of neoplasm localization in the wing-jaw space and in the pre-ear region.
After the examination of patient the doctor passes to the next stage of observation of the sick child, called palpation. By means of this method a doctor determines the character of the new-formation surface, its borders and consistency, mobility, relation to surrounding tissues, zone and depth of infiltration, painfulness. The palpation of soft tissues of jaw facial area is carried out bi-manually.
The reveal of pulsation in the tumor sickness – testifies to its good blood supply, saturation with vessels. The soft, dough-like thickness of the new formation, fluctuation testify to its nonosteogenic origin, presence of cyst or a cyst-like new formation, or the inflammatory process.
During palpation of lymphatic nodes doctors pay attention to the degree of their enlargement, their mobility, painfulness, form, consistency and connection with surrounding tissues. The enlarged, painless, combined into packets lymphatic nodes allow to make an assumption about the presence of metastases of malignant tumors.
The hyperplasias of neck lymphatic nodes, which may often occur in children, make it difficult to diagnose their tumors and metastases.That’s why, doctors must remember, that in case of hyperplasia, the nodes have the egg-like form, elastic consistency and their size is not larger than
Basing on the above mentioned data, received in the processs of collecting the anamnesis, complaints and clinical examination-the prepreliminary diagnosis is being put. To put a final diagnosis, a dentist must carry out the additional examinations: rentgenologic, including a computer tomography, radioisotopic scanning. The dentists often make a dento- and heiloscopy with a pre-life painting of tissues, and the angiography..The improvement of cytodiagnostics allows to reveal the cancer of mucosal layer at the pre-invasive stage.The aspirational or punctional biopsy according to d-r. Panikarovskyi method, helps to reveal the tumors located more deeply. But the most important in making a final diagnosis of the tumour is the pathomorphological investigation of material, received by method of invasive or punctional biopsy. But in children the enough informational pathomorphological investigation may manifest
a disputable pathomorphologic diagnosis,that may be explained by a disposition of a child to different tumour-like hyperplasiae, large similarity of nonmature tissues at early age of a child – to blastomatic ones, and also by specific for children morphologic similarity of a row of benign and malignant tumors.
Rather complex for children is a differential diagnostics of malignant and benign tumors, because the latter don’t have the specific symptoms at early stages of the disease. And
for benign tumors the more rapid growth is characteristic. It is rather difficult to differ a malignant tumor from a chronic osteomyelitis, because in children the latter happens more often
with an abundant bone formation and a rapidly progressing bone deformation.
In children, in connection with a porous bone structure, the destructive process may spread more rapidly, than in adults, and a rather high reparational potential of periostium assists to appearance of distinct signs of periostal bone formation on X-ray picture.
The evaluation of age and a general child’s condition, comparing and analysis of complaints, anamnesis and the results of clinical and paraclinical examination allow the doctor
to put a final diagnosis.
The reasons of late diagnostics are: weak clinical signs, especially at the early stages of tumorous process, incomplete knowledge of the early signs of tumors, self-treatment, too late visit to a dentist, many-stage examination (long lasting), diagnostic mistakes, non-grounded treatment. The tragedy of situation with oncologic diseases of jaw-facial area in children is stipulated by 3 reasons: the absence of oncologic caution of dentists-pediatritians, insufficient knowledge by dentists of early clinical manifestations of tumors, non ability to read the X-ray pictures, by psycho-physiological peculiarities of children – their non ability to tell the doctor in a true way their own feelings at early stages of the disease.
The tumors’ prophylaxis includes the antenatal protection of a fetus, maximally early reveal and removal of pre-tumor and the background processes, formation of dispensary groups of children with an increased risk of tumor appearance, in the hardened oncoanamnesis in mothers, who were irradiated or used cytostatics during pregnancy.
The good knowledge of oncology by dentists, knowledge of early signs of tumor
processes and main points of organization of medico–prophylactic work allows to ensure the optimal level of rendering a specialized help to children with oncologic diseases of maxillo-facial area.
The ideal opportunity for early detection of cancerous or pre-cancerous growths is during the annual hygiene examination. Unfortunately, the cellular changes that lead to oral cancer start below the surface of the epithelium at the basement membrane, making them difficult to detect by conventional screening methods.
The annual hygiene exam should basically comprise of traditional incandescent light examinations to enhance the visualization of oral mucosal abnormalities that may not be visible to the naked eye, such as oral cancer or pre-malignant dysplasia. There have been scientific breakthroughs in the world of dentistry giving them more accurate devices to detect oral cancer. The devices are portable and can be used by hygienists or dentists themselves and the examination takes only one or two minutes. The oral cancer detection devices use fluorescence visualization technology resulting in abnormal tissue appearing irregular, dark areas that stand out against the otherwise normal, green fluorescence pattern of surrounding healthy tissue.This significant advancement in early detection is very easy for the dental staff to administer and completely non-invasive for the patient. It takes very little time, is pain-free, and involves no distasteful rinses or staining.
The tests that may be used include:
· A X-ray,
- a magnetic resonance imaging scan,
- a computerized tomography (CT) scan, and
- a positron emission tomography (PET) scan.
A PET scan involves injecting a part of your body with a radioactive ‘tracer’ chemical which can be seen on a special camera. Further biopsies oearby lymph nodes may also be carried out. The basis of early diagnostics of tumors of jaw-facial area in children is the oncologic caution of children dentists. In pediatric practice the principles of oncologic caution are formed in the following way:
1. Every doctor –dentist must know the symptomatic and clinics of main types of tumors
in children.
2. During examination of every patient by dentist, independently of the child’s age, complaints, clinics of main dental disease, it is necessary to exclude the presence of a tumor or pre-tumor condition in jaw-facial area, that’s why he (she) must be examined taking into consideration the possibility to reveal this pathology.
3. The basis of suspicion of oncologic pathology in patient is:
a) appearance of exofite formation with infiltrated basis, which is being enlarged in sizes, and bleeding;
b) presence of bleeding ulcer with an infiltrate in the basis,
c) appearance of constant pains of moderate intensivity in pathologic process zone, which are strengthened at night;
d) appearance of mobility of I or several intact teeth, accompanied by pain;
e) changes of character of nose secretions, in patients with chronic antritis (appearance of purulent secretions).
f) paresis of mimic muscles, which grows gradually, parastesias and numbling in zone of innervations by an “under eye” and under chin nerves.
g) the presence of circle-like tough painless or slightly painful (in palpation) lymphatic nodes on the neck, which may grow.
4. The doctor must observe the skin of neck and head of every patient, and in case of revealing any changes on it, to direct a child for examination of a dermatologist or oncologist.
5. The tumor process must be excluded in any unusual course of a disease or if it’s
impossible to explain some symptoms or if a clinical picture is not clear.
6. In case of atypical course of any disease, the paraclinical investigations must be carried out (hysto- and cytological, roengenological, laboratory), the doctor must consult the colleagues, to direct patients for consultations to specialists-oncologists.
7. The doctor must remember that any chronic or acute disease may be accompanied by oncologic pathology and press by its symptoms the signs of it. That’s why in rendering help in case of trauma or acute inflammatory process the oncologic caution must be manifested.
8. The examination of a child with a suspicion of tumor the doctor must carry out in short terms, by principle of urgent surgery.
9. All patients with malignant tumors must be discussed, so as to reveal the possible mistakes in prophylactic, diagnostic and medical work of doctors, in forming an oncologic caution in them.
10. The knowledge of doctors of organizational bases of oncologic help to children ensures the timely and correct direction of them by allocation for giving aid.
Here are some clinical cases, which illustrate the pointed out postulates.
A child, aged 15 months old, during a game with stick, which she kept in mouth, injured a mucous cavity of hard palate, in consequence of which a bleeding appeared, which stopped after some time without calling a doctor. After some time has passed, the parents noticed that an under mucosal bleeding on hard palate doesn’t disappear and they addressed the doctors with complains of this. During the examination a hemangioma of hard palate was revealed, may be a congenital one, which has not been revealed earlier. And only in connection with the trauma which a child has got, doctors by chance, diagnosed a tumor.
Here is another case. During pre-new year party, the parents of 5 year old boy addressed the surgeon on duty. The boy complained of general malaise, fatigue, increased body temperature, swelling and pain in the area of left corner of mandible, difficulty in opening the mouth. These symptoms lasted for 2 days. Basing on anamnesis, the doctor found out that during 10 months the boy has been treated by dentist in the case of chronic periodontitis of 75 tooth. As the preliminary extraction of this tooth may lead to irregular growth of teeth of permanent bite (such was the explanation of the doctor). The durable treatment of the tooth was complicated by periodical acuteness of the disease. The physic-therapeutic procedures have been prescribed. 4 month ago the doctors noticed the thickening of child’s jaw, where the tooth has been located. Rentgenologically hyperostosis has been revealed, the reasons of which was systematic acuteness of inflammatory process in the periodontium of treated tooth.
At that moment the child had all signs of acute inflammatory process of a bone in the area of left corner of mandible, regional lymphadenitis, trism of 3rd degree, body temperature was 38.2ºC. After the anesthesia has been carried out and trism removed it was revealed that 75th tooth has been ruined on 2/3 by caries, hyperemia, odema (swelling) of the surrounding mucosal cover, smoothing of transitional fold. The tooth was movable (3rd degree). After its extraction 3 ml of pus were excreted from the socket. The adequate medicament therapy has been prescribed.
In 2 days after repeated examination the child’s condition was much better. The body temperature lowered to subfebrile, the swelling in the injured area decreased and no signs of inflammation was observed. The painless tight thickening of a bone in the mandible corner of
And in its corner area – a tumor was revealed with a characteristic of osteosarcoma structure. The morphologic investigation of biopsy material confirmed the prior diagnosis. In some months the child died.
This clinical case shows that even in presence of all signs of acute inflammatory process, the dentist must manifest onco-caution. In this case the inflammation, chronic trauma during endodontic manipulations, and also carrying out the physiotherapeutic procedures, in the sprout zone of bone – turned out to be a direct reason, as well as a favorable background for malignant tumor development. At its certain stage an acute inflammatory process appeared, which has masked the oncologic disease.
One more clinical example will show, that rather often the doctors don’t apply the necessary efforts to reveal the reason of the signs of pathology, they don’t use all possible diagnostic methods, don’t consult the colleagues.
The parents noticed in a 5 year old son the mobility of 51 and 81 teeth, what they connected with a natural change of teeth in this age. They saw a doctor, who extracted those teeth. In 4 weeks the 11th and 41st teeth began to erupt. They erupted in conversion with crown parts and the roots diverged. When the teeth partially erupted in this irregular position, the dentist saw them once more. A dental roentgenologic photo (screening) of alveolar sprout was made in area of notified teeth, with the aim to reveal the reason of irregular placement of teeth. As a rule, the reason of it is a middle cyst of upper jaw, or the upper complex – retinated tooth (one or several). On the X-Ray picture neither a cyst, nor a retinated tooth were revealed. The child was begun treatment with the help of removable orthodontic apparatus with the aim to correct the teeth convergence. The treatment lasted from June to September, but not successfully. The central upper constant incisors have erupted, converging with crowns.
When in September the parents addressed to another dentists they revealed the protrusion of upper lip, paste-like liquid on it, a large thickening of alveolar sprout in area of upper frontal teeth, convergence and mobility (II degree) of central incisors (the side incisors were absent and temporary – fell out). On the picture of face skeleton the changes, characteristic for osteoblastoclastoma were observed. The tumor process grasped the alveolar sprout, palate and the bridge of nose. After operation the child was put a denture.
This example helps to arrive at a conclusion that the doctor’s mistake was in unknowing the real reason of teeth eruption. He did not ask for a help of colleagues, did not make X-Ray photo. It must be noted that on dental X-Ray photos it’s very difficult to reveal the pathologic changes in bone, that are characteristic for tumor process, and the observational photos allow doing it rather easily.
Even in case of benign course of tumor process, taking into account the rapidity of tumor growth in child’s age, the replacement tightening or even ruining of neighboring organs by tumors and disturbance of their functions, -the doctor must timely and correctly solve the complex of questions, concerning organization of diagnostic and medicinal aid to a child. In case of rapid growth of a tumor in a child, the observation of its growth, delay of operation – lead to considerable growth of tumors and formation of large defects in jaw-facial area that is not favorable in child’s age.
So, having put the diagnosis to a tumor at a visit to a dentist, or having a suspicion of a tumor, a doctor must immediately direct a child for the next stage of diagnostics and treatment, orienting upon structure of dental service in this region. The principal scheme of connection of dental and oncological service for ensuring prophylaxis, diagnostics treatment and rehabilitation in case of tumors of maxillo-facial area in children looks in the following way:
• a district dentist;
• polyclinics or a dental department, attached to a polyclinics ;
• dental in-patient department or department of tumors of neck and head at oncologic dispensary.
During the choice of treatment tactics, the doctor must take into consideration the hystologic type and a clinical course of the tumor, its localisation, age and a general condition of a child’s health. The choice both of treatment method and a place of its performance in the polyclinics, or
at the dental or an oncologic in-patient department depends on the age, clinical course of the disease (type of a tumor, its localisation and spread) and on the other individual peculiarities of a child.
In early childhood it is more advisable to carry out all kinds of surgical intervention or treatment of neoplasm , applying other methods – at the in-patient department. In elder children – all limited benign tumors may be cured at the dispensary, taking into attention a general condition of children health. All malignant tumors must be treated at the in-patient department. The treatment is carried out according to previously composed plan, which follows the sequence of medicinal measures, their durability, a number of seances, dosage and so on.
In surgical treatment oeoplasm in children a doctor must follow such 2 conditions:
1. Radicality of an operation, because a not complete extraction of malignant and benign tumors leads to speeding of their growth or to recurrency, in which the possibilities of further radical treatment are worsened;
2. Absolute necessity of hystologic investigation of all extracted tumors, even if according to their clinics, macro- and morphologically they don’t case any doubts of their benignity.
It’s necessary to follow the principles of antiblastics and ablastics.
Ablastics-is the prevention of dessimination of tumor cells by way of scaree intrussion on the cell itself ( to avoid traumatezing of the cell, cuttings, pricks) and on surrounding tissues-to prevent the injury of lymphatic ducts, a doctor must protect the operational field, passing from tumorous tissues on surrounding healthy ones, to wash hands; to change gloves and instruments, operational gawn.
Antiblastics-a complex of measures, directed to ruin tumorous cells, which may penetrate into the operational wound, treating it by alcohol (spirit), iodine, applying an electric knife; diathermocoagulation or criosurgical instruments.
The indications for therapy by X-rays or to distant γ –therapy in children are:
• technical impossibility of radical surgical intervention;
• presence of tumors, disposed to postoperational recurrences;
• possibility to cure the tumors without surgical intervention ( with a necessary confirmation of the diagnosis by biopsy methods).
The following preparations are applied for chemiotherapy: antimetabolites, alkilous preparations, antitumor antibiotics, hormonal means and phytopreparations (e.g. fitohematoglutins, which assists to transformation of neutral lymphocytes into killer-cells). Gen-enginering and antisenstherapy are used, that is the influence on a concrete gen by way of syntesis inhibition of the appropriate protein.
At present doctors perform a row of reconstructive operations on lower jaw( mandible). As a rule, the resection of mandible in case of tumor leads to formation of partial or complete defect and that is why it is accompanied by primary or remote bone plastics. In the latter case a postoperational orthodontic treatment is carried out. It’s rather important, that the head of a joint is preserved during resection and to preserve the function of a joint.
In all cases of surgical intervention on upper jaw with further defects the children 2-3 years old must be made dentures 2-3 weeks after operation. The child is discharged from the hospital to be watched by the local orthodontist.
In treatment of malignant tumors the main role belongs to surgical interventions. If to take a group of Yuing sarcomas, and reticular cyst the chemio- and ray therapy may be appropriate.
After a course of treatment at the oncologic in-patient department the children with malignant neoplasms must be constantly examined by dispensary oncologists and dentists. This may help to prevent the progress of a disease, prolong the remission of the disease and a patient’s life. The task of postoperational dispensary observation is the control of possibility of recurrence,renewal of anatomical form, and a disturbed function , ensuring of correct growth and development of jaw-facial bones. That’s why the dispensary care of the patient includes examinations of such specialists as: an orthodontist, pediatrician., logopedist and otolaryngologist.
The clinical, roengenological and hematological control in process of dispensary observation allows to timely reveal the recurrences or the progress of tumor process and to carry out the appropriate preventive therapy, to direct a child to onco-clinics. The repeated courses of therapy by cytostatics, scarcing diet, the all-round strengthening therapy and other recommendations of oncologists are carried out and rendered by place of living of a patient. The dispensarised child at the onset of any respiratory infection, acuteness of periostitis, lymphadenitis, or a tonsilitis must be examined and cured with a special care, as these illnesses may be a result of a main oncopathology.
When the children become 18 years old, they pass to the analogical registration of grown-up persons.
Taking into account the low percent of early diagnostics and the timely visit to a doctor,
low efficiency in treatment of tumors, especially of malignant ones, it is necessary to strengthen a prophylactic work in such directions :
1. Sanitary educational work among population.
2. Formation and support of oncologic warning in all dentists.
3. Increase of level of appropriate qualification of dentists and formation of their knowledge of early symptoms for a timely diagstics of tumors.
4. Improvement of methods of diagnostics and organisation of rendering help to patients in case of slightest suspicion of tumor.
5. Maximally complete involvement by dispanserisation of children with pre-tumorous and chronic processes in jaw-facial area.
So, the oncologic diseases in children have their characteristic features.Only the sufficient knowledge of them as well as the knowledge of oncology theoretical bases in combination with
a clinical mind of a dentist will allow the child dentist to ensure the rendering the proper
specialised help as in organisation of aid, just so – concerning the optimal treatment.
Papilloma refers to a benign epithelial tumor growing exophytically (outwardly projecting) in finger-like fronds. In this context Papilla refers to the projection created by the tumor, not a tumor on an already existing papilla (such as the nipple.)
Nearly 70% are white , but are pink if not keratinized. The affected ages range from 2 -91 years.They are located most frequently on the palate, but also on the tongue, lips of gingivaeWhen used without context, it frequently refers to infections caused by Human papillomavirus (HPV). However, there are other conditions that cause papilloma, such as Choroid plexus papilloma (CPP).
Two types of papilloma often associated with HPV are “squamous cell papilloma” and “transitional cell papilloma” (also known as “bladder papilloma”). Simple papillomas are not infective and have no tendency to spread by autoinoculation.
Microscopy.
Papillomas have a branching structure consisting of a vascular connective tissue core , supporting a thick hyperplastic epithelium, which may be ortho- or parakeratinized.
Management.
The diagnosis should be confirmed by microscopy. Excision should be curative and recurrence is rare.
Epulis is a tumor-like neoplasm of the connective tissue, which arises from marginal periodontal tissue. It can be caused by the chronic trauma by crown or filling or abnormal localization of the tooth in the dental row.
These are of four types:
1. Granulomatous epulis: A mass of granulomatous tissue forms around a carious tooth, or at the site of irritation by a denture requiring extraction of tooth and scraping away of granulation, a part of which should always be examined histologically to rule out malignancy.
2. Fibrous (fibroid) epulis: It is the commonest type of epulis. It is a simple whorled fibroma arising from the periodontal membrane, present under the gum. Rarely a soft bluish-red, bleeding and rapidly growing fibrosarcomatous epulis occurs. Both require removal of adjacent tooth or teeth and resection of a wedge of bone, including a portion of the gum containing the growth.
3. Giant cell (myeloid) epulis: This is an osteoclastoma arising peripherally in the jaw and presenting under the gum. It is soft, sessile and plum coloured because of vascularity. Ulceration and serious haemorrhage can occur. X-ray shows bone destruction with ridging of the walls (pseudo-trabaculation). Treatment is curettage for small lesions but segmental mandibulectomy with mandibular reconstruction for larger tumours.
*Carcinomatous epulis -and ulcerating, invading the bone and spreading to cervical lymph nodes. A biopsy must be performed to confirm the diagnosis. Treatment remains a commando procedure with reconstruction of the jaw and soft tissue defect using a vascularized composite tissue – skin, soft tissue and bone.
Granulomatous, Fibrous and Giant cell epulis are benign epulis, whereas Carcinomatous epulis is a malignant epulis.
Fibromas are growths that form in a person’s mouth in response to repeated injury, irritation or disease. These elevated areas of mostly scar tissue can appear anywhere inside the mouth, including on the tongue, lips, gums and inner cheeks. They can take months or even years to form.
Most fibromas occur as a result of repeatedly biting a certain area of the mouth. Excessive grinding of teeth (bruxism) and a rare genetic disorder called Cowen’s syndrome also are sometimes responsible for fibromas. Fibromas can occur in people of any age, but are most likely to affect adults. Fibromas affect males and females equally.
Fibromas that are not surgically removed continue to grow. If left untreated, fibromas may grow large enough to displace the teeth or cause other oral health problems. For this reason, surgical removal is recommended.
Fibromas typically appear as small areas of elevated tissue that are pink or white. When these scars are traumatized, they may appear reddish or blue. They tend to have a smooth surface and may be round, oval or elliptical in shape. They may have a stalk-like base or be fixed to the surface.
The size of a fibroma can vary from a few millimeters to about
Treatment
-cutting the lesion from the mouth using a local anesthetic to prevent any pain. The area is then usually closed with stitches. Once removed, fibromas do not normally return, unless the area continues to be irritated.
– in some cases a mouth guard can be prescribed to be worn at night by patients who grind their teeth.
Nasopharyngeal (juvenile) angiofibroma- is a rare benign tumor which consists of immature well-vascularised connective tissue. Nevertheless it has tendency to quick invasive growth with germination into adjacent anatomical areas (anterior cranial fossa, maxilla sinus, eye-socket, fossa pterygopalatinae and fossa subtemporalis ) is characterized by high recurrence frequency.
Fibromatoses are proliferative lesions of connective tissue which infiltrate surrounding tissues, have a strong tendency to recur, but are non- neoplastic and no metastasize. They do not appear to be reactive , but their etiology is unclear. Fibromatoses typically form relatively slow-growing , usually painless, poorly circumscribed tumor-like masses.They may be entirely within soft tissues such as muscle or beneath periosteum and cause bone erosion.Later, involvement of nerve fibers can cause pain.
Treatment should be wide excision , but mutilating operations should be avoided. The recurrence rate is less than 25%.
Desmoplastic fibroma is another form of fibromatosis. It is arised from the tendon and fascia- sheath structures. It is aggressive and progressive but does not metastasize.
Lipoma is a benign tumor composed of fatty tissue. These are the most common form of soft tissue tumor. Lipomas are soft to the touch, usually movable, and are generally painless. Many lipomas are small (under one centimeter diameter) but can enlarge to sizes greater than six centimeters. Lipomas are commonly found in adults from 40 to 60 years of age, but can also be found in children.
There are several subtypes of lipoma:
Angiolipoma
Angiolipoleiomyoma
Neural fibrolipoma
Chondroid lipoma
Spindle-cell lipoma
Pleomorphic lipoma
Intradermal spindle cell lipoma
Hibernoma
The most common type is the “superficial subcutaneous lipoma”, i.e. just below the surface of the skin.Most occur on the trunk, thighs and the forearms, although they may be found anywhere in the body where fat is located.
Lipoma of the corpus callosum is a rare congenital condition which may or may not present with symptoms. Lipomas are usually relatively small with diameters of about 1-
Usually, treatment of a lipoma is not necessary, unless the tumor becomes painful or restricts movement. They are usually removed for cosmetic reasons, if they grow very large, or for histopathology to check that they are not a more dangerous type of tumor such as a liposarcoma.Lipomas are normally removed by simple excision. This cures the majority of cases, with about 1-2% of lipomas recurring after excision.
A rhabdomyoma is a benign tumor of striated muscle. Cardiac rhabdomyomas are the most common primary tumor of the heart in infants and children.
It has an association with tuberous sclerosis.
It is most commonly associated with the tongue and heart, but can also occur in other locations. Rhabdomyomas are well circumscribed or encapsulated and consist of large cells with eosinophilic cytoplasm.
The malignant form of rhabdomyoma is called rhabdomyosarcoma.
A leiomyoma (plural is ‘leiomyomata’) is a benign smooth muscle neoplasm that is not premalignant. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus, in the derm of the tongue back. The tumor growth slowly , but sometimes it can achieve a quite large size. Clinically it is represented as circumscribed node or nodes. It has solid elastic consistency, smooth surface, clear borders. It could be painful during palpation. The skin and mucosa are without changes.
The surgical excision is the choice of the treatment.
Vascular tumors of Jaw-Facial area.
Hemangioma is the most common type of vascular anomaly (birthmark). It is a benign (noncancerous) tumor of the cells, called endothelial cells, that normally line the blood vessels. In hemangiomas, the endothelial cells multiply at an abnormally rapid rate.
Hemangioma may be:
– In the top skin layers (capillary hemangioma)
– Deeper in the skin (cavernous hemangioma)
– Branchy hemangioma
– Mixed hemangiomas
Infantile hemangiomas have a fairly predictable pattern of growth. Most appear during the first weeks of life and grow rapidly (called the proliferative phase) for 6 to 12 months. Then they begin a much slower process of shrinking, or regressing (called the involuting phase), which may take from one to about seven years. Finally, the tumor enters its final, shrunken state (called the involuted phase), after which it will never regrow. Tumor regression is complete in 50% of children by age 5 and in 70% of children by age 7. By the time a child reaches 10 to 12 years of age, involution of the tumor is always complete. Some residual fatty tissue or thin skin may remain after involution.
A tumor near the skin’s surface is called a superficial hemangioma. It often looks like a raised bright red patch, sometimes with a textured surface (hence the once-commonly used term “strawberry hemangioma”). Veins radiating from the tumor may also be visible beneath the skin. As the hemangioma begins to or shrink, the red color fades. Usually, the last traces of color are gone by the time the child reaches age 7.
Hemangiomas that grow in the lower layers of the skin, called deep hemangiomas; they appear bruise-like or bluish or may not be visible at all. They are usually found at two to four months of age.
Congenital hemangiomas look different than the more common type that grows after birth. They are large at birth, round or oval and have a grayish cast with prominent veins and may be encircled by a pale halo.
The most often hemangioma’s localization are chicks, nasal lateral surface, naso-labial sulcus, lips, infraorbital area, floor of the oral cavity.
Capillary hemangioma- is an excrescence of dilatating and twisting capillaries and small vessels which are deeply intertwined and have a lot of anastomosis. During the palpation capillary hemangiomas are painful. They are getting paleness while pressing and renew the color after ending the pressure. There are two forms of capillary hemangiomas : the flat ( doesn’t arise under the skin) and the hypertrophic one ( arise under the skin and has hilly surface ) .
Branchy hemangioma consists of twisted thick-walled vessels of arterial or venous type. It is rarely occur in the oral-facial areas and considered as developmental malformation of large vessels. Clinically it is represented as a single node with tense pulsation that becomes weak after the vessel‘s squeezing. During an inclination of a head, the tumour is increased at a rate of size and after returning in target position the tumor decreases( so-called filling- devastation symptom).
Cavernous hemangioma is a group of cavities filled with blood that have endothelium lining which are incorporated or divided by connective tissue partitions. During diagnostic puncture the venous blood is obtained and long-lasting haemorrhage can occur.
Mixed hemanhgiomas are the association of all types of hemangiomas written above.
There are no ways to prevent hemangioma. Nothing the mother does or does not do prior to or during pregnancy plays any role in whether her child develops a hemangioma.
While complications are uncommon, they can occur in some children. Complications include ulceration (skin breakdown), which can bleed or become infected; obstruction of vital functions such as vision, hearing, or breathing; distortion of facial features; and, very rarely, internal bleeding or high output cardiac (heart) failure resulting from a hemangioma in an internal organ. Only about 1% of hemangiomas cause life-threatening complications.
About 5 percent to 10 percent of children with a hemangioma develop an ulcer, typically on the lip or the peri anal or genital region. An ulcer is usually effectively treated with topical antibiotics and frequent cleansing and dressings. Sometimes oral medications, laser treatment, or surgical removal may be necessary. Bleeding, which is rare, can usually be controlled by applying pressure to the area. An ulcer usually heals within a few weeks and does not recur. However, it may result in scarring that requires surgical correction.
Treatment should be given when the benefits of treatment outweigh the risks involved. All treatments have side effects.
Most haemangiomas disappear by themselves and do not need any treatment.
Sometimes a small biopsy of skin is taken in order to make sure what type of haemangioma it is.
Haemangiomas need treatment if:
- They are pressing on important structures such as the eyes, nose, ears or windpipe.
- It is on your child’s eyelid or if it is large and on your child’s face. These haemangiomas need urgent treatment to prevent serious problems.
- They become ulcerated and painful and do not heal.
- To prevent your child having problems with their appearance when they reach school age.
Methods of treatment :
– medical dispensary observation;
– surgical treatment;
– tumor embolization;
– sclerotherapy;
– laser;
– criotherapy and electrocoagulation;
– steroids and interferon medicines
Surgery therapy includes:
– dermabrasion;
– excision ;
– suture ligation of the vessels;
– subcutaneous devastation ;
– combination of all listed methods above.
Lymphangioma is a rare, benign, congenital disorder in which a blockage in the lymphatic system causes fluid to accumulate in bubbles beneath the skin.
These proliferation of lymph vessels may occur anywhere, but around 75% occur in the head and neck regions, or in the groin. Around 90% are either evident at birth or become evident before age two years. Since they have no chance of becoming malignant, lymphangiomas are usually treated for cosmetic reasons only.
