SOFT TISSUE TUMORS OF MAXILLOFACIAL REGION IN CHILDREN (VASCULAR TUMORS, LIPOMA, MYOMA,PAPILLOMA, FIBROMA, NEUROFIBROMAS)

SOFT TISSUE TUMORS OF MAXILLOFACIAL REGION IN CHILDREN (VASCULAR TUMORS, LIPOMA, MYOMA,PAPILLOMA, FIBROMA, NEUROFIBROMAS). THE ETIOLOGY, CLINICAL FEATURES, DIAGNOSIS, METHODS OF TREATMENT

TUMOR-LIKE FORMATIONS OF SOFT TISSUES OF THE FACE (EPIDERMOID, DERMOID, NEVUS, ATHEROMA, SEBACEOUS CYST). CONGENITAL CYSTS AND FISTULAS OF THE NECK. NEUROFIBROMATOSIS. ETIOLOGY, CLINICAL MANIFESTATIONS, DIAGNOSIS AND TREATMENT.

 

 

Benign Soft Tissue TumorsSoft tissue tumors develop in connective tissue other than bone such as the skeletal muscle, fat, tendon, fibrous tissue and nerve and blood vessel (neurovascular) tissue.

Soft tissue tumors can occur anywhere in the body but are most frequent in the lower extremities, trunk and abdomen and upper extremities. The cause is unknown. Trauma may bring attention to a previous existing tumor.

Benign soft tissue tumors rarely metastasize. They are categorized according to their behavior to be aggressive or not, ranging from inactive, to active, to aggressive.

In adults, the most common benign soft tissue tumor is a lipoma. In children, popliteal (Baker’s) cysts, lipomas and hemangiomas are common. Benign tumors may be very large and deep but are usually soft – except for the fibrous tumors which may feel firm.

LipomaThe most common benign soft tissue tumor made of fat and is usually large and soft. They are located on the back, shoulders, abdomen and upper and lower extremities. They usually do not cause symptoms unless they begin to push oearby nerves. Lipomas usually grow slowly with little change over many years. Many patients seek medical attention for cosmetic reasons when a lipoma grows too large. An angiolipoma which involves blood vessels usually occurs in children located deep in the muscle and is tender because it involves the vessels. On the MRI scan, the lipoma is seen as a bright, well defined mass. Treatment includes removing (excising) the mass or observing it if it is not bothersome. Recurrences are unusual.

HemangiomaA benign vascular (involving blood vessels) soft tissue tumor. It is the most common soft tissue tumor in children. It can develop in the top skin (superficial) layer or deep within the muscle. They occur more often in the lower extremities than the upper extremities. Hemangiomas can range from being well-defined, noninvasive and involving small vessels (capillaries) to less defined, invasive and involving large vessels. The most common type of hemangioma is made of both large and small vessels. The MRI scan is the best type of imaging to show the location and extent of the tumor. Angiograms may also be done to evaluate the large blood vessels.

Treatment is not necessary unless they cause pain. Aspirin and compression stockings may be quite successful in relieving symptoms. Surgical excision is sometimes necessary if symptoms persist. Although hemangiomas are vascular, they do not spread to other areas or turn malignant. Occasionally for large tumors that caot be removed, radiation therapy and embolization (a procedure to plug/stop the blood supply in the tumor area preventing tumor growth) has been attempted to treat hemangiomas with little success. Recently, treatment has also included injections with alcohol into the tumor (sclerotherapy).

Fibroma and FibromatosisBenign soft tissue tumors made of fibrous tissue come in many different forms. Congenital fibromatosis occurs in infants and usually presents as a solitary mass. Fibrous tumors in adolescents and adults include fibromas, extra-abdominal desmoid tumors, palmer fibromatosis and nodular fasciitis. Fibromatosis (desmoid tumor) refers to a benign but aggressive tumor usually located in the lower extremity. Fibromatoses are very aggressive at the original site and invade the nearby muscle, soft tissue and bone but do not metastasize (spread to other sites). MRI scans or CT scans are done preoperatively. Plain x-rays will rule out any bone involvement under the soft tissue mass, and a bone scan will show any other bony invasion.

Treatment includes removal (excision) of the soft tissue mass. In some cases the surgical margin (area around the tumor) is not large enough because the tumor extends microscopically beyond the main mass. Thus, there is a high rate of recurrence. These tumors should be treated aggressively with wide margin excisions. Radiation therapy is also used for local control.

Neurofibroma and NeurofibromatosisBenign soft tissue tumors that are made of nerve tissue. They are also called nerve sheath tumors or schwannomas because the tumor tissue has cells like the nerve sheath (envelope around the nerve fibers), or Schwann cell. Neurofibromas may occur as a single tumor or many tumors and may be found anywhere on the body. They range from simple, small masses to gross enlargement of an extremity (elephantiasis), to masses causing bony erosion and deformities of the spine. Since neurofibromas come from nerve roots, those located in the spine can press on the spinal cord causing neurologic symptoms.

Neurofibromatosis is an inherited syndrome and is the most common genetic disorder, usually diagnosed in childhood. The patient presents with greater than six cafe au lait spots (‘coffee with milk’ colored, brownish, birthmark spots on the skin) and/or many neurofibromas (called von Recklinghausen’s disease) over their entire body. Patients with severe disease may have large neurofibromas involving an entire extremity.

An MRI scan is necessary to evaluate the size and extent of the neurofibroma. The mass is usually seen in connection with a major nerve. Examination of the tumor tissue shows a tumor composed of spindle cells. The treatment involves excision of neurofibromas if they are large, painful or interfere with function. Single neurofibromas once excised rarely recur. The multiple neurofibromas of neurofibromatosis may become malignant. Most often they are observed and not excised unless they are growing or painful. If a sarcoma develops, the patient must undergo staging studies to rule out metastatic disease. Pre- and/or post-operative radiation therapy is usually included in the treatment plan, and sometimes chemotherapy.

Pigmented Villonodular Synovitis (PVNS)A benign soft tissue mass involving the synovial membrane (lining of a joint). It is most often seen in the knee or hip joint of adults under age 40. Patients usually present with a boggy, swollen, painful joint. The synovial membrane becomes thick. Many times the disease process goes beyond the joint and causes severe degenerative joint disease. If an aspirate (fluid withdrawn from an area with a needle) of the joint is done, it will show a bloody, brown fluid. Other diagnoses that must be ruled out are infection, rheumatoid arthritis, hemangioma, giant cell tumors of tendon sheath or malignant synovial sarcoma. X-rays of PVNS show an increase in joint fluid, a thick synovial membrane and sometimes bone erosion. Bone scans show increased activity in the joint area, and synovial thickening and nodularity or a mass are seen on the MRI scan. A biopsy should be performed on large nodular tumors to rule out sarcoma. Tumor tissue reveals many rounded synovial-like cells with a good amount of giant cells and inflammatory cells. Treatment involves an excision of the tumor. If the PVNS is widespread, a complete synovectomy (excision of the membrane that lines joints lubricating them with fluid) must be done. Localized nodular synovitis is simply excised. PVNS may recur unless the entire synovial membrane is removed. Widespread PVNS usually causes chronic degenerative joint disease which may require total joint replacements. Radiation is an alternative adjuvant therapy in recurrent cases.

Myositis OssificansA non-tumorus soft tissue mass that occurs after a blunt trauma. The soft tissue reacts to the trauma by forming a bony mass. Patients present with a painful or painless mass which is increasing in size. The tumor is usually located in the upper arm, thigh or buttock. X-rays show a round ossified (bony) mass which may be read as a sarcoma. However, the myositis ossificans has a distinct margin of ossification (bone formation) with an active center containing immature cells. Sarcomas have active and inactive tissues on the outer margin with an inactive center. Bone scans show increased activity in the area of the mass for about 8-12 weeks, and then the activity decreases. The CT scan is the best imaging to show the bony mass. Treatment involves observation or excision usually after an 8-12 week period because if it is excised before full maturation, recurrence is likely. There lesions sometimes resolve without treatment.

Ganglion or Synovial CystA benign soft tissue mass ‘cyst like’ iature and comes from the capsule of the joint, synovial membrane (lining) or tendon sheath (covering). It usually develops on the top of the wrist in adults between 25 and 45 years of age, and are more common in women. The cause is unknown, but repeated trauma is a contributing factor. Some patients have no symptoms, while other have tenderness, pain and problems with wrist function. A needle aspiration should be done if a sarcoma is suspected. Staging studies are usually not necessary because of the ganglion cyst’s classic appearance, although ultrasound is helpful in confirming the cystic nature of the lesion. The excised cyst or nodule has an outer fibrous layer with an inner lining made of clear colorless, gelatin-like fluid.

Some ganglia need no treatment because they go away on their own. Usually needle aspiration or rupture of the cyst give temporary relief. Recurrence is common. The best treatment for a patient who has symptoms is to completely excise the cyst down to the base of the cyst which should prevent recurrence. Baker’s cysts behind the knee in childreearly always resolve without treatment.

 

Bone tumours include both benign and malignant lesions:

·                 Benign lesions may cause pain, expansion into local structures, joint dysfunction and predispose to pathological fractures.

·                 Secondary malignant tumours are much more common than primary malignant bone tumours.

Classification

Benign

·                 Bone: osteoid osteoma.

·                 Cartilage: chondroma, osteochondroma.

·                 Fibrous tissue: fibroma.

·                 Bone marrow: eosinophilic granuloma (see separate article Langerhans’ cell histiocytosis).

·                 Vascular: haemangioma.

·                 Uncertain: giant cell tumour.

Malignant

·                 Bone: osteosarcoma.

·                 Cartilage: chondrosarcoma.

·                 Fibrous tissue: fibrosarcoma.

·                 Bone marrow: Ewing’s sarcoma^[1], myeloma.

·                 Vascular: angiosarcoma.

·                 Uncertain: malignant giant cell tumour.

Benign bone tumours

Osteoid osteoma

·                 Usually less than 1 cm in diameter and surrounded by dense osteoid.

·                 Often occurs in young adults.

·                 Most common sites are the tibia, femur and vertebrae.

·                 Presents with pain, which is often worse at night and relieved by non-steroidal anti-inflammatory drugs.

·                 X-ray has characteristic appearance of a radiolucency surrounded by dense bone.

·                 Local excision is curative.

Osteochondroma

·                 One of the most common benign bone tumours.

·                 Sessile or pedunculated lesions arising from the cortex of a long bone adjacent to the epiphyseal plate.

·                 Lesions can be single or multiple.

·                 Often presents in adolescence as cartilaginous overgrowth at epiphyseal plate.

·                 Grows with the underlying bone.

·                 Presents as a painless lump or occasionally joint pain.

·                 Multiple hereditary exostosis is an autosomal-dominant disorder with a mild decrease in stature, normal intelligence, and multiple osteochondromas. It is commonly accompanied by leg length discrepancy, knee and elbow angular deformities, and other skeletal abnormalities.

·                 Excision should be considered if it is causing significant symptoms.

·                 Problems include nerve compression (especially peroneal nerve), ankle diastasis, angular deformities. Malignant transformation to low-grade chondrosarcoma is more common with multiple osteochondromas and more proximal lesions.

Chondroma

·                 Lesions may be single or multiple (Ollier’s disease).

·                 Appears in tubular bones of the hands and feet.

·                 X-ray shows well-defined osteopenic area in the medulla.

·                 Lesion should be excised and bone grafted.

Giant-cell tumour (osteoclastoma)

·                 Represents about 20% of primary bone tumours.

·                 Aggressive, locally recurrent tumour with a low metastatic potential.

·                 Found in the sub-articular cancellous region of long bones. Most lesions occur in closed epiphyses around the knee joint and distal radius.

·                 Only occurs after closure of epiphyses.

·                 Patients are usually aged between 20 and 40 years. It is more common in females.

·                 X-ray shows an asymmetric rarefied area at the end of a long bone.

·                 Cortex is thinned or even perforated.

·                 Treatment is by local excision and grafting often leads to recurrence.

·                 The treatment of choice is wide excision and joint replacement.

·                 Amputation if there is malignant or recurrent tumour.

Chondroblastoma

·                 Rare, normally in epiphysis of long bones, eg the hip, shoulder and knee.

·                 Usually presents at age 10-19 years with pain in the joint, muscle atrophy and tenderness.

·                 Treatment is with curettage and bone grafting.

Osteoblastoma

·                 Locally destructive progressive lesion commonly found in vertebrae.

·                 Usually presents with dull aching pain.

·                 Frequently needs biopsy to exclude malignancy.

·                 Treatment is with curettage/bone grafting or en bloc excision.

Fibromas

·                 These occur in 40% of children aged >2 years.

·                 Usually asymptomatic.

·                 Usually no treatment is required, except when it occupies >50% bone diameter when there is a need for curettage/bone grafting to avoid pathological fracture.

Unicameral bone cysts

·                 Fluid-filled lesion. It is rare before the age of 3 years and after skeletal maturity.

·                 They usually present as pathological fractures (asymptomatic before then) following relatively minor trauma, normally involving the proximal humerus or femur.

·                 Treatment is to allow a fracture to heal and then aspirate and inject with either methylprednisolone or bone marrow.

Aneurysmal cyst

·                 Usually present before the age of 20, with pain and swelling.

·                 They are cavernous spaces filled with blood and solid lumps of tissue.

·                 They mainly affect the femur, tibia and spine, which may lead to cord or nerve root compression resulting ieurological symptoms.

·                 They grow rapidly and may be confused with malignancy.

·                 Treated with curettage/bone grafting or excision.

·                 There is recurrence in 20-30%, usually in the first 1-2 years after treatment and mainly in younger children.

Fibrous dysplasia

·                 Fibrous replacement of cancellous bone – may be multiple or solitary, stable or progressive.

·                 Usually asymptomatic but, if involving the skull, may cause swelling or exophthalmos.

·                 Femoral involvement causes pain and a limp. May also cause limb length discrepancy, bowing and pathological fractures.

Osteofibrous dysplasia

·                 Presents in children aged 1-10 years.

·                 Usually involves the tibia with anterior swelling or enlargement of the leg. Usually painless.

·                 Treatment is with excision and bone grafting, delayed until after the age of 10 years because of the high risk of recurrence if younger.

Eosinophilic granuloma

·                 Most common in boys aged 5-10 years; usually occurs before the age of 30.

·                 Most often affects the skull with local pain and swelling, marked tenderness and warmth in the area.

·                 Treatment is with curettage/bone grafting, low-dose radiotherapy or steroid injection.

Malignant bone tumours

Osteosarcoma

·                 The most common primary bone malignancy in children.^[2] The incidence is highest in 15-19 year olds – 0.8-1.1/100,000/year.^[3]

·                 The male:female ratio is 1.4:1.

·                 In later life, it is seen associated with Paget’s disease of bone.

·                 Occurs in the metaphyses of long bones. The most common sites are around the knee (75%) or proximal humerus.

·                 Often presents as a relatively painless tumour.

·                 Destroys bone and spreads into the surrounding tissue. Rapidly metastasises to the lung.

·                 X-ray shows combination of bone destruction and formation. Soft tissue calcification produces a ‘sunburst’ appearance.

·                 Disease-free survival has increased to 55-75% with surgery and effective chemotherapy.^[4] Chemotherapy alone is not as effective.

·                 Pulmonary metastases are particularly problematic and are associated with a poorer prognosis.

Ewing’s sarcoma

·                 This is a primitive neuroectodermal tumour (PNET) thought to arise from mesenchymal stem cells. Ewing’s sarcoma is rare, affecting around 30 children per year in the UK. It is diagnosed in white Caucasians under the age of 25 at an incidence of 0.3/100,000 per year.^[3] It is very uncommon in the African and Asian population. The median age at diagnosis is 15 years and there is a male predilection of 1.5:1. The condition is extremely rare over the age of 40.^[5]

·                 It usually presents as a mass or swelling – most commonly in the long bones of the arms and legs, pelvis or chest but also in the skull and flat bones of the trunk. Other symptoms and signs include pain in the area of the tumour, redness in the area surrounding the tumour, malaise, anorexia, weight loss, fever (a poor prognostic sign), paralysis and/or incontinence if affecting the spine, and numbness or tingling as a result of nerve compression by the tumour.

·                 Investigations:

·                         X-ray of the affected bone shows bone destruction with overlying onion-skin layers of periosteal bone formation.^[6]

·                         Biopsy of the tumour site is used for diagnosis.

·                         Molecular pathology techniques can be used on fresh, frozen formalin-fixed paraffin-embedded tissues.^[7]

·                         FBC and lactic dehydrogenase (LDH) measurement – anaemia and raised LDH levels at diagnosis suggest the presence of metastases and are an indication of a poor prognostic outcome.^[8]

·                         CT/MRI scan are used to assess the extent of disease and the local structures involved.

·                         Bone scintigraphy is useful in identifying metastases and assessing response to treatment.

·                 Staging of the tumour is undertaken to determine the treatment and also give some indication of the likely prognosis:^[9]

·                         Stage IA – low-grade tumour found only within the hard coating of the bone.

·                         Stage IB – low-grade tumour extending locally into the soft tissues.

·                         Stage IIA – high-grade tumour found only within the hard coating of the bone.

·                         Stage IIB – high-grade tumour extending locally to the soft tissues.

·                         Stage III – low- or high-grade tumour which has metastasised.

·                 The family of a child with Ewing’s sarcoma will require long-term support from a number of professionals in both primary care and the hospital setting.^[10] It is important that all members of the family know where to access information, support and practical help when required and it is vital that there is good communication between all professionals involved in the care of the child.

·                 Chemotherapy is usually the first line of treatment and is currently initiated using a combination of vincristine, ifosfamide, doxorubicin and etoposide (VIDE).The treatment usually takes the form of six courses of treatment at intervals of three weeks, following which further management decisions will be based partly on the response to treatment. Further courses of chemotherapy using different combinations of drugs are generally used following surgery or radiotherapy.

·                 Radiotherapy may be used in conjunction with surgery and/or chemotherapy. Radiotherapy may occasionally be used in place of surgery where removal of the bone is not possible, eg in the spine. Some patients are treated with radiotherapy alone but one trial suggests that there is a higher rate of treatment failure and relapse compared to surgery.^[11]

·                 Peripheral blood stem cell harvest may be undertaken midway through chemotherapy. The recovered cells are stored in case of future need following further courses of chemotherapy. Allogenic stem cell transplantation may offer a way forward in refractory metastatic patients.^[12]

·                 Surgery is often required to remove the tumour. Limb-sparing surgery, where only a part of the bone is removed and replaced if necessary with a segment of prosthetic bone, is increasingly carried out, although amputation of the limb may be required if the tumour is affecting one of the long bones of the arm or leg. Physiotherapy ±/ prosthetic limb fitting may be required following surgery.

·                 The overall five-year survival rate for Ewing’s sarcoma is 50%.^[13] When chemotherapy, radiotherapy and surgery are combined, survival is approximately 60-70% for localised tumours and around 20-40% for disease that has metastasised.^[3]

Chondrosarcoma

·                 Chondrosarcoma is one of the most frequently occurring bone sarcomas of adulthood. The incidence is about 0.1/100,000 per year.^[3] They most commonly present at between 30 and 60 years old. Males and females are equally affected.

·                 They may arise from pre-existing lesions (osteochondromas, chondromas) or they can be primary.

·                 They are usually associated with dull, deep pain.

·                 Radiographs may show invasiveness and soft tissue extension.

·                 Occurs in two forms:

·                         Central: tumour in the pelvis or proximal long bones.

·                         Peripheral: tumour in the cartilaginous cap of an osteochondroma.

·                 They tend to metastasise late.

·                 Wide local excision is often possible.

Spindle cell sarcomas

·                 These are a mixed group of malignant tumours including fibrosarcoma, malignant fibrous histiocytoma (MFH), leiomyosarcoma and undifferentiated sarcoma.

·                 They present between 30-60 years of age and men are more frequently affected than women.

·                 They are usually found in the metaphysis of long bones, present with pain and have a high incidence of fracture at presentation.

Metastatic tumours

·                 The most common bone malignancies are metastatic carcinomas.

·                 They are usually multiple but may be solitary.

·                 The most common primaries are breast, prostate, lung, kidney and thyroid.

·                 Wilms’ tumour and neuroblastoma are the most common metastatic lesions in childhood.

Epidemiology

·                 Primary malignant bone tumours are rare.

·                 Secondary tumours are more common, especially in the elderly.

Presentation

·                 Most present with pain, swelling and localised tenderness.

·                 Rapid growth and erythema are suggestive of malignancy.

·                 They may cause pathological fractures.

Investigations

·                 Plain X-ray.

·                 MRI and CT scan.

·                 Bone scan.

·                 Biopsy.

·                 Investigation of any occult primary lesion, especially breast, prostate, lung, kidney and thyroid.

Management

·                 There may be considerable difficulty recognising tumours as malignant ion-specialised centres; therefore, all patients with a suspected primary malignant bone tumour should be referred to a bone sarcoma reference centre or an institution belonging to a specialised bone sarcoma network before biopsy.^[3]

·                 As malignant primary bone tumours are rare and management is complex, the accepted standard is treatment either in reference centres or withietworks able to provide access to the full spectrum of care or shared with such centres within reference networks.

Pathological fractures

·                 If there is an existing pathological fracture in a possible primary malignant bone tumour, there is potential for dissemination of tumour cells into surrounding tissues which may increase the risk of local recurrence. In these patients there may be a strong case for immobilising the part following the biopsy, usually by application of an external splint.

·                 Internal fixation is contra-indicated, as it disseminates tumour further into both bone and soft tissues and also increases the risk of local recurrence. External splintage is recommended, along with appropriate pain control.

Follow-up

The purpose of follow-up is to detect either local recurrence or metastatic disease early enough that treatment is still possible and might be effective. It should include physical examination, imaging of the site and CXR or CT scan.

After completion of chemotherapy, patients should be seen every 6 weeks to 3 months for the first 2 years, every 2-4 months for years 3 and 4, every 6 months for years 5-10 and thereafter every 6-12 months according to local practice.

Types of Skin Cancer

Skin cancers are named for the type of cells that become malignant (cancer). The three most common types are:

·                     Melanoma: Melanoma begins in melanocytes (pigment cells). Most melanocytes are in the skin. See the picture of a melanocyte and other skin cells.

Melanoma can occur on any skin surface. In men, it’s often found on the skin on the head, on the neck, or between the shoulders and the hips. In women, it’s often found on the skin on the lower legs or between the shoulders and the hips.

Melanoma is rare in people with dark skin. When it does develop in people with dark skin, it’s usually found under the fingernails, under the toenails, on the palms of the hands, or on the soles of the feet.

·                     Basal cell skin cancer: Basal cell skin cancer begins in the basal cell layer of the skin. It usually occurs in places that have been in the sun. For example, the face is the most common place to find basal cell skin cancer.

In people with fair skin, basal cell skin cancer is the most common type of skin cancer.

·                     Squamous cell skin cancer: Squamous cell skin cancer begins in squamous cells. In people with dark skin, squamous cell skin cancer is the most common type of skin cancer, and it’s usually found in places that are not in the sun, such as the legs or feet.

However, in people with fair skin, squamous cell skin cancer usually occurs on parts of the skin that have been in the sun, such as the head, face, ears, and neck.

Unlike moles, skin cancer can invade the normal tissue nearby. Also, skin cancer can spread throughout the body. Melanoma is more likely than other skin cancers to spread to other parts of the body. Squamous cell skin cancer sometimes spreads to other parts of the body, but basal cell skin cancer rarely does.

When skin cancer cells do spread, they break away from the original growth and enter blood vessels or lymph vessels. The cancer cells may be found iearby lymph nodes. The cancer cells can also spread to other tissues and attach there to form new tumors that may damage those tissues.

The spread of cancer is called metastasis. See the Staging section for information about skin cancer that has spread.

Risk Factors

When you’re told that you have skin cancer, it’s natural to wonder what may have caused the disease. The main risk factor for skin cancer is exposure to sunlight (UV radiation), but there are also other risk factors. A risk factor is something that may increase the chance of getting a disease.

People with certain risk factors are more likely than others to develop skin cancer. Some risk factors vary for the different types of skin cancer.

Risks for Any Type of Skin Cancer

Studies have shown that the following are risk factors for the three most common types of skin cancer:

·                     Sunlight: Sunlight is a source of UV radiation. It’s the most important risk factor for any type of skin cancer. The sun’s rays cause skin damage that can lead to cancer.

·                     Severe, blistering sunburns: People who have had at least one severe, blistering sunburn are at increased risk of skin cancer. Although people who burn easily are more likely to have had sunburns as a child, sunburns during adulthood also increase the risk of skin cancer.

·                     Lifetime sun exposure: The total amount of sun exposure over a lifetime is a risk factor for skin cancer.

·                     Tanning: Although a tan slightly lowers the risk of sunburn, even people who tan well without sunburning have a higher risk of skin cancer because of more lifetime sun exposure.

Sunlight can be reflected by sand, water, snow, ice, and pavement. The sun’s rays can get through clouds, windshields, windows, and light clothing.

In the United States, skin cancer is more common where the sun is strong. For example, more people in Texas than Minnesota get skin cancer. Also, the sun is stronger at higher elevations, such as in the mountains.

Doctors encourage people to limit their exposure to sunlight. See the Prevention section for ways to protect your skin from the sun.

·                     Sunlamps and tanning booths: Artificial sources of UV radiation, such as sunlamps and tanning booths, can cause skin damage and skin cancer.  Health care providers strongly encourage people, especially young people, to avoid using sunlamps and tanning booths. The risk of skin cancer is greatly increased by using sunlamps and tanning booths before age 30.

·                     Personal history: People who have had melanoma have an increased risk of developing other melanomas. Also, people who have had basal cell or squamous cell skin cancer have an increased risk of developing another skin cancer of any type.

·                     Family history: Melanoma sometimes runs in families. Having two or more close relatives (mother, father, sister, brother, or child) who have had this disease is a risk factor for developing melanoma. Other types of skin cancer also sometimes run in families. Rarely, members of a family will have an inherited disorder, such as xeroderma pigmentosum or nevoid basal cell carcinoma syndrome, that makes the skin more sensitive to the sun and increases the risk of skin cancer.

·                     Skin that burns easily: Having fair (pale) skin that burns in the sun easily, blue or gray eyes, red or blond hair, or many freckles increases the risk of skin cancer.

·                     Certain medical conditions or medicines: Medical conditions or medicines (such as some antibiotics, hormones, or antidepressants) that make your skin more sensitive to the sun increase the risk of skin cancer. Also, medical conditions or medicines that suppress the immune systemincrease the risk of skin cancer.

Other Risk Factors for Melanoma

The following risk factors increase the risk of melanoma:

·                     Dysplastic nevus: A dysplastic nevus is a type of mole that looks different from a common mole. A dysplastic nevus may be bigger than a common mole, and its color, surface, and border may be different. It’s usually wider than a pea and may be longer than a peanut. A dysplastic nevus can have a mixture of several colors, from pink to dark brown. Usually, it’s flat with a smooth, slightly scaly or pebbly surface, and it has an irregular edge that may fade into the surrounding skin.

A dysplastic nevus is more likely than a common mole to turn into cancer. However, most do not change into melanoma. A doctor will remove a dysplastic nevus if it looks like it might have changed into melanoma.

·                     More than 50 common moles: Usually, a common mole is smaller than a pea, has an even color (pink, tan, or brown), and is round or oval with a smooth surface. Having many common moles increases the risk of developing melanoma.

Other Risk Factors for Both Basal Cell and Squamous Cell Skin Cancers

The following risk factors increase the risk of basal cell and squamous cell skin cancers:

·                     Old scars, burns, ulcers, or areas of inflammation on the skin

·                     Exposure to arsenic at work

·                     Radiation therapy

Other Risk Factors for Squamous Cell Cancer

The risk of squamous cell skin cancer is increased by the following:

·                     Actinic keratosis: Actinic keratosis is a type of flat, scaly growth on the skin. It is most often found on areas exposed to the sun, especially the face and the backs of the hands. The growth may appear as a rough red or brown patch on the skin. It may also appear as cracking or peeling of the lower lip that does not heal. Without treatment, this scaly growth may turn into squamous cell skin cancer.

·                     HPV (human papillomavirus): Certain types of HPV can infect the skin and may increase the risk of squamous cell skin cancer. These HPVs are different from the HPV types that cause cervical cancer and other cancers in the female and male genital areas.

Symptoms of Melanoma

Often the first sign of melanoma is a change in the shape, color, size, or feel of an existing mole. Melanoma may also appear as a new mole. Thinking of “ABCDE” can help you remember what to look for:

·                     Asymmetry: The shape of one half does not match the other half.

·                     Border that is irregular: The edges are often ragged, notched, or blurred in outline. The pigment may spread into the surrounding skin.

·                     Color that is uneven: Shades of black, brown, and tan may be present. Areas of white, gray, red, pink, or blue may also be seen.

·                     Diameter: There is a change in size, usually an increase. Melanomas can be tiny, but most are larger than the size of a pea (larger than 6 millimeters or about 1/4 inch).

·                     Evolving: The mole has changed over the past few weeks or months.

Melanomas can vary greatly in how they look. Many show all of the ABCDE features. However, some may show changes or abnormal areas in only one or two of the ABCDE features.

In more advanced melanoma, the texture of the mole may change. The skin on the surface may break down and look scraped. It may become hard or lumpy. The surface may ooze or bleed. Sometimes the melanoma is itchy, tender, or painful.

 

Symptoms of Basal Cell and Squamous Cell Skin Cancers

A change on the skin is the most common sign of skin cancer. This may be a new growth, a sore that doesn’t heal, or a change in an old growth. Not all skin cancers look the same. Usually, skin cancer is not painful.

Common symptoms of basal cell or squamous cell skin cancer include:

A lump that is small, smooth, shiny, pale, or waxy	A lump that is firm and red
A sore or lump that bleeds or develops a crust or a scab	A flat red spot that is rough, dry, or scaly and may become itchy or tender

 

 

Diagnosis

If you have a change on your skin, your doctor must find out whether or not the problem is from cancer. You may need to see a dermatologist, a doctor who has special training in the diagnosis and treatment of skin problems.

Your doctor will check the skin all over your body to see if other unusual growths are present.

If your doctor suspects that a spot on the skin is cancer, you may need a biopsy. For a biopsy, your doctor may remove all or part of the skin that does not look normal. The sample goes to a lab. Apathologist checks the sample under a microscope. Sometimes it’s helpful for more than one pathologist to check the tissue for cancer cells.

You may have the biopsy in a doctor’s office or as an outpatient in a clinic or hospital. You’ll probably have local anesthesia.

There are four common types of skin biopsies:

·                     Shave biopsy: The doctor uses a thin, sharp blade to shave off the abnormal growth

·                     Punch biopsy: The doctor uses a sharp, hollow tool to remove a circle of tissue from the abnormal area

·                     Incisional biopsy: The doctor uses a scalpel  to remove part of the growth

·                     Excisional biopsy: The doctor uses a scalpel to remove the entire growth and some tissue around it. This type of biopsy is most commonly used for growths that appear to be melanoma.

 

Staging

If the biopsy shows that you have skin cancer, your doctor needs to learn the stage (extent) of the disease to help you choose the best treatment.

The stage is based on:

·                     The size (width) of the growth

·                     How deeply it has grown beneath the top layer of skin

·                     Whether cancer cells have spread to nearby lymph nodes or to other parts of the body

When skin cancer spreads from its original place to another part of the body, the new tumor has the same kind of abnormal cells and the same name as the primary (original) tumor. For example, if skin cancer spreads to the lung, the cancer cells in the lung are actually skin cancer cells. The disease ismetastatic skin cancer, not lung cancer. For that reason, it’s treated as skin cancer, not as lung cancer. Doctors sometimes call the new tumor “distant” disease.

Blood tests and an imaging test such as a chest x-ray, a CT scan, an MRI, or a PET scan may be used to check for the spread of skin cancer. For example, if a melanoma growth is thick, your doctor may order blood tests and an imaging test.

For squamous cell skin cancer or melanoma, the doctor will also check the lymph nodes near the cancer on the skin. If one or more lymph nodes near the skin cancer are enlarged (or if the lymph node looks enlarged on an imaging test), your doctor may use a thieedle to remove a sample of cells from the lymph node (fine-needle aspiration biopsy). A pathologist will check the sample for cancer cells.

Even if the nearby lymph nodes are not enlarged, the nodes may contain cancer cells. The stage is sometimes not known until after surgery to remove the growth and one or more nearby lymph nodes. For thick melanoma, surgeons may use a method called sentinel lymph node biopsy to remove the lymph node most likely to have cancer cells. Cancer cells may appear first in the sentinel node before spreading to other lymph nodes and other places in the body.

Stages of Melanoma

These are the stages of melanoma:

·                     Stage 0: The melanoma involves only the top layer of skin. It is called melanoma in situ.

·                     Stage I: The tumor is no more than 1 millimeter thick (about the width of the tip of a sharpened pencil.) The surface may appear broken down. Or, the tumor is between 1 and 2 millimeters thick, and the surface is not broken down.

·                     Stage II: The tumor is between 1 and 2 millimeters thick, and the surface appears broken down. Or, the thickness of the tumor is more than 2 millimeters, and the surface may appear broken down.

·                     Stage III: The melanoma cells have spread to at least one nearby lymph node. Or, the melanoma cells have spread from the original tumor to tissues nearby.

·                     Stage IV: Cancer cells have spread to the lung or other organs, skin areas, or lymph nodes far away from the original growth. Melanoma commonly spreads to other parts of the skin, tissue under the skin, lymph nodes, and lungs. It can also spread to the liver, brain, bones, and other organs.

Stages of Other Skin Cancers

These are the stages of basal cell and squamous cell skin cancers:

·                     Stage 0: The cancer involves only the top layer of skin. It is called carcinoma in situ.

Bowen disease is an early form of squamous cell skin cancer. It usually looks like a reddish, scaly or thickened patch on the skin. If not treated, the cancer may grow deeper into the skin.

·                     Stage I: The growth is as large as 2 centimeters wide (more than three-quarters of an inch or about the size of a peanut).

·                     Stage II: The growth is larger than 2 centimeters wide.

·                     Stage III: The cancer has invaded below the skin to cartilage, muscle, or bone. Or, cancer cells have spread to nearby lymph nodes. Cancer cells have not spread to other places in the body.

·                     Stage IV: The cancer has spread to other places in the body. Basal cell cancer rarely spreads to other parts of the body, but squamous cell cancer sometimes spreads to lymph nodes and other organs.

 

Treatment

Surgery
Chemotherapy
Photodynamic Therapy
Biological Therapy
Radiation Therapy

Treatment for skin cancer depends on the type and stage of the disease, the size and place of the tumor, and your general health and medical history. In most cases, the goal of treatment is to remove or destroy the cancer completely. Most skin cancers can be cured if found and treated early.

Sometimes all of the skin cancer is removed during the biopsy. In such cases, no more treatment is needed.

If you do need more treatment, your doctor can describe your treatment choices and what to expect. You and your doctor can work together to develop a treatment plan that meets your needs.

Surgery is the usual treatment for people with skin cancer. In some cases, the doctor may suggestchemotherapy, photodynamic therapy, or radiation therapy. People with melanoma may also havebiological therapy.

You may have a team of specialists to help plan your treatment. Your doctor may refer you to a specialist, or you may ask for a referral. Specialists who treat skin cancer include dermatologists and surgeons. Some people may also need a reconstructive or plastic surgeon.

People with advanced skin cancer may be referred to a medical oncologist or radiation oncologist. Your health care team may also include an oncology nurse, a social worker, and a registered dietitian.

Because skin cancer treatment may damage healthy cells and tissues, unwanted side effectssometimes occur. Side effects depend mainly on the type and extent of the treatment. Side effects may not be the same for each person. Before treatment starts, your health care team will tell you about possible side effects and suggest ways to help you manage them.

Many skin cancers can be removed quickly and easily. But some people may need supportive care to control pain and other symptoms, to relieve the side effects of treatment, and to help them cope with the feelings that a diagnosis of cancer can bring. Information about such care is available on NCI’s Web site at http://www.cancer.gov/cancertopics/coping and from NCI’s Cancer Information Service at 1–800–4–CANCER (1–800–422–6237) and at LiveHelp (https://livehelp.cancer.gov/).

You may want to talk with your doctor about taking part in a clinical trial, a research study of new treatment methods. See the Taking Part in Cancer Research section.

You may want to ask your doctor these questions before you begin treatment:

·                     What is the stage of the disease? Has the cancer spread? Do any lymph nodes or other organs show signs of cancer?

·                     What are my treatment choices? Which do you suggest for me? Why?

·                     What are the expected benefits of each kind of treatment?

·                     What can I do to prepare for treatment?

·                     Will I need to stay in the hospital? If so, for how long?

·                     What are the risks and possible side effects of each treatment? How can side effects be managed?

·                     Will there be a scar? Will I need a skin graft or plastic surgery?

·                     What is the treatment likely to cost? Will my insurance cover it?

·                     How will treatment affect my normal activities?

·                     Would a research study (clinical trial) be a good choice for me?

·                     How often should I have checkups?

Surgery

In general, the surgeon will remove the cancerous growth and some normal tissue around it. This reduces the chance that cancer cells will be left in the area.

There are several methods of surgery for skin cancer. The method your doctor uses depends mainly on the type of skin cancer, the size of the cancer, and where it was found on your body.

Your doctor can further describe these methods of surgery:

·                     Excisional skin surgery: This is a common treatment to remove any type of skin cancer. After numbing the area of skin, the surgeon removes the growth (tumor) with a scalpel. The surgeon also removes a border (a margin) of normal skin around the growth. The margin of skin is examined under a microscope to be certain that all the cancer cells have been removed. The thickness of the margin depends on the size of the tumor.

·                     Mohs surgery (also called Mohs micrographic surgery): This method is often used for basal cell and squamous cell skin cancers. After numbing the area of skin, a specially trained surgeon shaves away thin layers of the tumor. Each layer is examined under a microscope. The surgeon continues to shave away tissue until no cancer cells can be seen under the microscope. In this way, the surgeon can remove all the cancer and only a small bit of healthy tissue.

Some people will have radiation therapy after Mohs surgery to make sure all of the cancer cells are destroyed.

·                     Electrodesiccation and curettage: This method is often used to remove a small basal cell or squamous cell skin cancer. After the doctor numbs the area to be treated, the cancer is removed with a sharp tool shaped like a spoon (called a curette). The doctor then uses a needle-shaped electrode to send an electric current into the treated area to control bleeding and kill any cancer cells that may be left. This method is usually fast and simple. It may be performed up to three times to remove all of the cancer.

·                     Cryosurgery: This method is an option for an early-stage or a very thin basal cell or squamous cell skin cancer. Cryosurgery is often used for people who are not able to have other types of surgery. The doctor applies liquid nitrogen (which is extremely cold) directly to the skin growth to freeze and kill the cancer cells. This treatment may cause swelling. It also may damage nerves, which can cause a loss of feeling in the damaged area. The NCI fact sheet Cryosurgery in Cancer Treatment has more information.

For people with cancer that has spread to the lymph nodes, the surgeon may remove some or all of the nearby lymph nodes. Additional treatment may be needed after surgery. See the Staging section for information about finding cancer in lymph nodes.

If a large area of tissue is removed, the surgeon may do a skin graft. The doctor uses skin from another part of the body to replace the skin that was removed. After numbing the area, the surgeon removes a patch of healthy skin from another part of the body, such as the upper thigh. The patch is then used to cover the area where skin cancer was removed. If you have a skin graft, you may have to take special care of the area until it heals.

The time it takes to heal after surgery is different for each person. You may have pain for the first few days. Medicine can help control your pain. Before surgery, you should discuss the plan for pain relief with your doctor or nurse. After surgery, your doctor can adjust the plan if you need more pain relief.

Surgery nearly always leaves some type of scar. The size and color of the scar depend on the size of the cancer, the type of surgery, the color of your skin, and how your skin heals.

For any type of surgery, including skin grafts or reconstructive surgery, follow your doctor’s advice on bathing, shaving, exercise, or other activities.

You may want to ask your doctor these questions before having surgery:

·                     What kind of surgery do you recommend for me? Why?

·                     Will you remove lymph nodes? Why?

·                     Will I need a skin graft?

·                     What will the scar look like? Can anything be done to help reduce the scar? Will I need plastic surgery or reconstructive surgery?

·                     How will I feel after surgery?

·                     If I have pain, how will you control it?

·                     Will I need to stay in the hospital? If so, for how long?

·                     Am I likely to have infection, swelling, blistering, or bleeding, or to get a scab where the cancer was removed?

·                     Will I have any long-term side effects?

Chemotherapy

Chemotherapy uses drugs to kill cancer cells. Drugs for skin cancer can be given in many ways.

Put directly on the skin

A cream or lotion form of chemotherapy may be used to treat very thin, early-stage basal cell or squamous cell skin cancer (Bowen disease). It may also be used if there are several small skin cancers. The doctor will show you how to apply the cream or lotion to the skin one or two times a day for several weeks.

The cream or lotion contains a drug that kills cancer cells only in the top layer of the skin:

·                     Fluorouracil (another name is 5-FU): This drug is used to treat early-stage basal cell and squamous cell cancers.

·                     Imiquimod: This drug is used to treat early-stage basal cell cancer.

These drugs may cause your skin to turn red or swell. Your skin also may itch, ooze, or develop a rash. Your skin may be sore or sensitive to the sun after treatment. These skin changes usually go away after treatment is over.

A cream or lotion form of chemotherapy usually does not leave a scar. If healthy skin becomes too red or raw when the skin cancer is treated, your doctor may stop treatment.

Swallowed or injected

People with melanoma may receive chemotherapy by mouth or through a vein (intravenous). You may receive one or more drugs. The drugs enter the bloodstream and travel throughout the body.

If you have melanoma on an arm or leg, you may receive drugs directly into the bloodstream of that limb. The flow of blood to and from the limb is stopped for a while. This allows a high dose of drugs in the area with the melanoma. Most of the chemotherapy remains in that limb.

You may receive chemotherapy in an outpatient part of the hospital, at the doctor’s office, or at home. Some people need to stay in the hospital during treatment.

The side effects depend mainly on which drugs are given and how much. Chemotherapy kills fast-growing cancer cells, but the drugs can also harm normal cells that divide rapidly:

·                     Blood cells: When drugs lower the levels of healthy blood cells, you’re more likely to get infections, bruise or bleed easily, and feel very weak and tired. Your health care team will check for low levels of blood cells. If your levels are low, your health care team may stop the chemotherapy for a while or reduce the dose of the drug. There are also medicines that can help your body make new blood cells.

·                     Cells in hair roots: Chemotherapy may cause hair loss. If you lose your hair, it will grow back after treatment, but the color and texture may be changed.

·                     Cells that line the digestive tract: Chemotherapy can cause a poor appetite, nausea and vomiting, diarrhea, or mouth and lip sores. Your health care team can give you medicines and suggest other ways to help with these problems. They usually go away when treatment ends.

You may want to read the NCI booklet Chemotherapy and You.

You may want to ask your doctor these questions about chemotherapy:

·                     Why do I need this treatment?

·                     Which drug or drugs will I have?

·                     How do the drugs work?

·                     Do I need to take special care when I put chemotherapy on my skin? What do I need to do? Will I be sensitive to the sun?

·                     When will treatment start? When will it end?

·                     Will I have any long-term side effects?

Photodynamic Therapy

Photodynamic therapy (PDT) uses a drug along with a special light source, such as a laser light, to kill cancer cells. PDT may be used to treat very thin, early-stage basal cell or squamous cell skin cancer (Bowen disease).

The drug is either rubbed into the skin or injected intravenously. The drug is absorbed by cancer cells. It stays in cancer cells longer than iormal cells. Several hours or days later, a special light is focused on the cancer. The drug becomes active and destroys the cancer cells.

The side effects of PDT are usually not serious. PDT may cause burning or stinging pain. It also may cause burns, swelling, or redness. It may scar healthy tissue near the growth. If you have PDT, you will need to avoid direct sunlight and bright indoor light for at least 6 weeks after treatment.

The NCI fact sheet Photodynamic Therapy for Cancer has more information.

You may want to ask your doctor these questions about PDT:

·                     Will I need to stay in the hospital while the drug is in my body?

·                     Will I need to have the treatment more than once?

Biological Therapy

Some people with advanced melanoma receive a drug called biological therapy. Biological therapy for melanoma is treatment that may improve the body’s natural defense (immune system response) against cancer.

One drug for melanoma is interferon. It’s injected intravenously (usually at a hospital or clinic) or injected under the skin (at home or in a doctor’s office). Interferon can slow the growth of melanoma cells.

Another drug used for melanoma is interleukin-2. It’s given intravenously. It can help the body destroy cancer cells. Interleukin-2 is usually given at the hospital.

Other drugs may be given at the same time to prevent side effects. The side effects differ with the drug used, and from person to person. Biological therapies commonly cause a rash or swelling. You may feel very tired during treatment. These drugs may also cause a headache, muscle aches, a fever, or weakness.

You may find it helpful to read the NCI booklet Biological Therapy. You may also wish to read the NCI fact sheet Biological Therapies for Cancer.

You may want to ask your doctor these questions about biological therapy:

·                     What is the goal of treatment?

·                     When will treatment start? When will it end?

·                     Will I need to stay in the hospital for treatment? If so, how long will I be in the hospital?

Radiation Therapy

Radiation therapy uses high-energy rays to kill cancer cells. The radiation comes from a large machine outside the body. It affects cells only in the treated area. You will go to a hospital or clinic several times for this treatment.

Radiation therapy is not a common treatment for skin cancer. But it may be used for skin cancer in areas where surgery could be difficult or leave a bad scar. For example, you may have radiation therapy if you have a growth on your eyelid, ear, or nose. Radiation therapy may also be used after surgery for squamous cell carcinoma that can’t be completely removed or that has spread to the lymph nodes. And it may be used for melanoma that has spread to the lymph nodes, brain, bones, or other parts of the body.

Although radiation therapy is painless, it may cause other side effects. The side effects depend mainly on the dose of radiation and the part of your body that is treated. It’s common for the skin in the treated area to become red, dry, tender, and itchy. Your health care team can suggest ways to relieve the side effects of radiation therapy.

You may find it helpful to read the NCI booklet Radiation Therapy and You.

You may want to ask your doctor these questions about radiation therapy:

·                     How will I feel after treatment?

·                     Am I likely to have infection, swelling, blistering, or bleeding after radiation therapy?

·                     Will I get a scar on the treated area?

·                     How should I take care of the treated area?

Soft Tissue Sarcomas: Questions and Answers

The term soft tissue refers to tissues that connect, support, or surround other structures and organs of the body. Soft tissue includes muscles, tendons (bands of fiber that connect muscles to bones), fibrous tissues, fat, blood vessels, nerves, and synovial tissues (tissues around joints).

Malignant (cancerous) tumors that develop in soft tissue are called sarcomas, a term that comes from a Greek word meaning “fleshy growth.” There are many different kinds of soft tissue sarcomas. They are grouped together because they share certain microscopic characteristics, produce similar symptoms, and are generally treated in similar ways. (Bone tumors [osteosarcomas] are also called sarcomas, but are in a separate category because they have different clinical and microscopic characteristics and are treated differently.)

Sarcomas can invade surrounding tissue and can metastasize (spread) to other organs of the body, forming secondary tumors. The cells of secondary tumors are similar to those of the primary (original) cancer. Secondary tumors are referred to as “metastatic soft tissue sarcoma” because they are part of the same cancer and are not a new disease.

Some tumors of the soft tissue are benign (noncancerous). These tumors do not spread and are rarely life-threatening. However, benign tumors can crowd nearby organs and cause symptoms or interfere with normal body functions.

Scientists do not fully understand why some people develop sarcomas while the vast majority do not. However, by identifying common characteristics in groups with unusually high occurrence rates, researchers have been able to single out some factors that may play a role in causing soft tissue sarcomas.

Studies suggest that workers who are exposed to phenoxyacetic acid in herbicides and chlorophenols in wood preservatives may have an increased risk of developing soft tissue sarcomas. An unusual percentage of patients with a rare blood vessel tumor, angiosarcoma of the liver, have been exposed to vinyl chloride in their work. This substance is used in the manufacture of certain plastics.

In the early 1900s, when scientists were just discovering the potential uses of radiation to treat disease, little was known about safe dosage levels and precise methods of delivery. At that time, radiation was used to treat a variety of noncancerous medical problems, including enlargement of the tonsils, adenoids, and thymus gland. Later, researchers found that high doses of radiation caused soft tissue sarcomas in some patients. Because of this risk, radiation treatment for cancer is now planned to ensure that the maximum dosage of radiation is delivered to diseased tissue while surrounding healthy tissue is protected as much as possible.

Researchers believe that a retrovirus plays an indirect role in the development of Kaposi’s sarcoma, a rare cancer of the cells that line blood vessels in the skin and mucus membranes. Kaposi’s sarcoma often occurs in patients with AIDS (acquired immune deficiency syndrome). AIDS-related Kaposi’s sarcoma, however, has different characteristics and is treated differently than typical soft tissue sarcomas.

Studies have focused on genetic alterations that may lead to the development of soft tissue sarcomas. Scientists have also found a small number of families in which more than one member in the same generation has developed sarcoma. There have also been reports of a few families in which relatives of children with sarcoma have developed other forms of cancer at an unusually high rate. Sarcomas in these family clusters, which represent a very small fraction of all cases, may be related to a rare inherited genetic alteration.

Certain inherited diseases are associated with an increased risk of developing soft tissue sarcomas. For example, people with Li-Fraumeni syndrome (associated with alterations in the p53 gene) or von Recklinghausen’s disease (also called neurofibromatosis, and associated with alterations in the NF1 gene) are at an increased risk of developing soft tissue sarcomas.

Soft tissue sarcomas can arise almost anywhere in the body. About 50 percent occur in the extremities (the arms, legs, hands, or feet), 40 percent occur in the trunk (chest, back, hips, shoulders, and abdomen), and 10 percent occur in the head and neck.

The tables on pages 5 and 6 list several types of sarcomas that occur in adults and children.

Soft tissue sarcomas are relatively uncommon cancers. They account for less than 1 percent of all new cancer cases each year. In 2000, there will be an estimated 8,100 new cases of soft tissue sarcoma in the United States. Approximately 850 to 900 of these cases will occur among children and adolescents under age 20.

In their early stages, soft tissue sarcomas usually do not cause symptoms. Because soft tissue is relatively elastic, tumors can grow rather large, pushing aside normal tissue, before they are felt or cause any problems. The first noticeable symptom is usually a painless lump or swelling. As the tumor grows, it may cause other symptoms, such as pain or soreness, as it presses against nearby nerves and muscles.

The only reliable way to determine whether a soft tissue tumor is benign or malignant is through a surgical biopsy. Therefore, all soft tissue lumps that persist or grow should be biopsied. During this procedure, a doctor makes an incision or uses a special needle to remove a sample of tumor tissue. A pathologist examines the tissue under a microscope. If cancer is present, the pathologist can usually determine the type of cancer and its grade. The grade of the tumor is determined by how abnormal the cancer cells appear when examined under a microscope. The grade predicts the probable growth rate of the tumor and its tendency to spread. Low-grade sarcomas, although cancerous, are unlikely to metastasize. High-grade sarcomas are more likely to spread to other parts of the body.

In general, treatment for soft tissue sarcomas depends on the stage of the cancer. The stage of the sarcoma is based on the size and grade of the tumor, and whether the cancer has spread to the lymph nodes or other parts of the body (metastasized). Treatment options for soft tissue sarcomas include surgery, radiation therapy, and chemotherapy.

Surgery is the most common treatment for soft tissue sarcomas. If possible, the doctor may remove the cancer and a safe margin of the healthy tissue around it. Depending on the size and location of the sarcoma, it may occasionally be necessary to remove all or part of an arm or leg (amputation). However, the need for amputation rarely arises; no more than 10 percent to 15 percent of individuals with sarcoma undergo amputation. In most cases, limb-sparing surgery is an option to avoid amputating the arm or leg. In limb-sparing surgery, as much of the tumor is removed as possible, and radiation therapy and/or chemotherapy are given either before the surgery to shrink the tumor or after surgery to kill the remaining cancer cells.

Radiation therapy (treatment with high-dose X-rays) may be used either before surgery to shrink tumors or after surgery to kill any cancer cells that may have been left behind.

Chemotherapy (treatment with anticancer drugs) may be used with radiation therapy either before or after surgery to try to shrink the tumor or kill any remaining cancer cells. If the cancer has spread to other areas of the body, chemotherapy may be used to shrink tumors and reduce the pain and discomfort they cause, but is unlikely to eradicate the disease. The use of chemotherapy to prevent the spread of soft tissue sarcomas has not been proven to be effective. Patients with soft tissue sarcomas usually receive chemotherapy intravenously (injected into a blood vessel).

Doctors are conducting clinical trials in the hope of finding new, more effective treatments for soft tissue sarcomas, and better ways to use current treatments. Clinical trials are in progress at hospitals and cancer centers around the country. Clinical trials are an important part of the development of new methods of treatment. Before a new treatment can be recommended for general use, doctors conduct clinical trials to find out whether the treatment is safe for patients and effective against the disease.

Benign soft tissue tumours are lumps and bumps that are non-cancerous. Soft tissue is defined as the supportive or connective tissue of the body and includes fibrous connective tissue, bone, muscle, fat, blood/lymph vessels and the nervous system. All lumps are usually referred to as tumours whether they are benign or malignant. Benign soft tissue tumours are relatively common in the general population. Benign tumours cannot spread to other parts of the body but they can continue to grow at the original site where they can cause a problem by pressing on the surrounding organs. They can also be cosmetically unsightly. There are a number of different types of benign soft tissue tumour that I will explain below.

Lipomas

A lipoma is a benign tumour composed of fatty tissue. It is the most common benign soft tissue tumour and occurs in at least 1% of the population. The symptoms of a lipoma are usually a painless, slowly growing mass which is mobile and has a soft consistency on examination. Most lipomas occur in the superficial soft tissues but benign lipomas can occur deep to the connective tissue or intramuscular areas. Treatment of a simple lipoma is usually removal either because it is causing pressure on surrounding structures or for cosmetic reasons.  The possibility of a lipoma recurring is expected to be less than 5%; however, the recurrence rate can increase substantially with large deep-seated lipomas that infiltrate muscle. 

Haemangioma

Haemangioma is the most frequently encountered soft tissue tumour of the blood vessel system and accounts for approximately 7% of all benign soft tissue tumours. Infantile haemangiomas are present at or around birth and are commonly recognised birthmarks. Intramuscular haemangiomas are a less common variant which often occur during teenage or adult life. The lower extremity is the most common location for intramuscular haemangiomas. They constitute the most common benign tumour in the skeletal muscles. MRI can be very helpful in the diagnosisof intramuscular haemangioma. Treatment can include simple re-assurance when they cause no or little symptoms. For lesions that cause symptoms surgical removal or embolisation (where the feeding blood vessels are selectively blocked through a catheter introduced under X-ray guidance) can be considered.

Neurogenic tumour 

Benign peripheral nerve sheath tumours (PNST) are soft tissue neoplasms that develop from a nerve and subtypes include schwannomas and neurofibromas. Benign schwannoma is the most common tumour originating from peripheral nerves. Benign PNST can occur sporadically or as manifestations of genetic syndromes such asneurofibromatosis (NF) types 1 and 2. Schwannomas can develop in any nerve trunk in the entire body but are most commonly found in cranial nerves and in the peripheral nerves of the upper limb. Approximately 3% occurs in the abdomen. The clinical sign of a schwannoma arising within a nerve trunk of the upper or lower limb is often typical. Patients have a swelling which is painful to pressure; the tumour is mobile from side to side, but not in the vertical axis of the limb (selective mobility). Tapping on the lump can induce a painful prickling or tingling sensation in the area of the nerve. 

MR imaging is very helpful and can show a well-defined mass in relation to a nerve. A biopsy may be required if the diagnosis is in doubt after both a clinical examination and imaging, but this unfortunately can be very painful.

Benign schwannomas are best treated by marginal excision with nerve preservation if they become symptomatic or cause cosmetic embarrassment. These encapsulated neoplasms are located within the nerve and do not invade the nerve fibres. This allows marginal excision of the tumour whilst at the same time preserving the nerve involved.

Fibromatosis

Fibromatosis are rare benign tumours that have a propensity for locally aggressive behaviour and for invading surrounding structures but they do not have the potential to spread to other parts of the body. They can be painful. Fibromatosis can occur anywhere in the body, but most commonly affect three locations. Firstly the limb and limb girdle (shoulders, hips, buttocks), secondly the abdominal wall (most commonly in women and closely associated with a recent pregnancy) and lastly within the abdomen arising from the bowel wall. 

Fibromatosis of the limbs and limb girdle have a high local recurrence rate after complete surgical removal ranging from 24% to 77%. Abdominal wall tumours mostly occur in female patients and usually develop during or soon after pregnancy and can also develop in the scar from a caesarean section. In marked contrast to limb or limb girdle fibromatosis, tumours isolated to the abdominal wall very rarely recur after surgical removal.

Treatment is best performed in the context of a specialist multidisciplinary team, and as with other soft tissue tumours diagnosis is established by core needle biopsy. Most are slow-growing but some can behave aggressively.  Surgical removal with clear margins is the standard treatment, but observation does also have a role in some cases. For recurrent fibromatosis after previous surgical removal, further surgery with radiotherapyor systemic therapy (anti-inflammatory drugs, chemotherapy, or hormonal treatment) may be required.

Myositis ossificans

Myositis ossificans is a benign condition of bone formation. More than half of these cases develop after a traumatic event. Myositis ossificans occurs most commonly in the second and third decades of life and usually in extremities exposed to previous trauma such as blunt muscular trauma (contusion, muscular tears and strains). Symptoms often include pain, a palpable lump and muscle contractures with a decreased range of motion. Myositis ossificans frequently reabsorbs spontaneously and removal should only be carried out in patients with significant symptoms (continued pain, limited motion, or deterioration of function with matured ectopic bone) after a period of conservative treatment.

Glomus tumour

Glomus tumours are benign tumours mostly located in the hands and they can cause severe joint tenderness and pain. Most glomus tumours occur in the nail-base.

Dermatofibroma

Dermatofibroma are common benign skin tumours that cause lumps in the skin and frequently cause concern upon discovery. The causes of dermatofibroma may include a reaction to trauma such as insect bites but the precise cause is often unclear. They occur more frequently in women than men, most commonly in young adulthood. Usually a single nodule develops on an extremity, most commonly the lower legs, but lesions can occur at any skin site and individuals may have several lesions. Removal and biopsy is usually performed when uncertainty remains after an initial clinical examination.

Non-tumour conditions that can cause lumps and bumps

Ganglion cysts

A ganglion cyst is a swelling that often appears on or around joints and tendons in the wrist, hand or foot.  They are the most usual cause of a palpable lump in the wrist and hand; in the lower limbs the majority are related to the foot and ankle. Treatment includes reassurance and/or surgical removal.

Epidermoid and pilar cysts

Epidermoid and pilar cysts are small smooth cystic lumps under the skin surface (also called sebaceous cysts or trichilemmal cyst) and they represent the most common skin cysts. While they may occur anywhere on the body, they occur most frequently on the scalp, neck, face and trunk. Epidermoid cysts are usually slow-growing and symptomless although discharge of a foul-smelling material sometimes occurs. The cysts can become inflamed or infected, resulting in pain and tenderness. Surgical removal of a sebaceous cyst is a simple procedure and can often be performed under local anaesthetic. 

Haematomas 

A haematoma occurs when blood leaks outside the blood vessels and it can follow an injury or be spontaneous. Causes for the latter include a systemic bleeding predisposition (including anticoagulation therapy). Importantly, bleeding into a pre-existing soft tissue tumour has to be considered. A previous injury is often forgotten. Haematomas may mimic tumours by continuing to expand. Diagnosis can be accomplished by clinical history, imaging and core needle biopsy.

Abscesses

An abscess can often cause a painful soft tissue lump. An abscess is caused by an infection that results in a collection of pus within inflamed tissues. Treatment includes drainage and antibiotics.

Chronic inflammation or granulomatous lesions 

Chronic inflammation or granulomatous lesions can mimic soft tissue tumours. Diagnosis can be established by imaging and tissue biopsy. The typical radiological appearance in chronic inflammation or granulomatous lesions is very different from soft tissue tumours and appears to lack uniformity, with ill-defined margins on imaging. A definitive diagnosis can be established with core needle biopsy and laboratory analysis.

Characteristic Tumors ¹

Edwin D. Murphy

The tumors of the mouse described in this chapter have been selected primarily on the basis of frequency of occurrence among the available inbred strains and the amount of research interest shown in them, Many less frequent types repeatedly appear as incidental findings in tabulations of tumors of untreated mice of inbred strains. Some rare types that have occurred spontaneously in mice at The Jackson Laboratory have been included for completeness. Selected tumors that rarely occur spontaneously but are readily induced have been included, particularly tumors that can be induced by hormonal imbalance. Emphasis has been given to the induced tumors of types important in human pathology, More references have been cited for the less well known tumors than for the common types which have been extensively reviewed.

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.