Management of patients with lymphadenopathy

MANAGEMENT OF PATIENTS WITH LYMPHADENOPATHY

The Lymphatic System

The lymphatic system and the blood cell-forming system in the marrow are closely related. Most lymphocytes are in the lymph nodes and other parts of the lymphatic system such as the skin, spleen, tonsils and adenoids (special lymph nodes), intestinal lining, and in young people, the thymus. The lymphocytes circulate through channels called lymphatics that connect the lymph nodes scattered throughout the body. The lymphatic channels collect into large ducts that empty into a blood vessel. The lymphocytes enter the blood via these ducts. There are three types of lymphocytes. T lymphocytes (T cells) originate in the thymus, hence the designation “T.” The B lymphocytes (B cells) originate in the marrow in bone. (The “B” comes from the word “bursa,” an organ in birds that was first found to be the source of B lymphocytes.) B lymphocytes make antibodies in response to foreign antigens, especially microbes. Collections of B lymphocytes are present in the marrow, which is an important site for their function.

The T lymphocytes have several functions, including assisting B lymphocytes to make antibodies against invading bacteria, viruses, or other microbes. The antibodies attach to the microbe and in so doing make it possible for other white cells to ingest and kill them. The white cells recognizes the antibody and pull (ingest) it into the cell with its attached microbe. The cells can then kill and digest the microbes.

The third type of lymphocyte, natural killer or NK cells, attack virus-infected cells as a natural function without requiring antibody or other mediation. T cells and NK cells have other functions as well, and are important elements in studies that are designing immunotherapies to treat leukemia and other cancers.

LYMPHADENOPATHY GENERALIZED

1.                 M—Malformations include sickle cell anemia and other congenital hemolytic anemias, the reticuloendothelioses (Niemann–Pick disease, Hand–Schьller–Christian disease, and Gaucher disease), and lymphangiomas.

2.                 I—Inflammatory disorders constitute the largest group of lymphadenopathies. Breaking them down into subgroups according to the size of the organism further assists the recall.

1.                                         Viral illnesses include infectious mononucleosis, lymphogranuloma venereum, German measles, chickenpox, and viral upper respiratory illnesses. There are many other conditions in this category.

2.                                         Rickettsial diseases include typhus and Rocky Mountain spotted fever.

3.                                         Bacterial diseases include typhoid, plague, tuberculosis, skin infections, tularemia, meningococcemia, and brucellosis.

4.                                         Spirochetes includes syphilis and Borrelia vincentii.

5.                                         Parasites include malaria, filariasis, and trypanosomiasis.

6.                                         Fungi include histoplasmosis, disseminated coccidioidomycosis, and blastomycosis.

3.                 N—Neoplasms. Dissemination of almost every malignancy may cause generalized lymphadenopathy. The most likely ones to present with generalized lymphadenopathy, however, are lymphatic leukemia, monocytic leukemia, Hodgkin disease, and lymphosarcoma. Myelophthisic anemia must be considered too.

4.                 T—Toxic disorders that cause generalized lymphadenopathy are numerous. Dilantin toxicity may mimic Hodgkin disease. Drug allergies from sulfonamides, hydralazine, and iodides are just a few of the others.

Approach to the Diagnosis

Obviously, it is tempting simply to do a lymph node biopsy, but certain other procedures should be done first. If the patient is febrile, febrile agglutinins, Monospot test, blood cultures, and cultures of any other suspicious body fluid should be made. An FTA-ABS test should be done as well as a chest x-ray and tuberculin test to rule out tuberculosis. A blood count usually shows leukemia, but a bone marrow may be necessary to diagnose leukemia, Hodgkin disease, and the reticuloendothelioses. Other x-rays, skin tests, and special diagnostic procedures may be necessary.

Other Useful Tests

1.                 CBC (infection, leukemia)

2.                 Sedimentation rate (inflammation)

3.                 Chemistry panel (liver disease, kidney disease)

4.                 Brucellin antibody titer (brucellosis)

5.                 X-ray of the long bones (metastatic neoplasm)

6.                 Kveim test (sarcoidosis)

7.                 Brucellergen skin test (brucellosis)

8.                 Lyme disease antibody titer

9.                 Lymphangiogram (lymphosarcoma)

10.            CT scan of the abdomen and pelvis (Hodgkin disease, lymphoma)

11.            CT scan of the mediastinum (lymphoma, metastatic neoplasm)

12.            ANA analysis (collagen disease)

13.            Skin tests for fungi; (histoplasmosis, etc.)

 

Algorithm for the evaluation of a patient with lymphadenopathy. (HIV = human immunodeficiency virus; CBC = complete blood count; PPD = purified protein derivative; RPR = rapid plasma reagin; ANA = antinuclear antibody; HBsAg = hepatitis B surface antigen)

PHYSICAL EXAMINATION

When lymphadenopathy is localized, the clinician should examine the region drained by the nodes for evidence of infection, skin lesions or tumors. Other nodal sites should also be carefully examined to exclude the possibility of generalized rather than localized lymphadenopathy. This is an important aspect of the examination, as a study of primary care physicians found that generalized lymphadenopathy was identified in only 17 percent of the patients in whom it was present. Careful palpation of the submandibular, anterior and posterior cervical, supraclavicular, axillary and inguinal nodes can be accomplished in a short time and will identify patients with generalized lymphadenopathy.

Early symptomatic HIV infection includes persistent generalized lymphadenopathy, often the earliest symptom of primary HIV infection; oral lesions such as thrush and oral hairy leukoplakia; hematologic disturbances such as hypoproliferative anemia and thrombocytopenia; neurologic disorders such as aseptic meningitis; and dermatologic disorders such as varicella-zoster virus (shingles).

TABLE Lymph Node Groups: Location, Lymphatic Drainage and Selected Differential Diagnosis

Location	Lymphatic drainage	Causes
Submandibular	Tongue, submaxillary gland, lips and mouth, conjunctivae	Infections of head, neck, sinuses, ears, eyes, scalp, pharynx
Submental	Lower lip, floor of mouth, tip of tongue, skin of cheek	Mononucleosis syndromes, Epstein-Barr virus, cytomegalovirus, toxoplasmosiss
Jugular	Tongue, tonsil, pinna, parotid	Pharyngitis organisms, rubella
Posterior cervical	Scalp and neck, skin of arms and pectorals, thorax, cervical and axillary nodes	Tuberculosis, lymphoma, head and neck malignancy
Suboccipital	Scalp and head	Local infection
Postauricular	External auditory meatus, pinna, scalp	Local infection
Preauricular	Eyelids and conjunctivae, temporal region, pinna	External auditory canal
Right supraclavicular node	Mediastinum, lungs, esophagus	Lung, retroperitoneal or gastrointestinal cancer
Left supraclavicular node	Thorax, abdomen via thoracic duct	Lymphoma, thoracic or retroperitoneal cancer, bacterial or fungal infection
Axillary	Arm, thoracic wall, breast	Infections, cat-scratch disease, lymphoma, breast cancer, silicone implants, brucellosis, melanoma
Epitrochlear	Ulnar aspect of forearm and hand	Infections, lymphoma, sarcoidosis, tularemia, secondary syphilis
Inguinal	Penis, scrotum, vulva, vagina, perineum, gluteal region, lower abdominal wall, lower anal canal	Infections of the leg or foot, STDs (e.g., herpes simplex virus, gonococcal infection, syphilis, chancroid, granuloma inguinale, lymphogranuloma venereum), lymphoma, pelvic malignancy, bubonic plague

STDs= sexually transmitted diseases.

If lymph nodes are detected, the following five characteristics should be noted and described:

Size. Nodes are generally considered to be normal if they are up to 1 cm in diameter; however, some authors suggest that epitrochlear nodes larger than 0.5 cm or inguinal nodes larger than 1.5 cm should be considered abnormal. Little information exists to suggest that a specific diagnosis can be based oode size. However, in one series of 213 adults with unexplained lymphadenopathy, no patient with a lymph node smaller than 1 cm² (1 cm × 1 cm) had cancer, while cancer was present in 8 percent of those with nodes from 1 cm² to 2.25 cm² (1 cm × 1 cm to 1.5 cm × 1.5 cm) in size, and in 38 percent of those with nodes larger than 2.25 cm² (1.5 cm × 1.5 cm). In children, lymph nodes larger than 2 cm in diameter (along with an abnormal chest radiograph and the absence of ear, nose and throat symptoms) were predictive of granulomatous diseases (i.e., tuberculosis, cat-scratch disease or sarcoidosis) or cancer (predominantly lymphomas). These studies were performed in referral centers, and conclusions may not apply in primary care settings.

Pain/Tenderness. When a lymph node rapidly increases in size, its capsule stretches and causes pain. Pain is usually the result of an inflammatory process or suppuration, but pain may also result from hemorrhage into the necrotic center of a malignant node. The presence or absence of tenderness does not reliably differentiate benign from malignant nodes.⁴

Consistency. Stony-hard nodes are typically a sign of cancer, usually metastatic. Very firm, rubbery nodes suggest lymphoma. Softer nodes are the result of infections or inflammatory conditions. Suppurant nodes may be fluctuant. The term “shotty” refers to small nodes that feel like buckshot under the skin, as found in the cervical nodes of children with viral illnesses.

Matting. A group of nodes that feels connected and seems to move as a unit is said to be “matted.” Nodes that are matted can be either benign (e.g., tuberculosis, sarcoidosis or lymphogranuloma venereum) or malignant (e.g., metastatic carcinoma or lymphomas).

Location. The anatomic location of localized adenopathy will sometimes be helpful iarrowing the differential diagnosis. For example, cat-scratch disease typically causes cervical or axillary adenopathy, infectious mononucleosis causes cervical adenopathy and a number of sexually transmitted diseases are associated with inguinal adenopathy.

Supraclavicular lymphadenopathy has the highest risk of malignancy, estimated as 90 percent in patients older than 40 years and 25 percent in those younger than age 40.⁴ Having the patient perform a Valsalva’s maneuver during palpation of the supraclavicular fossae increases the chance of detecting a node. Lymphadenopathy of the right supraclavicular node is associated with cancer in the mediastinum, lungs or esophagus. The left supraclavicular (Virchow’s) node receives lymphatic flow from the thorax and abdomen, and may signal pathology in the testes, ovaries, kidneys, pancreas, prostate, stomach or gallbladder. Although rarely present, a paraumbilical (Sister Joseph’s) node may be a sign of an abdominal or pelvic neoplasm.

In patients with generalized lymphadenopathy, the physical examination should focus on searching for signs of systemic illness. The most helpful findings are rash, mucous membrane lesions, hepatomegaly, splenomegaly or arthritis. Splenomegaly and lymphadenopathy occur concurrently in many conditions, including mononucleosis-type syndromes, lymphocytic leukemia, lymphoma and sarcoidosis.

TABLE Evaluation of Suspected Causes of Lymphadenopathy

Disorder		Associated findings	Test
Mononucleosis-type syndromes		Fatigue, malaise, fever, atypical lymphocytosis
	Epstein-Barr virus*	Splenomegaly in 50% of patients	Monospot, IgM EA or VCA
	Toxoplasmosis*	80 to 90% of patients are asymptomatic	IgM toxoplasma antibody
	Cytomegalovirus*	Often mild symptoms; patients may have hepatitis	IgM CMV antibody, viral culture of urine or blood
Initial stages of HIV infection*		“Flu-like” illness, rash	HIV antibody
Cat-scratch disease		Fever in one third of patients; cervical or axillary nodes	Usually clinical criteria; biopsy if necessary
Pharyngitis due to group A streptococcus, gonococcus		Fever, pharyngeal exudates, cervical nodes	Throat culture on appropriate medium
Tuberculosis lymphadenitis*		Painless, matted cervical nodes	PPD, biopsy
Secondary syphilis*		Rash	RPR
Hepatitis B*		Fever, nausea, vomiting, icterus	Liver function tests, HBsAg
Lymphogranuloma venereum		Tender, matted inguinal nodes	Serology
Chancroid		Painful ulcer, painful inguinal nodes	Clinical criteria, culture
Lupus erythematosus*		Arthritis, rash, serositis, renal, neurologic, hematologic disorders	Clinical criteria, antinuclear antibodies, complement levels
Rheumatoid arthritis*		Arthritis	Clinical criteria, rheumatoid factor
Lymphoma*		Fever, night sweats, weight loss in 20 to 30% of patients	Biopsy
Leukemia*		Blood dyscrasias, bruising	Blood smear, bone marrow
Serum sickness*		Fever, malaise, arthralgia, urticaria; exposure to antisera or medications	Clinical criteria, complement assays
Sarcoidosis		Hilar nodes, skin lesions, dyspnea	Biopsy
Kawasaki disease*		Fever, conjunctivitis, rash, mucous membrane lesions	Clinical criteria
Less common causes of lymphadenopathy
Lyme disease*		Rash, arthritis	IgM serology
Measles*		Fever, conjunctivitis, rash, cough	Clinical criteria, serology
Rubella*		Rash	Clinical criteria, serology
Tularemia		Fever, ulcer at inoculation site	Blood culture, serology
Brucellosis*		Fever, sweats, malaise	Blood culture, serology
Plague		Febrile, acutely ill with cluster of tender nodes	Blood culture, serology
Typhoid fever*		Fever, chills, headache, abdominal complaints	Blood culture, serology
Still’s disease*		Fever, rash, arthritis	Clinical criteria, antinuclear antibody, rheumatoid factor
Dermatomyositis*		Proximal weakness, skin changes	Muscle enzymes, EMG, muscle biopsy
Amyloidosis*		Fatigue, weight loss	Biopsy

*—Causes of generalized lymphadenopathy.

EA = early antibody; VCA = viral capsid antigen; CMV = cytomegalovirus; HIV = human immunodeficiency virus; PPD = purified protein derivative; RPR = rapid plasma reagin; HBsAg = hepatitis B surface antigen; EMG = electromyelography.

Clinical Evaluation for Algorithm’s ‘Suggestive’ Branch

Laboratory tests that may be useful in confirming the cause of lymphadenopathy are listed in Table . The presence of certain characteristic clinical syndromes may help the physician determine a suspected cause of lymphadenopathy.

MONONUCLEOSIS-TYPE SYNDROMES

Patients with these syndromes present with lymphadenopathy, fatigue, malaise, fever and an increased atypical lymphocyte count. Mononucleosis is most commonly due to Epstein-Barr virus infection. The presence of the typical syndrome and positive results on a heterophilic antibody test (Monospot test) confirms the diagnosis. The most common cause of heterophil-negative mononucleosis is early Epstein-Barr virus infection. False-negative results on heterophilic antibody tests are especially common in patients younger than four years of age. Epstein-Barr virus infection may be confirmed by repeating the Monospot test in seven to 10 days. Rarely is it necessary to confirm the diagnosis with IgM viral capsid antigen or early antigen antibody titers.

If Epstein-Barr virus antibodies are absent, other causes of the mononucleosis syndrome should be considered. These include toxoplasmosis, cytomegalovirus infection, streptococcal pharyngitis, hepatitis B infection and acute human immunodeficiency virus (HIV) infection. Acute infections with cytomegalovirus and Toxoplasma may be identified with IgM serology for those organisms.

ULCEROGLANDULAR SYNDROME

This syndrome is defined by the presence of a skin lesion with associated regional lymphadenopathy. The classic cause is tularemia, acquired by contact with an infected rabbit or tick; more common causes include streptococcal infection (e.g., impetigo), cat-scratch disease and Lyme disease.

OCULOGLANDULAR SYNDROME

This syndrome involves the combination of conjunctivitis and associated preauricular nodes. Common causes include viral kerato-conjunctivitis and cat-scratch disease resulting from an ocular lesion.

HIV INFECTION

Enlargement of the lymph nodes that persists for at least three months in at least two extrainguinal sites is defined as persistent generalized lymphadenopathy and is common in patients in the early stages of HIV infection. Other causes of generalized lymphadenopathy in HIV-infected patients include Kaposi’s sarcoma, cytomegalovirus infection, toxoplasmosis, tuberculosis, cryptococcosis, syphilis and lymphoma.

Unexplained Lymphadenopathy

When, after the initial evaluation and after exploration of the “diagnostic” and “suggestive” branches of the algorithm, a cause for the lymphadenopathy remains unexplained, the physician must decide whether to pursue a specific diagnosis. The decision will depend primarily on the clinical setting as determined by the patient’s age, the duration of the lymphadenopathy and the characteristics and location of the nodes.

GENERALIZED LYMPHADENOPATHY

Because generalized lymphadenopathy almost always indicates that a significant systemic disease is present, the clinician should consider the diseases listed in and proceed with specific testing as indicated. If a diagnosis cannot be made, the clinician should obtain a biopsy of the node. The diagnostic yield of the biopsy can be maximized by obtaining an excisional biopsy of the largest and most abnormal node (which is not necessarily the most accessible node). If possible, the physician should not select inguinal and axillary nodes for biopsy, since they frequently show only reactive hyperplasia.

LOCALIZED LYMPHADENOPATHY

If the lymphadenopathy is localized, the decision about when to biopsy is more difficult. Patients with a benign clinical history, an unremarkable physical examination and no constitutional symptoms should be reexamined in three to four weeks to see if the lymph nodes have regressed or disappeared. Patients with unexplained localized lymphadenopathy who have constitutional symptoms or signs, risk factors for malignancy or lymphadenopathy that persists for three to four weeks should undergo a biopsy. Biopsy should be avoided in patients with probable viral illness because lymph node pathology in these patients may sometimes simulate lymphoma and lead to a false-positive diagnosis of malignancy.

Initial Management

Many patients worry about the cause of their abnormal lymph nodes. To adequately address their fears, the physician should ask the patient about his or her concerns and respond to questions about specific diagnoses. When biopsy is deferred, the physician should explain to the patient the rationale for waiting. Patients should be cautioned to remain alert for the reappearance of the nodes because lymphomatous nodes have been known to temporarily regress.

Final Comment

In most patients, lymphadenopathy has a readily diagnosable infectious cause. A diagnosis of less obvious causes can often be made after considering the patient’s age, the duration of the lymphadenopathy and whether localizing signs or symptoms, constitutional signs or epidemiologic clues are present. When the cause of the lymphadenopathy remains unexplained, a three- to four-week observation period is appropriate when the clinical setting indicates a high probability of benign disease.

Leukemia

Leukemia is a cancer of the marrow and blood. The earliest observations of patients who had marked elevation of their white cells by European physicians in the 19th century led to their coining the term weisses blut or white blood as a designation for the disorder. Later, the term leukemia, which is derived from the Greek words leukos, meaning white, and haima, meaning blood, was used to indicate the disease.

The major forms of leukemia are divided into four categories. The terms myelogenous or lymphocytic denote the cell type involved. Myelogenous and lymphocytic leukemia each have an acute or chronic form. Thus, the four major types of leukemia are acute or chronic myelogenous and acute or chronic lymphocytic leukemia.

Acute leukemia is a rapidly progressing disease that affects mostly cells that are unformed or immature (not yet fully developed or differentiated). These immature cells cannot carry out their normal functions. Chronic leukemia progresses slowly and permits the growth of greater numbers of more developed cells. In general, these more mature cells can carry out some of their normal functions.

The ability to measure additional specific features of cells has led to further subclassification of the major categories of leukemia. The categories and subsets allow the physician to decide what treatment works best for the cell type and how quickly the disease may progress.

Symptoms

nDamage to the bone marrow, by way of displacing the normal marrow cells with increasing numbers of malignant cells, results in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may become bruised, bleed excessively, or develop pinprick bleeds (petechiae).

Leukemia. Symptoms

nWhite blood cells, which are involved in fighting pathogens, may be suppressed or dysfunctional, putting the patient at the risk of developing infections.

nFinally, the red blood cell deficiency leads to anemia, which may cause dyspnea. All symptoms may also be attributable to other diseases; for diagnosis, blood tests and a bone marrow biopsy are required.

Some other related symptoms

nFever, chills, and other flu-like symptoms

·        Weakness and fatigue

·        Loss of appetite and/or weight

·        Swollen or bleeding gums

·        Neurological symptoms (headache)

·        Enlarged liver and spleen

 Leukemia

–         Leukemia is clinically and pathologically split into its acute and chronic forms

–        

 

 

Acute leukemia is a rapidly progressing disease that affects mostly cells that are unformed or immature (not yet fully developed or differentiated). These immature cells cannot carry out their normal functions.

–         Acute forms of leukemia can occur in children and young adults. (In fact, it is a more common cause of death for children than any other type of malignant disease.)

–         Immediate treatment is required in acute leukemias due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. If left untreated, the patient will die within months or weeks.

 

Chronic leukemia progresses slowly and permits the growth of greater numbers of more developed cells. In general, these more mature cells can carry out some of their normal functions.

–         Typically taking months to years to progress, the cells are produced at a much higher rate thaormal cells, resulting in many abnormal white blood cells in the blood.

–         Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy.

 

–         Furthermore, the diseases are classified according to the type of abnormal cell found most in the blood.

–         When leukemia affects lymphoid cells (lymphocytes and plasma cells), it is called lymphocytic leukemia.

–         When myeloid cells (eosinophils, neutrophils, and basophils) are affected, the disease is called myeloid ormyelogenous leukemia.

 

The major forms of leukemia are divided into four categories. The terms myelogenous or lymphocytic denote the cell type involved. Myelogenous and lymphocytic leukemia each have an acute or chronic form. Thus, the four major types of leukemia are acute or chronic myelogenous and acute or chronic lymphocytic leukemia.

 

Acute leukemias

Acute leukemias are clonal diseases of hematopoietic precursors with molecular genetic abnormalities. All hematopoietic cell lines may be affected. Proliferation of the leukemic cell clone replaces normal hematopoiesis in varying degrees. In acute myeloid leukemia (AML), it is most common for granulocytopoiesis and monocytopoiesis to be affected. Erythropoiesis is less frequently affected, and megakaryopoiesis rarely so. The distribution of the subtypes varies according to age. Acute lymphocytic leukemia (ALL) occurs predominantly in children, while AML has its peak in adults. The involvement of several myeloid cell lines is relatively common, but the simultaneous involvement of myeloid and lymphoid cell lines is very rare (hybrid and bilinear acute leukemias). WHO has recently proposed that the percentage of blasts in the bone marrow must be approximately 20 % to justify a diagnosis of acute leukemia. Examination of the peripheral blood is not essential for diagnosis but can provide important additional information. The diagnosis and classification (subtype assignment) always rely on the bone marrow. The most widely accepted system at present for the classification of AML is based on the criteria of the French-American- British (FAB) Cooperative Group and of the WHO.

 

Table 1. FAB classification of akute myeloid leukemia (AML), modified

 

  

Table 2. WHO classification of acute myeloid leukemias

 

 

 

Acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL may be distinguished from other malignant lymphoid disorders by the immunophenotype of the cells, which is similar to B- or T-precursor cells. Immunochemistry, cytochemistry, and cytogenetic markers also may aid in categorizing the malignant lymphoid clone.

Pathophysiology: The malignant cells of ALL are lymphoid precursor cells (ie, lymphoblasts) that are arrested in an early stage of development. This arrest is caused by an abnormal expression of genes, often as a result of chromosomal translocations. The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymph nodes.

Clinical picture

History:

·                     Patients with ALL present with either (1) symptoms relating to direct infiltration of the marrow or other organs by leukemic cells or (2) symptoms relating to the decreased production of normal marrow elements.

o                                            Infiltration of the marrow by massive numbers of leukemic cells frequently manifests as bone pain.

o                                            This pain can be severe and is often atypical in distribution.

·                     Uncommonly (10-20%), patients may present with left upper quadrant fullness and early satiety due to splenomegaly.

·                     Other patients, particularly those with T-cell ALL, present with symptoms related to a large mediastinal mass, such as shortness of breath.

·                     Although patients may present with symptoms of leukostasis (eg, respiratory distress, altered mental status) because of the presence of large numbers of lymphoblasts in the peripheral circulation, leukostasis is much less common in persons with ALL than in persons with AML and occurs only in patients with the highest WBC counts, ie, several hundred thousand per microliter.

·                     Patients with ALL also present with symptoms related to a depletion of normal marrow elements. Symptoms of anemia are common and include fatigue, dizziness, palpitations, and dyspnea upon even mild exertion.

·                     Patients with ALL often have decreased neutrophil counts, despite an increased total WBC count. As a result, they are at increased risk of infection. The prevalence and severity of infections are inversely correlated with the absolute neutrophil count, which is defined as the number of mature neutrophils plus bands per unit of volume. Infections are common when the absolute neutrophil count is less than 500/mL and are especially severe when it is less than 100/mL.

·                     Patients with ALL often have fever without any other evidence of infection. However, in these patients, one must assume that all fevers are from infections until proven otherwise because a failure to treat infections promptly and aggressively can be fatal. Infections are still the most common cause of death in patients undergoing treatment for ALL.

·                     Approximately 10% of patients with ALL have disseminated intravascular coagulation (DIC) at the time of diagnosis, usually as a result of sepsis. Consequently, some patients may present with hemorrhagic or thrombotic complications. Bleeding symptoms are usually more often the result of a coexisting thrombocytopenia caused by marrow replacement. The thrombocytopenia, however, tends to be less severe than that observed in patients with AML.

Physical:

·                     Patients commonly have physical signs of anemia, including pallor and a cardiac flow murmur.

·                     Fever and other signs of infection, including lung findings of pneumonia, can occur. Fever should be interpreted as evidence of infection, even in the absence of other signs.

·                     Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. A large number of ecchymoses is usually an indicator of a coexistent coagulation disorder such as DIC.

·                     Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy.

·                     Occasionally, patients have rashes resulting from infiltration of the skin with leukemic cells.

Causes:

·                     Less is known about the etiology of ALL in adults compared with AML. Most adults with ALL have no identifiable risk factors.

·                     An increased prevalence of ALL was noted in survivors of the Hiroshima atomic bomb but not in those who survived the Nagasaki atomic bomb. Most leukemias occurring after exposure to radiation are AML rather than ALL.

·                     Rare patients have an antecedent hematologic disorder (AHD) such as myelodysplastic syndrome (MDS) that evolves to ALL. However, most patients with MDS that evolves to acute leukemia develop AML rather than ALL.

·                     Increasingly, cases of ALL with abnormalities of chromosome band 11q23 following treatment with topoisomerase II inhibitors for another malignancy have been described. However, most patients who develop secondary acute leukemia after chemotherapy for another cancer develop AML rather than ALL.

Lab Studies:

·                     A CBC count with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with ALL can have a high, normal, or low WBC count, but usually exhibit neutropenia.

·                       

Pic.1 Small blasts. These may closely resemble lymphocytes but are distinguished by their finer chromatin structure and the occasional presence of nucleoli

 

 

 

Pic. 2 Different case showing blasts of varying sizes, some with pleomorphic nuclei. Panels a and b illustrate B-lineage ALL

 

 

Pic. 3. Peroxidase reaction. All lymphoblasts are negative and are interspersed with residual cells of granulocytopoiesis, whose proportion is more clearly demonstrated by the peroxidase reaction

 

·                     Abnormalities in the prothrombin time/activated partial thromboplastin time/fibrinogen/fibrin degradation products may suggest concomitant DIC, which results in an elevated prothrombin time, decreased fibrinogen levels, and the presence of fibrin split products.

·                     A review of the peripheral blood smear confirms the findings of the CBC count.

o                                            Circulating blasts are usually seen.

o                                            Schistocytes are sometimes seen if DIC is present.

·                     A chemistry profile is recommended.

o                                            Most patients with ALL have an elevated lactic dehydrogenase level and frequently have an elevated uric acid level.

o                                            Liver function tests and BUN/creatinine determinations are necessary prior to the initiation of therapy.

·                     Appropriate cultures, in particular blood cultures, should be obtained in patients with fever or with other signs of infection without fever.

Imaging Studies:

·                     Chest x-ray films may reveal signs of pneumonia and/or a prominent mediastinal mass in some cases of T-cell ALL.

·                     Multiple gated acquisition scan or ECG is needed when the diagnosis is confirmed because many chemotherapeutic agents used in the treatment of acute leukemia are cardiotoxic.

Other Tests:

·                     ECG is recommended prior to

·                     Histologic Findings:

French-American-British Classification

·                     L1 – Small cells with homogeneous chromatin, regular nuclear shape, small or absent nucleolus, and scanty cytoplasm; subtype represents 25-30% of adult cases

·                     L2 – Large and heterogeneous cells, heterogeneous chromatin, irregular nuclear shape, and nucleolus often large; subtype represents 70% of cases (most common)

·                     L3 – Large and homogeneous cells with multiple nucleoli, moderate deep blue cytoplasm, and cytoplasmic vacuolization that often overlies the nucleus (most prominent feature); subtype represents 1-2% of adult cases

The WHO classifies the L1 and L2 subtypes of ALL as either precursor B lymphoblastic leukemia/lymphoblastic lymphoma or precursor T lymphoblastic leukemia/lymphoblastic lymphoma depending on the cell of origin. The L3 subtype of ALL is included in the group of mature B-cell neoplasms, as the subtype Burkitt lymphoma/leukemia.

Cytogenetic abnormalities occur in approximately 70% of cases of ALL in adults. These abnormalities included balanced translocations as occur in cases of AML. However, abnormalities of chromosome number (hypodiploidy, hyperdiploidy) are much more common in ALL than in AML.

 

Table 3. Common Cytogenetic Abnormalities in ALL

 

Table 4. Effect of Chromosome Number on Prognosis

 

Eighty-five percent of cases of ALL are derived from B cells. The primary distinction is between (1) early (pro-B) ALL, which is TDT positive, CD10 (CALLA) negative, surface Ig negative; (2) precursor B ALL, which is TDT positive, CD10 (CALLA) positive, surface Ig negative; and (3) mature B cell (Burkitt) ALL, which is TdT negative, surface Ig positive. Fifteen percent of cases are derived from T cells. These cases are subclassified into different stages corresponding to the phases of normal thymocyte development. The early subtype is surface CD3 negative, cytoplasmic CD3 positive, and either double negative (CD4^–, CD8^–) or double positive (CD4⁺, CD8⁺). The latter subtype is surface CD3 positive, CD1a negative, and positive for either CD4 or CD8, but not both.

 

Table 5. Immunophenotyping of ALL Cells – ALL of B-Cell Lineage (85% of cases of adult ALL)

*Cytoplasmic immunoglobulin
†Surface immunoglobulin

Pic. 5. Diagnostic workup of a patient with pre–B-cell acute lymphoblastic leukemia. Bone marrow aspiration revealed French-American-British L2 morphology.

 

Table 6. Immunophenotyping of ALL Cells – ALL of T-Cell Lineage (15% of cases of adult ALL)

 

Treatment

Medical Care: Currently, only 20-30% of adults with ALL are cured with standard chemotherapy regimens. Consequently, all patients must be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy. Traditionally, the 4 components of ALL treatment are induction, consolidation, maintenance, and CNS prophylaxis. Other aspects of treatment are also discussed.

·                     Induction therapy

o                                            Standard induction therapy typically involves either a 4-drug regimen of vincristine, prednisone, anthracycline, and cyclophosphamide or L-asparaginase or a 5-drug regimen of vincristine, prednisone, anthracycline, cyclophosphamide, and L-asparaginase given over the course of 4-6 weeks.

o                                            Using this approach, complete remissions are obtained in 65-85% of patients. The rapidity with which a patient’s disease enters complete remission is correlated with treatment outcome.

o                                            In a large French study (French Group on Therapy for Adult Acute Lymphoblastic Leukemia 1987), patients with greater than 5% blasts in their bone marrow on day 15 had a lower response rate (34% vs 91%), worse disease-free survival, and worse overall survival than patients with low blast counts on day 15.

o                                            Several other studies have shown that patients whose disease is in complete remission within 4 weeks of therapy have longer disease-free survival and overall survival than those whose disease enters remission after 4 weeks of treatment.

·                     Consolidation therapy

o                                            The use of consolidation chemotherapy is supported by several studies. In 1987, Fiere et al compared consolidation therapy with daunorubicin and cytosine arabinoside (Ara-C) versus no consolidation therapy in adults with ALL. The 3-year, leukemia-free survival rate was 38% for subjects receiving consolidation and maintenance therapy compared with 0% for those receiving maintenance therapy without consolidation (P <.05).

o                                            In a 1984 study reported by Hoelzer et al, subjects whose disease was in remission after induction received consolidation therapy consisting of dexamethasone, vincristine, and doxorubicin (Adriamycin), followed by cyclophosphamide, Ara-C, and 6-thioguanine beginning at week 20. Subjects also received maintenance therapy with 6-mercaptopurine and methotrexate during weeks 10-20 and 28-130. The median remission of 20 months was among the longest reported at the time.

o                                            In the United Kingdom Acute Lymphoblastic Leukemia XA study, subjects were randomized to receive early intensification with Ara-C, etoposide, thioguanine, daunorubicin, vincristine, and prednisone at 5 weeks; late intensification with the same regimen at 20 weeks; both; or neither. The disease-free survival rates at 5 years were 34%, 25%, 37%, and 28%, respectively. These data suggest a benefit to early, rather than late, intensification.

o                                            One study by the Cancer and Leukemia Group B (CALGB) did not show a benefit to consolidation therapy. Subjects whose disease was in complete remission were randomized to receive maintenance therapy or intensification with 2 courses of Ara-C and daunorubicin followed by maintenance. Remission duration and overall survival were not affected by the randomization.

o                                            Because most studies showed a benefit to consolidation therapy, regimens using a standard 4- to 5-drug induction usually include consolidation therapy with Ara-C in combination with an anthracycline or epipodophyllotoxin.

·                     Maintenance therapy

o                                            The effectiveness of maintenance chemotherapy in adults with ALL has not been studied in a controlled clinical trial. However, several phase 2 studies without maintenance therapy have shown inferior results compared with historical controls.

o                                            A CALGB study of daunorubicin or mitoxantrone, vincristine, prednisone, and methotrexate induction followed by 4 intensifications and no maintenance was closed early because the median remission duration was shorter than in previous studies. A Dutch study using intensive postremission chemotherapy, 3 courses of high-dose Ara-C in combination with amsacrine (course 1), mitoxantrone (course 2), and etoposide (course 3), without maintenance, also yielded inferior results.

o                                            Although maintenance appears necessary, using a more intensive versus less intensive regimen does not appear to be beneficial. Intensification of maintenance therapy from a 12-month course of a 4-drug regimen compared with a 14-month course of a 7-drug regimen (Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto 0183) did not show a difference in disease-free survival between the 2 groups.

·                     CNS prophylaxis

o                                            In contrast to patients with AML, patients with ALL frequently have meningeal leukemia at the time of relapse. A minority of patients have meningeal disease at the time of initial diagnosis. As a result, CNS prophylaxis with intrathecal chemotherapy is essential.

o                                            Cortes analyzed the prevalence of CNS leukemia in 4 consecutive clinical trials at the M.D.Anderson Cancer Center.

§                                                                     In the first group, subjects received standard systemic chemotherapy without CNS prophylaxis. In the second, subjects received high-dose systemic chemotherapy and no CNS prophylaxis. The third group received high-dose systemic chemotherapy and intrathecal chemotherapy for high-risk subjects after achieving remission. The fourth group received hyperfractionated cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone (ie, hyper-CVAD protocol).

§                                                                     All subjects received intrathecal chemotherapy starting in induction. High-risk subjects received 16 intrathecal treatments, and low-risk subjects received 4 intrathecal treatments.

§                                                                     Overall, CNS relapse rates were 31%, 18%, 17%, and 3%, respectively.

o                                            This study demonstrated that high-dose systemic chemotherapy reduces CNS relapse; however, early intrathecal chemotherapy is necessary to achieve the lowest risk of CNS relapse.

·                     Treatment of mature B-cell ALL

o                                            Mature B-cell ALL is a special type, representing only 5% of adult patients with ALL. The hallmark of mature B-cell ALL is the presence of surface immunoglobulin on the lymphoblasts. Using conventional regimens, only 30-40% of patients enter complete remission and few patients survive long-term.

o                                            Newer short-term intensive therapies are showing improved results. A report of the hyper-CVAD regimen showed that disease in 93% of subjects entered complete remission, median survival was 16 months, and disease in 67% of subjects alive at 5 years.

o                                            In a 1996 report by Hoelzer et al, using regimens containing intensive cyclophosphamide and intermediate methotrexate or ifosfamide and high-dose methotrexate, complete remission rates were 63% and 74%, respectively. Disease-free survival rates increased to 50% and 71%, respectively, and overall survival increased to 50% compared with 0% for historical controls. Although previously these patients were referred for transplantation in first remission, many physicians now defer transplantation for the time of relapse because of these improved results.

·                     Burkitt ALL cell are CD20 positive. This allows for the addition of targeted therapy with rituximab. Many studies are have demonstrated improved efficacy, including prolonged survival, when rituximab is added to chemotherapy in these patients.

·                     Treatment of Philadelphia chromosome positive ALL

o                                            In the past, Ph+ ALL was treated with the same regimens as other types of ALL, with poor results. However, imatinib inhibits the bcr-abl fusion protein of Ph+ ALL and thus allows targeted therapy of this disease. As a single agent, imatinib has limited activity.

o                                            In an early study of patients with Ph+ ALL or CML in lymphoid blast crisis, only 4 of 20 patients had a complete response, and all patients progressed in less than 6 months. Several newer studies are demonstrating improved outcomes when imatinib is added to chemotherapy.

·                     Transplantation

o                                            Relatively few studies have compared transplantation with chemotherapy in adults with ALL. In a study by the Groupe Ouest Est d’etude des Leucenies et Autres Maladies du Sang, subjects younger than 45 years who had a sibling donor and whose disease was in remission were assigned to allogeneic transplantation. The remaining subjects received methylprednisolone, Ara-C, mitoxantrone, and etoposide chemotherapy followed by autologous bone marrow transplantation (BMT). For subjects undergoing allogeneic BMT, the rate of freedom from relapse was 70% at 4 years. However, because of transplant-related complications, the event-free survival rate was only 33%. No toxic deaths occurred in the subjects who underwent autologous BMT. However, the event-free survival rate was only 17% at 4 years because of a high rate of relapse.

o                                            The Bordeaux, Grenoble, Marseille, Toulouse group conducted a prospective nonrandomized trial comparing allogeneic with autologous BMT and also tested the impact of recombinant interleukin 2 after autologous BMT. The treatment arm was selected based on the availability of an HLA-matched sibling donor. The 3-year probability of disease-free survival was significantly higher in the group assigned to allogeneic BMT compared with subjects assigned to autologous BMT (68% vs 26%, respectively, P <.001). No benefit was observed with the addition of interleukin 2 after autologous BMT.

·                     Newer drugs

o                                            A number of new drugs are currently in development for the treatment of ALL. A few examples are as follows.

o                                            Clofarabine is a novel nucleoside analogue that was recently approved for the treatment of pediatric patients with refractory or relapsed ALL. Clofarabine inhibits DNA synthesis at both DNA polymerase I and at RNA reductase. Overall response rates average 25%.

o                                            506U78 (nelarabine [Arranon]) is a novel purine nucleoside that is a prodrug of ara-G. It was approved as an orphan drug by the FDA in October, 2005. Complete responses are reported in 31% of patients and in 54% of patients with T-cell ALL. The dose-limiting toxicity of this drug is neurotoxicity.

o                                            Dasatinib is a dual ABL-SARC inhibitor that differs from imatinib in that it binds to both the active and inactive form of the ABL kinase. Dasatinib is active against most bcr-abl mutations (except T315I) that render the kinase resistant to imatinib. In a preliminary study, 8 of 10 patients with Ph+ ALL had a major hematologic response and major cytogenetic response to dasatinib. However response durations were brief.

o                                            Supportive care with replacement of blood products

§                                                                     Patients have a deficiency in the ability to produce normal blood cells, and they need replacement therapy. This deficiency is temporarily worsened by the addition of chemotherapy. All blood products must be irradiated to prevent transfusion-related graft versus host disease, which is almost invariably fatal.

§                                                                     Packed red blood cells are given to patients with a hemoglobin level of less than 7-8 g/dL or at a higher level if the patient has significant cardiovascular or respiratory compromise.

§                                                                     Platelets are transfused if the count is less than 10,000-20,000/mL. Patients with pulmonary or gastrointestinal hemorrhage receive platelet transfusions to maintain a value greater than 50,000/mL. Patients with CNS hemorrhage are transfused to achieve a platelet count of 100,000/mL.

§                                                                     Fresh frozen plasma is given to patients with a significantly prolonged prothrombin time, and cryoprecipitate is given if the fibrinogen level is less than 100 g/dL.

o                                            Supportive care with antibiotics

§                                                                     The use of prophylactic antibiotics ieutropenic patients who are not febrile is controversial. However, most clinicians prescribe them for patients undergoing induction therapy. A commonly used regimen includes the following:

§                                                                                             Ciprofloxacin (500 mg PO bid)

§                                                                                             Fluconazole (200 mg PO daily) or itraconazole (200 mg PO bid)

§                                                                                             Acyclovir (200 mg PO 5 times/d) or Valtrex (500 mg PO daily)

§                                                                     Once patients taking these antibiotics become febrile, they are switched to intravenous antibiotics per above.

o                                            Supportive care with growth factors

§                                                                     The use of granulocyte colony-stimulating factor (G-CSF) during induction chemotherapy is supported by several studies. In a randomized phase 3 trial conducted by Ottoman, 76 subjects received either G-CSF or no growth factor with the induction chemotherapy (ie, cyclophosphamide, Ara-C, 6-mercaptopurine, intrathecal methotrexate, and cranial irradiation). The median duration of neutropenia was 8 days in subjects receiving G-CSF versus 12 days in subjects receiving no growth factor (P <.002), and the prevalence of nonviral infections was decreased by 50% in subjects receiving G-CSF. No difference in disease-free survival was observed between the 2 groups.

Surgical Care: Placement of a central venous catheter, such as a triple lumen, Broviac, or Hickman catheter, may be necessary.

Diet: A neutropenic diet is recommended.

·                     No fresh fruits or vegetables may be eaten.

·                     All foods must be cooked.

·                     Meats are to be cooked until well done.

Activity: Activity may occur as tolerated by the patient, but the patient may not participate in strenuous activities such as lifting or exercise.

The medications used to treat acute leukemia cause severe bone marrow depression. Only physicians specifically trained in their use should administer these medications. In addition, access to appropriate supportive care is required.

Drug Category: Corticosteroids — May be used during induction, consolidation, and/or maintenance therapy.

 

Further Inpatient Care:

·                     Patients require admission for induction chemotherapy and require readmission for consolidation chemotherapy or for the treatment of toxic effects of chemotherapy.

Further Outpatient Care:

·                     Maintenance therapy is administered in an outpatient setting.

·                     Patients come to the office to be monitored for disease status and the effects of chemotherapy.

Deterrence/Prevention:

·                     While talking chemotherapy, patients with leukemia should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections.

Complications:

·                     Death may occur as a result of uncontrolled infection or hemorrhage. This may occur even after the use of appropriate blood product and antibiotic support.

·                     The most common complication is failure of the leukemia to respond to chemotherapy. These patients do poorly because they usually do not respond to other chemotherapy regimens.

 

Acute Myelogenous Leukemia

Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.

Pathophysiology: The underlying pathophysiology consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities.

This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, blood, and, frequently, the spleen and liver.

Clinical diagnostic

Physical:

·                     Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present.

·                     Fever and other signs of infection can occur, including lung findings of pneumonia.

·                     Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. Petechiae are small, often punctate, hemorrhagic rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder such as DIC. Purpura is characterized by flat bruises that are larger than petechiae but smaller than ecchymoses.

·                     Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy. Occasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma may precede the development of marrow infiltration by AML (granulocytic sarcoma).

·                     Signs relating to leukostasis include respiratory distress and altered mental status.

Causes:

·                     Although several factors have been implicated in the causation of AML, most patients who present with de novo AML have no identifiable risk factor.

·                     Antecedent hematologic disorders

o                                            The most common risk factor is the presence of an AHD, the most common of which is MDS. MDS is a disease of the bone marrow of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years.

o                                            Patients with low-risk MDS (eg, refractory anemia with normal cytogenetics findings) generally do not develop AML, whereas patients with high-risk MDS (eg, refractory anemia with excess blasts-type 2) frequently do develop AML.

o                                            Other AHDs that predispose patients to AML include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, and polycythemia vera.

·                     Congenital disorders

o                                            Some congenital disorders that predispose patients to AML include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis.

o                                            Usually, these patients develop AML during childhood; rarely, some may present in young adulthood.

o                                            More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to AML. For example, polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML. Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both. Likewise, polymorphisms in glutathione S-transferase are associated with secondary AML following chemotherapy for other malignancies.

·                     Familial syndromes

o                                            Germ-line mutations in the gene AML1 (RUNX1, CBFA2) occur in the familial platelet disorder with predisposition for AML, an autosomal-dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and propensity to develop AML.

o                                            Mutation of CEBPA (the gene encoding CCAAT/enhancer binding protein, alpha; a granulocytic differentiation factor and member of the bZIP family) was described in a family with 3 members affected by AML.

o                                            Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia. However, cases of leukemia are less common than the solid tumors that generally characterize these syndromes.

·                     Environmental exposures

o                                            Several studies demonstrate a relationship between radiation exposure and leukemia.

o                                            Early radiologists (prior to appropriate shielding) were found to have an increased likelihood of developing leukemia.

o                                            Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia.

o                                            Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia.

o                                            Persons who smoke have a small but statistically significant (odds ratio, 1.5) increased risk of developing AML. In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke.

o                                            Exposure to benzene is associated with aplastic anemia and pancytopenia. These patients often develop AML. Many of these patients demonstrate M6 morphology.

·                     Prior exposure to chemotherapeutic agents for another malignancy

o                                            As more patients with cancer survive their primary malignancy and more patients receive intensive chemotherapy (including bone marrow transplantation [BMT]), the number of patients with AML increases because of exposure to chemotherapeutic agents. For example, the cumulative incidence of acute leukemia in patients with breast cancer who were treated with doxorubicin and cyclophosphamide as adjuvant therapy was 0.2-1.0% at 5 years.

o                                            Patients with prior exposure to chemotherapeutic agents can be divided into 2 groups: (1) those with prior exposure to alkylating agents and (2) those with exposure to topoisomerase-II inhibitors.

o                                            Patients with a prior exposure to alkylating agents, with or without radiation, often have a myelodysplastic phase prior to the development of AML. Cytogenetics testing frequently reveals -5 and/or -7 (5q- or monosomy 7).

o                                            Patients with a prior exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase. Cytogenetics testing reveals a translocation that involves chromosome band 11q23. Less commonly, patients developed leukemia with other balanced translocations, such as inversion 16 or t(15;17).

o                                            The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents/radiation exposure but only 9-12 months for topoisomerase inhibitors.

Lab Studies:

·                     CBC count with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with acute myelogenous leukemia (AML) can have high, normal, or low WBC counts.

·                     Prothrombin time/activated partial thromboplastin time/fibrinogen/fibrin degradation products

o                                            The most common abnormality is disseminated intravascular coagulation (DIC), which results in an elevated prothrombin time, a decreasing fibrinogen level, and the presence of fibrin split products.

o                                            Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of AML associated with DIC.

·                     Peripheral blood smear

o                                            Review of peripheral blood smear confirms the findings of the CBC count.

o                                            Circulating blasts are usually seen.

o                                            Schistocytes are occasionally seen if DIC is present.

 

Pict. 6 Two type I blasts. The cytoplasm is devoid of granules

 

Pict. 7 Blood smear in AML. Undifferentiated blasts with scant cytoplasm

  

Pict. 8 Peroxidase reaction in the same patient. All blasts in the field are strongly positive

 

Pict. 9 Bone marrow from the same patient shows pronounced maturation (more than 10 %)

 

Pict. 10 Very strong peroxidase reaction in the same patient. This case demonstrates that bone marrow examination is necessary for an accurate classification

  

·                     Chemistry profile

o                                            Most patients with AML have an elevated lactic dehydrogenase level and, frequently, an elevated uric acid level.

o                                            Liver function tests and BUN/creatinine level tests are necessary prior to the initiation of therapy.

o                                            Appropriate cultures should be obtained in patients with fever or signs of infection, even in the absence of fever.

·                     Perform HLA or DNA typing in patients who are potential candidates for allogeneic transplantation.

·                     Bone marrow aspiration (see pict. 20-34)

o                                            A blast count can be performed with bone marrow aspiration. Historically, by French-American-British (FAB) classification, AML was defined by the presence of more than 30% blasts in bone marrow. In the newer World Health Organization (WHO) classification, AML is defined as the presence of greater than 20% blasts in the marrow.

o                                            The bone marrow aspirate also allows evaluation of the degree of dysplasia in all cell lines.

·                     Flow cytometry (immunophenotyping) can be used to help distinguish AML from acute lymphocytic leukemia (ALL) and further classify the subtype of AML. The immunophenotype correlates with prognosis in some instances.

·                     Cytogenetic studies performed on bone marrow provide important prognostic information and are useful to confirm a diagnosis of APL, which bears the t(15;17) and is treated differently.

 

Pict. 11 Schematic diagram and partial karyotype of the translocation t(8;21)(q22;q22), found predominantly in the M2 subtype of AML

 

Pict. 12 Schematic diagram and partial karyotype of the t(3;12)(q26;p13), which is found in AML and MDS. Changes in the short arm of chromosome 12 (12p), like t(6;9) [below t(3;12)], may be associated with increased basophilic granulocytes in the bone marrow. A similar increase is occasionally found in the M4 subtype in the absence of detectable anomalies

  

·                     Recently, several molecular abnormalities that are not detected with routine cytogenetics have been shown to have prognostic importance in patients with AML. When possible, the bone marrow should be evaluated for the following abnormalities:

o                                            Fms-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene in persons with AML and is constitutively activated in one third of AML cases. Internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3 exist in 25% of AML cases. In other cases, mutations exist in the activation loop of FLT3. Most studies demonstrate that patients with AML and FLT3 mutations have a poor prognosis.

o                                            Mutations in CEBPA are detected in 15% of patients with normal cytogenetics findings and are associated with a longer remission duration and longer overall survival.

o                                            Mutations iucleophosmin (NPM) are associated with increased response to chemotherapy in patients with a normal karyotype.

·                     Gene-expression profiling is a research tool that allows a comprehensive classification of AML based on the expression pattern of thousands of genes.

Imaging Studies:

·                     Chest radiographs help assess for pneumonia and signs of cardiac disease.

·                     Multiple gated acquisition (MUGA) scan is needed once the diagnosis is confirmed because many chemotherapeutic agents used in treatment are cardiotoxic.

Histologic Findings: The older, more traditional, FAB classification is as follows:

·                     M0 – Undifferentiated leukemia

·                     M1 – Myeloblastic without differentiation

·                     M2 – Myeloblastic with differentiation

·                     M3 – Promyelocytic

·                     M4 – Myelomonocytic

o                                            M4eo – Myelomonocytic with eosinophilia

·                     M5 – Monoblastic leukemia

o                                            M5a – Monoblastic without differentiation

o                                            M5b – Monocytic with differentiation

·                     M6 – Erythroleukemia

·                     M7 – Megakaryoblastic leukemia

The newer WHO classification is as follows:

·                     AML with recurrent genetic abnormalities

o                                            AML with t(8;21)(q22;q22), (AML1/ETO)

o                                            AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13)(q22),(CBFB/MYH11)

o                                            APL with t(15;17)(q22;q12), (PML/RARa) and variants

o                                            AML with 11q23 (MLL) abnormalities

·                     AML with multilineage dysplasia

o                                            Following myelodysplastic syndrome (MDS) or MDS/myeloproliferative disease (MPD)

o                                            Without antecedent MDS or MDS/MPD but with dysplasia in at least 50% of cells in 2 or more lineages

·                     AML and MDS, therapy related

o                                            Alkylating agent or radiation-related type

o                                            Topoisomerase II inhibitor type

o                                            Others

·                     AML, not otherwise classified

o                                            AML, minimally differentiated

o                                            AML, without maturation

o                                            AML, with maturation

o                                            Acute myelomonocytic leukemia

o                                            Acute monoblastic or monocytic leukemia

o                                            Acute erythroid leukemia

o                                            Acute megakaryoblastic leukemia

o                                            Acute basophilic leukemia

o                                            Acute panmyelosis and myelofibrosis

o                                            Myeloid sarcoma

  

Table 7. Common Cytogenetic Abnormalities in AML

*Refers to 3-5 different cytogenetic abnormalities, depending on the classification used

 

Table 8. Cytogenetic Abnormalities in APL

 

Table 9. Immunophenotyping of AML Cells

 

Treatment

Medical Care: Current standard chemotherapy regimens cure only a minority of patients. As a result, evaluate all patients for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy as described below.

Treatment of acute myelogenous leukemia (excluding acute promyelocytic leukemia)

·                     Induction therapy: Various acceptable induction regimens are available.

o                                            The most common approach is called ”3 and 7,” which consists of 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone), combined with 100 mg/m² of arabinosylcytosine (araC) as a 24-hour infusion daily for 7 days. Idarubicin is given at a dose of 12 mg/m²/d for 3 days, daunorubicin at 45-60 mg/m²/d for 3 days, or mitoxantrone at 12 mg/m²/d for 3 days.

o                                            These regimens require adequate cardiac, hepatic, and renal function.

o                                            Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% enter remission following a second course of therapy.

o                                            Alternatively, high-dose araC combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose araC outside the setting of a clinical trial is considered controversial. However, 2 studies demonstrated improved disease-free survival rates in younger patients who received high-dose araC during induction.

·                     Consolidation therapy in younger patients: In patients aged 60 years or younger, treatment options for consolidation therapy include high-dose araC, autologous stem cell transplantation, or allogeneic stem cell transplantation.

o                                            High-dose araC therapy: Mayer et al conducted a randomized study of 3 different doses of araC in patients with acute myelogenous leukemia (AML) who achieved remission after standard “3 and 7”induction chemotherapy. Patients received 4 courses of araC at one of the following doses: (1) 100 mg/m²/d by continuous infusion for 5 days, (2) 400 mg/m²/d by continuous infusion for 5 days, or (3) 3 g/m² in a 3-hour infusion every 12 hours on days 1, 3, and 5. The probability of remaining in continuous complete remission (CR) after 4 years in patients aged 60 years or younger was 24% in the 100-mg group, 29% in the 400-mg group, and 44% in the 3-g group (P = .002). The outcome in older patients did not differ. Based on this study, high-dose araC for 4 cycles is a standard option for consolidation therapy in younger patients.

o                                            Stem cell transplantation

§                    In order to define the best postremission therapy for young patients, several large, randomized studies have compared allogeneic bone marrow transplantation (BMT), autologous BMT, and chemotherapy without BMT. Unfortunately, the results of these studies are conflicting.

§                    Some studies suggest an advantage to BMT.

·                    In a Dutch study, patients received either allogeneic BMT or autologous BMT based on the availability of a sibling donor matched via human leukocyte antigen (HLA). This study demonstrated a decreased rate of relapse at 3 years for patients receiving allogeneic BMT versus autologous BMT (34% vs 60%, respectively; P = .03) and an increased overall survival rate at 3 years for patients receiving allogeneic BMT versus autologous BMT (66% vs 37%, respectively; P = .05). However, the median age of patients who received allogeneic BMT was 10 years younger that those who received autologous BMT.

Ø                 Consolidation therapy in older patients: No standard consolidation therapy exists for patients older than 60 years. Options include a clinical trial, high-dose araC in select patients, or repeat courses of standard-dose anthracycline and araC (2 and 5; ie, 2 d of anthracycline and 5 d of araC). Select patients can be considered for autologous stem cell transplantation or nonmyeloablative allogeneic transplantation.

o                   Nonmyeloablative allogeneic transplantation

§                    Although allogeneic stem cell transplantation is a potentially curative treatment option for patients with AML, all age groups have a significant risk of death from the procedure. The risk of death increases with age, particularly in patients older than age 40 years. However, the median age of patients with AML is 65 years; therefore, only a small percentage of patients with AML are candidates for such aggressive therapy.

§                    Following ablative allogeneic transplantation, death occurs due to sepsis, hemorrhage, direct organ toxicity (particularly affecting the liver; ie, venoocclusive disease [VOD]), and graft versus host disease. In an attempt to reduce these toxicities, several investigators have developed new, less toxic conditioning regimens known as nonmyeloablative transplants or mini-transplants. These transplants use conditioning drugs that are immunosuppressive to allow engraftment of donor cells with less direct organ toxicity than that of standard transplants. Patients who receive these transplants often also have less severe acute graft versus host disease than patients who receive standard transplants. These two factors result in a day 100 mortality rate of less than 10%.

 

Therapy-Induced Changes in Acute Leukemias

 

Pict. 13  AML, M2 subtype, prior to treatment

 

 

Pict. 14 Severe cytopenia following two cycles of chemotherapy

   

Pict. 15 Higher-power view of a small focus of granulocytopoietic regeneration with young promyelocytes. It can be difficult to distinguish betweeormal and leukemic precursors at this stage

 

 

Pict. 16 Complete remission after an additional four weeks’ therapy

 

Newer therapies

Ø                 Gemtuzumab ozogamicin

o                   Gemtuzumab ozogamicin is a monoclonal antibody against CD33 (a molecule present on most AML cells but not oormal stem cells) conjugated to calicheamicin (a potent chemotherapy molecule). Gemtuzumab ozogamicin is currently approved by the Food and Drug Administration in the United States for the treatment of patients with CD33-positive AML in first relapse who are aged 60 years or older and who are not considered candidates for other cytotoxic chemotherapy.

o                   Sievers reported the results of gemtuzumab ozogamicin administration in 142 patients with AML who were in their first relapse and who had no history of an antecedent hematologic disorder (AHD). Sixteen percent of patients obtained a formal complete response. An additional 13% of patients met criteria for complete response but did not have the required platelet recovery. Toxicity included infusion reactions, myelosuppression, and hepatic toxicity.

o                   Later studies have shown that use of gemtuzumab ozogamicin either prior to or following stem cell transplantation is associated with an increased risk of VOD. Additional studies have demonstrated that VOD occurs in patients who receive gemtuzumab ozogamicin but do not undergo stem cell transplantation. Newer studies are investigating the use of gemtuzumab ozogamicin in combination with other chemotherapy agents and in patients with newly diagnosed AML. Although gemtuzumab ozogamicin is an active drug, the response rate is lower than that obtained with standard “3 and 7”chemotherapy.

Complications:

·                     Death may occur because of uncontrolled infection or hemorrhage. This may happen even after use of appropriate blood product and antibiotic support.

·                     The most common complication is failure of the leukemia to respond to chemotherapy. The prognosis for these patients is poor because they usually do not respond to other chemotherapy regimens.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) results from an acquired injury to the DNA of a single cell, a lymphocyte, in the marrow. This injury is not present at birth. Scientists do not yet understand what produces this change in the DNA of CLL patients.

This change in the cell’s DNA confers a growth and survival advantage on the cell, which becomes abnormal and malignant (leukemic). The result of this injury is the uncontrolled growth of lymphocytic cells in the marrow, leading invariably to an increase in the number of lymphocytes in the blood. The leukemic cells that accumulate in the marrow in chronic lymphocytic leukemia do not impede normal blood cell production as profoundly as in the case of acute lymphocytic leukemia. This important distinction from acute leukemia accounts for the less severe early course of the disease.

Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. It is the most common form of leukemia found in adults in Western countries.

 

Frequency

·        In the US: More than 17,000 new cases are reported every year.

·        Internationally: Unlike the incidence of CLL in the Western countries, which is similar to that of the United States, the disease is extremely rare in Asian countries (ie, China, Japan), where it is estimated to comprise only 10% of all leukemias.

 

Race: The incidence is higher among whites compared to African Americans.

 

Sex: The incidence is higher in males than in females, with a male-to-female ratio of 1.7:1.

 

Age:

·        CLL is a disease that primarily affects elderly individuals, with the majority of cases reported in individuals older than 55 years.

·        The incidence continues to rise in those older than 55 years.

·        Recently, individuals aged 35 years or younger are being diagnosed more frequently.

Causes and Risk Factors

 As in the case of most malignancies, the exact cause of CLL is uncertain.

The protooncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis (programmed cell death) in the affected lymphoid cells.

CLL is an acquired disorder, and reports of truly familial cases are exceedingly rare.

Unlike the other three major types of leukemia, chronic lymphocytic leukemia is not associated with high-dose radiation or benzene exposure. First-degree relatives of patients with the disease have about a threefold greater likelihood of getting the disease than other people. This should be put into perspective, however. For example, the 60-year-old sibling or offspring of a patient with chronic lymphocytic leukemia would have three chances in 10,000 of developing the disease compared with the one chance in 10,000 for a 60-year-old person without a family history of the disease. The disease is very uncommon in individuals under 45 years of age. At the time of diagnosis, 95 percent of patients are over age 50, and the incidence of the disease increases dramatically thereafter (see Figure 3).

  

Symptoms and Signs

Early in the disease, chronic lymphocytic leukemia often has little effect on a person’s well being. The disease may be discovered after finding an abnormal blood count during the course of a periodic medical examination or while the patient is under care for an unrelated condition. The report of an elevated white cell count is the most common clue that leads a physician to consider the diagnosis of chronic lymphocytic leukemia.

The symptoms of chronic lymphocytic leukemia usually develop gradually. Patients tire more easily and may feel short of breath when physically active, as a result of anemia. They may lose weight. The leukemic lymphocytes (white cells) can accumulate in the lymphatic system and the lymph nodes and spleen may become enlarged. Patients may experience infections, sometimes recurrent, of the skin, lungs, kidneys, or other sites.

Bypass of CLL has three stages:

1. Initial (slight increasing of lymphatic nodes one or two groups, leucocytosis no more than 30 – 50 х 10⁹/l, working capacities preserved.

2. Unrolled (increasing leucocytosis, progressing generalized enlargement of lymph nodes, relapsinginfections, and autoimmune cytopenia).

3. Terminal – malignant transformation with expanding of leucosis process out of the borders of hemopoetic system.

 

Basis of clinical diagnostics of CLL is lymphadenopathy, splenomegaly, hepatomegaly, infiltration by tumoral lymphocytes of pleura, gastrointestinal tract (with simulation of stomach tumor, intestinal polyposis), prostate, bones and joint with development of osteoporosis and osteolisis of vertebra and pelvic bones; perivascular infiltration of retine of eye, middle ear, vestibular apparatus, nervous system (hemiplegia, meningisms, paralysis of cranial nerves), skin (lymphocytic tumoral erythema, macropapules, exematous placodes, rarely – specific skins leukemia’s, erythrodermia, prurigo). From general features – hyperhydrosis, weight loss, undue fatigue.

 

Physical:

Ø     Localized or generalized lymphadenopathy

Ø     Splenomegaly (30-40% of cases)

Ø     Hepatomegaly (20% of cases)

Ø     Petechiae

Ø     Pallor

Diagnosis

To diagnose the disease, the blood and, in most cases, the marrow cells are examined. The white cell count is increased in the blood. The increase is the result of an increase in blood lymphocytes. A marrow examination also will show an increase in the proportion of lymphocytes, often accompanied by some decrease in the normal marrow cells. In addition, a sample of marrow cells is examined to determine if there is an abnormality of chromosomes. The examination of cells to determine if an abnormality of chromosomes is present is referred to as a cytogenetics analysis. Low platelet counts and low red cell counts (anemia) may be present but are usually only slightly decreased in the early stage of the illness.

  

Lab Studies

 

·CBC count with differential shows absolute lymphocytosis with more than 5000 lymphocytes/mL. Some authors consider this to be a prerequisite for the diagnosis of CLL and classify cases that would otherwise meet the criteria as small lymphocytic lymphoma/diffuse well-differentiated lymphoma.

·Microscopic examination of the peripheral blood smear is indicated to confirm lymphocytosis. It usually shows the presence of smudge cells, which are artifacts due to damaged lymphocytes during the slide preparation.

·Peripheral blood flow cytometry is the most valuable test to confirm CLL.

·It confirms the presence of circulating clonal B-lymphocytes expressing CD5, CD19, CD20(dim), CD 23, and an absence of FMC-7 staining.

·Consider obtaining serum quantitative immunoglobulin levels in patients developing repeated infections because monthly intravenous immunoglobulin administration in patients with low levels of immunoglobulin G (<500 mg) may be beneficial in reducing the frequency of infectious episodes.

·The differential diagnosis of CLL includes several other entities, such as hairy cell leukemia, which is moderately positive for surface membrane immunoglobulins of multiple heavy-chain classes and typically negative for CD5 and CD21. Prolymphocytic leukemia has a typical phenotype that is positive for CD19, CD20, and surface membrane immunoglobulin and negative for CD5. Large granular lymphocytic leukemia has a natural killer cell phenotype (CD2, CD16, and CD56) or a T-cell immunotype (CD2, CD3, and CD8). The pattern of positivity for CD19, CD20, and the T-cell antigen CD5 is shared only by mantle cell lymphoma.

Pict. 17 Peripheral blood smear showing CLL cells

 

Pict. 18 This is a microscopic view of bone marrow from a person with chronic lymphocytic leukemia; it shows predominantly small, mature lymphocytes

 

Imaging Studies:

·Liver/spleen scan may demonstrate splenomegaly.

·Computed tomography of chest, abdomen, or pelvis generally is not required for staging purposes. However, be careful to not miss lesions such as obstructive uropathy or airway obstruction that are caused by lymph node compression on organs or internal structures.

 

Picture 19. Peripheral smear of a patient with chronic lymphocytic leukemia, small lymphocytic variety.

 

Picture 20. This is a peripheral smear of a patient with chronic lymphocytic leukemia, showing the large lymphocytic variety. Smudge cells also are observed. Smudge cells are the artifacts produced by the lymphocytes damaged during the slide preparation.

 

Procedures:

·Bone marrow aspiration and biopsy with flow cytometry is not required in all cases but may be necessary in selected cases to establish the diagnosis and to assess other complicating features such as anemia and thrombocytopenia. For example, bone marrow examination may be necessary to distinguish between thrombocytopenia of peripheral destruction (in the spleen) and that due to marrow infiltration.

·Consider a lymph node biopsy if lymph node(s) begin to enlarge rapidly in a patient with known CLL to assess the possibility of transformation to a high-grade lymphoma. When such transformation is accompanied by fever, weight loss, and pain, it is termed Richter syndrome.

   

Determining Disease Stage

CLL patients are assessed as having a specific stage of disease to judge disease progression and the need for treatment. Several staging classifications have been proposed. The Rai or Binet staging systems are commonly used. These systems consider:

·                     The elevation of blood and marrow lymphocyte counts;

·                     The size and distribution of lymph nodes;

·                     The spleen size;

·                     The degree of anemia and the extent of the decrease of the blood platelet count.

Staging:

Two staging systems are in common use, the Rai-Sawitsky in the United States and the Binet in Europe. Neither is completely satisfactory, and both have been often modified. Because of its historical precedent and wide use, the Rai-Sawitsky system is described first, followed by the Binet. The International Workshop on Chronic lymphocytic Leukemia (IWCLL) system is listed last.

The Rai-Sawitsky staging system divides CLL into 5 Stages, 0-IV.

Ø     Stage 0 is lymphocytosis in the blood and marrow only, with a survival of longer than 120 months.

Ø     Stage I is lymphocytosis and adenopathy, with a survival of 95 months.

Ø     Stage II is lymphocytosis plus splenomegaly and/or hepatomegaly, with a survival of 72 months.

Ø     Stage III is lymphocytosis plus anemia (hemoglobin <10 g), with a survival of 30 months.

Ø     Stage IV is lymphocytosis plus thrombocytopenia (platelets <100,000), with a survival of 30 months.

 

The Binet staging system uses 3 stages, A, B, and C.

Ø     Stage A requires a hemoglobin of greater than or equal to 100 g/L, platelets greater than or equal to 100 X 10-9, and fewer than 3 lymph node areas involved (Rai-Sawitsky stages 0, I, II). Survival is longer than 120 months.

Ø     Stage B requires hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved (Rai-Sawitsky stages I and II). Survival is 61 months.

Ø     Stage C is a hemoglobin less than 100 g/L, platelets less than 100 X 10-9, or both (Rai-Sawitsky stages III and IV). Survival is 32 months.

 

The main principles of CLL treatment:

Ø     Patients’ regimen.

Ø     Cytostatic therapy.

Ø     Medical lymphocytopheresis.

Ø     Radial therapy.

Ø     Splenectomy

Ø     Glucocorticoid agents.

Ø     Treatment of infectious complications.

Treatment of stage I, stage II, stage III, and stage IV chronic lymphocytic leukemia may include the following:

Ø    Watchful waiting when there are few or no symptoms.

Ø    Monoclonal antibody therapy.

Ø    Chemotherapy with 1 or more drugs, with or without steroids or monoclonal antibody therapy.

Ø    Low-dose external radiation therapy to areas of the body where cancer is found, such as thespleen or lymph nodes.

Ø    A clinical trial of chemotherapy and biologic therapy with stem cell transplant.

Ø    A clinical trial of biologic therapy.

Ø    Treatment of refractory chronic lymphocytic leukemia may include the following:

Ø    A clinical trial of chemotherapy with stem cell transplant.

Ø    A clinical trial of a new treatment.

 

Chemotherapy
The drugs most commonly used to treat progressive chronic lymphocytic leukemia are shown in Table 11. Drug combinations are sometimes used, depending on the patient’s health status, age, and the apparent rapidity of disease progression. Fludarabine or cladribine are usually the first drugs used because clinical trials have found them to be more effective than other options.

 

 

Patients at stage 0 whose disease is stable require only periodic follow-up. Early treatment has not been demonstrated to be advantageous.

 

Ø     Prednisolone alone, usually in a dose of 20-60 mg daily initially, with subsequent gradual dose reduction, may be useful in patients with autoimmune manifestations of the disease.

Ø     Nucleoside analogs (ie, fludarabine, cladribine, and pentostatin) include a new group of drugs with major activity against indolent lymphoid malignancies, including CLL.

Ø     Fludarabine is the most extensively studied and currently is the most commonly used second-line therapy in CLL.

Ø     Responses to treatment with chlorambucil and prednisone are observed in 38-47% of patients.

Ø     Patients treated with fludarabine have much higher rates (80%) of overall responses and a 37% complete remission rate.

Ø     Studies using purine analogs, especially fludarabine, compared to alkylator-based therapies have shown that the response rates are superior and the progression-free interval is longer, but evidence to show prolonged overall survival is premature.

Ø     The combination of fludarabine and cyclophosphamide has shown higher response rates, but direct comparative trials of fludarabine and cyclophosphamide to fludarabine alone are lacking.

Ø     The combination of fludarabine and chlorambucil recently has been shown to result in more infections than either single agent alone.

Ø     Various combination regimens have shown improved response rates in several randomized trials but failed to show any survival advantage. Common combination regimens include chlorambucil and corticosteroids; cyclophosphamide, doxorubicin, and prednisone (CAP); cyclophosphamide, vincristine, and prednisone (CVP); and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

Ø     Chlorambucil (alkylating agent) and fludarabine (antimetabolite) are commonly used in the treatment of CLL. Purine analogs and, in particular, fludarabine are very active against CLL. Fludarabine produces remissions in a significant proportion of patients. It appears to induce apoptosis in malignant lymphocytes upon exposure.

Ø     Chemotherapy for CLL typically is given in an outpatient setting.

Ø     Some patients require admission if they develop febrile neutropenia.

Ø     This is treated in the usual fashion by giving broad-spectrum intravenous antibiotics after obtaining blood cultures.

Ø     The antibiotics commonly used on empiric grounds are ceftazidime, cefepime, or imipenem.

Ø     If patients have indwelling central venous access devices and appear septic, consider adding vancomycin.

 

· Alkylating agents — These agents inhibit cell growth and proliferation.

 

· Nucleotide analogs

· Fludarabine (Fludara) — Nucleotide analog of vidarabine converted to 2-fluoro-ara-A that enters the cell and is phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis.

· Antineoplastic agents — Treat by inhibiting key factors responsible for neoplastic transformation of cells.

· Alemtuzumab (Compath) — Monoclonal antibody against CD52, an antigen found on B-cells, T-cells, and almost all CLL cells. Binds to the CD52 receptor of the lymphocytes, which slows the proliferation of leukocytes.

 

Monoclonal Antibody Therapy

Several monoclonal antibodies that kill malignant lymphocytes and were introduced as treatments for lymphoma may be useful in the treatment of CLL (Table 2). These antibodies are made by biotechnology methods and target the leukemic lymphocytes, causing them to die after attachment. Most chemotherapeutic agents affect cells of normal tissues as well as the CLL cells. The monoclonal antibodies may affect related, normal lymphocytes but spare most other tissues, limiting their undesirable effects. On average, the side effects are less when the monoclonal antibodies rituximab (Rituxan^®) or alemtuzumab (Campath^®) are used. (These agents are the two monoclonal antibodies that are most useful in treating CLL.)

Infusion of monoclonal antibodies into a vein may cause transient fever, chills, and low blood pressure. The monoclonal antibodies target a protein on the lymphocyte cell surface. In the case of rituximab, the target is referred to as CD20 and in the case of alemtuzumab, the target is CD52. These monoclonal antibodies have been used most frequently in CLL patients who do not or no longer respond to chemotherapy. Because they have a very good effect in a proportion of patients, they are being studied for use as initial treatment either alone or with chemotherapy.

Therapy with monoclonal antibodies has been evaluated in patients with CLL. The most useful agent in clinical trials so far appears to be CAMPATH-1H, an antibody directed at CD52. Rituxan (rituximab) also is effective as a second-line or third-line treatment and may assume a more prominent role in the future.

Stem Cell Transplantation

This is a treatment option for carefully selected younger patients who can be matched with a marrow donor. A special form of stem cell transplantation that uses very low doses of pretreatment radiation and/or chemotherapy to prepare the patient to receive the donor marrow is being studied. This treatment is referred to as nonablative or mini transplant because it does not lead to severe decreases in blood cell counts and can be used in older persons. It does not ablate or wipe out the blood forming function of the marrow. The beneficial effects develop gradually over months and are thought to result from an immune attack by the donor’s lymphocytes against the chronic leukemia cells. Eventually the donor marrow and immune cells become dominant. This approach is experimental.

Complications and Their Treatment

·                     Pyo-inflammatory.

·                     Autoimmune (autoimmune hemolytic anemia, autoimmune trombocytopenia).

 

·–Hypogammaglobinemia and impaired T-cell function associated with CLL predispose patients to potentially serious infections. Patients who demonstrate a pattern of repeated infections, such as pneumonia and septicemia, should be treated monthly with prophylactic parenteral gamma globulin.

·–Anemia secondary to bone marrow involvement with CLL, splenic sequestration of red blood cells, and autoimmune hemolytic anemia associated with a positive Coombs test are included in the differential diagnosis of a patient with anemia who has CLL.

·–Thrombocytopenia: The causes of low platelets in patients with CLL are very similar to the causes of anemia in patients with CLL and include bone marrow involvement, splenic sequestration, and immune thrombocytopenia.

Recurrent infections are a frequent complication for patients with chronic lymphocytic leukemia. A higher risk of infections results when chemotherapy depresses certain infection-fighting white cells in the blood, specifically the phagocytes (microbe-eating) white cells. The deficiency of phagocytes permits bacteria and fungi to establish infections. Antibiotic therapy is usually required to treat bacterial or fungal infections during the course of the disease. Very low neutrophil and monocyte (phagocyte) counts, along with the inability of the patient’s leukemic lymphocytes to make antibodies (immunoglobulins), combine to greatly heighten the risk of infections. Patients with recurrent infections may also receive injections of gamma globulin on a regular basis in order to correct the patient’s immune deficiency.

Clinical supervision provides each 2 months a blood test, regimen, that excludes the physical overloads, full value feeding, sanation of hearths of chronic infection, cytostatyc therapy by sustaining doses of drugs, to which remission was achieved, general strengthen therapy.

 Chronic myelogenous leukemia

 

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells. CML is a tumor arisen from one mutate predecessors-cells of mielopoiesis, morphological substrate of which, as a rule, is three- sprouts proliferation, which displays that with prevalentsurplus excrescence of cells of granulocytes row, also has a place moderate cell proliferation of erytrocytes and megacariocytes sprouts.  This peculiarity is associated with that these sprouts develop from one matter – predecessors-cells of mielopoiesis.

 

Causes:

· The initiating factor of CML is still unknown, but exposure to irradiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki.

· Other agents, such as benzene, are possible causes.

Among etiological factors the most essential are physical and chemical mutagens, viruses, congenital or acquireed defects of immune defense. However in majority of cases (87 %) the cause of  beginnings of leucocytosis growth is chromosomal pathology (Philadelphia chromosome).

In some cases the conditions of “slip out” are created of mutant from under immune control. As a result, happened to be outside of organism control, a mutant cell continues uncontrolledly to “reproductive”, that brings to fast accumulation of tumoral tissues and forcing out healthy haemopoiesis.

 

 · Most patients present in the chronic phase, characterized by splenomegaly and leukocytosis (see Image below) with generally few symptoms. This phase is easily controlled by medication. The major goal of treatment during this phase is to control symptoms and complications resulting from anemia, thrombocytopenia, leukocytosis, and splenomegaly. Newer forms of therapy aim at delaying the onset of the accelerated or blastic phase.

 

Picture 22. Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen.

 

· After an average of 3-5 years, the disease usually evolves into the blast crisis, which is marked by an increase in the bone marrow or peripheral blood blast count or by the development of soft tissue or skin leukemic infiltrates. Typical symptoms are due to increasing anemia, thrombocytopenia, basophilia, a rapidly enlarging spleen, and failure of the usual medications to control leukocytosis and splenomegaly. The manifestations of blast crisis are similar to those of acute leukemia. Treatment results are unsatisfactory, and most patients succumb to the disease once this phase develops. In approximately two thirds of cases, the blasts are myeloid. However, in the remaining one third of patients, the blasts exhibit a lymphoid phenotype, further evidence of the stem cell nature of the original disease. Additional chromosomal abnormalities are usually found at the time of blast crisis, including additional Ph chromosomes or other translocations.

·  In many patients, an accelerated phase occurs 3-6 months before the diagnosis of blast crisis. Clinical features in this phase are intermediate between the chronic phase and blast crisis.

 CLINICAL

History:

· The clinical manifestations of CML are insidious and are often discovered incidentally when an elevated WBC count is revealed by a routine blood count or when an enlarged spleen is revealed during a general physical examination.

· Nonspecific symptoms of tiredness, fatigue, and weight loss may occur long after the onset of the disease. Loss of energy and decreased exercise tolerance may occur during the chronic phase after several months.

· Patients often have symptoms related to enlargement of the spleen, liver, or both.

o  The large spleen may encroach on the stomach and cause early satiety and decreased food intake. Left upper quadrant abdominal pain described as “gripping” may occur from spleen infarction. The enlarged spleen may also be associated with a hypermetabolic state, fever, weight loss, and chronic fatigue.

O  The enlarged liver may contribute to the patient’s weight loss.

·  Some patients may have low-grade fever and excessive sweating related to hypermetabolism.

·  The disease has 3 clinical phases, and it follows a typical course of an initial chronic phase, during which the disease process is easily controlled; followed by a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which is usually fatal.

O Most patients are diagnosed while still in the chronic phase. The WBC count is usually controlled with medication (hematologic remission). This phase varies in duration depending on the maintenance therapy used. It usually lasts 2-3 years with hydroxyurea (Hydrea) or busulfan therapy, but it has lasted for longer than 9.5 years in patients who respond well to interferon alfa therapy. Recently, the addition of imatinib mesylate has dramatically improved the duration of hematologic and indeed cytogenetic remissions.

O Some patients progress to a transitional or accelerated phase, which may last for several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase is characterized by poor control of the blood counts with myelosuppressive medication and the appearance of peripheral blast cells (>15%), promyelocytes (>30%) (see Image below), basophils (>20%), and platelet counts less than 100,000 cells/mL unrelated to therapy. Usually, the doses of the medications need to be increased. Splenomegaly may not be controllable by medications, and anemia can worsen. Bone pain and fever, as well as an increase in bone marrow fibrosis, are harbingers of the last phase.

 

Picture 23. Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils.

 

Picture 23. Chronic Myelogenous Leukemia (A) Myeloblasts,(B) Neutrophilic Myelocyte. (C) Neutrophilic Metamyelocyte. (D) Band neutrophil. (E) Basophil.

 

O Acute phase, or blast crisis, is similar to acute leukemia, and survival is 3-6 months at this stage. Bone marrow and peripheral blood blasts of 30% or more are characteristic. Skin or tissue infiltration also defines blast crisis. Cytogenetic evidence of another Ph-positive clone (double) or clonal evolution (other cytogenetic abnormalities such as trisomy 8, 9, 19, or 21, isochromosome 17, or deletion of Y chromosome) is usually present.

· In some patients who present in the accelerated, or acute, leukemia phase of the disease (skipping the chronic phase), bleeding, petechiae, and ecchymoses may be the prominent symptoms. In these situations, fever is usually associated with infections.

 

Stages of CML

 

 

Physical:

· Splenomegaly is the most common physical finding in patients with CML.

· In more than half the patients with CML, the spleen extends more than 5 cm below the left costal margin at time of discovery.

· The size of the spleen correlates with the peripheral blood granulocyte counts (see Image below), with the biggest spleens being observed in patients with high WBC counts.

 

Picture 24. Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil.

 

 

· A very large spleen is usually a harbinger of the transformation into an acute blast crisis form of the disease.

· Hepatomegaly also occurs, although less commonly than splenomegaly. Hepatomegaly is usually part of the extramedullary hematopoiesis occurring in the spleen.

· Physical findings of leukostasis and hyperviscosity can occur in some patients, with extraordinary elevation of their WBC counts, exceeding 300,000-600,000 cells/mL. Upon funduscopy, the retina may show papilledema, venous obstruction, and hemorrhages.

 

 Lab Studies:

· Peripheral blood findings show a typical leukoerythroblastic blood picture, with circulating immature cells from the bone marrow.

 

Picture 25. Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and megakaryocytes is increased.

  

· The increase in mature granulocytes and normal lymphocyte counts (low percentage due to dilution in the differential count) results in a total WBC count of 20,000-60,000 cells/mL. A mild increase in basophils and eosinophils is present and becomes more prominent during the transition to acute leukemia.

O These mature neutrophils, or granulocytes, have decreased apoptosis (programmed cell death), resulting in accumulation of long-lived cells with low or absent enzymes, such as alkaline phosphatase. Consequently, the leukocyte alkaline phosphatase stains very low to absent in most cells, resulting in a low score.

O Early myeloid cells such as myeloblasts, myelocytes, metamyelocytes, and nucleated red blood cells are commonly present in the blood smear, mimicking the findings in the bone marrow. The presence of the different midstage progenitor cells differentiates this condition from the acute myelogenous leukemias, in which a leukemic gap (maturation arrest) or hiatus exists that shows absence of these cells.

O A mild-to-moderate anemia is very common at diagnosis and is usually normochromic and normocytic.

O The platelet counts at diagnosis can be low, normal, or even increased in some patients (>1 million in some).

· Bone marrow is characteristically hypercellular, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells. Megakaryocytes (see Image above) are prominent and may be increased. Mild fibrosis is often seen in the reticulin stain.

· Cytogenetic studies of the bone marrow cells, and even peripheral blood, should reveal the typical Ph1 chromosome, which is a reciprocal translocation of chromosomal material between chromosomes 9 and 22. This is the hallmark of CML, found in almost all patients with CML, and is present in CML throughout its entire clinical course.

O The Ph translocation is the translocation of the cellular oncogene c-abl from the 9 chromosome, which encodes for a tyrosine protein kinase, with a specific breakpoint cluster region (bcr) of chromosome 22, resulting in a chimeric bcr/c-abl messenger RNA that encodes for a mutation protein with much greater tyrosine kinase activity compared with the normal protein (see Image below). The latter is presumably responsible for the cellular transformation in CML. This m-RNA can be detected by polymerase chain reaction (PCR) in a sensitive test that can detect it in just a few cells. This is useful in monitoring minimal residual disease (MRD) during therapy.

 

Picture 26. The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows).

 Imaging Studies:

· Typical hepatomegaly and splenomegaly may be imaged by using a liver/spleen scan. Most often, these are so obvious that radiological imaging is not necessary.

· Histologic Findings: Diagnosis is based on the histopathologic findings in the peripheral blood and the Ph1 chromosome in the bone marrow cells.

 

Pic.28  Oil immersion field demonstrating myeloid cells of all degrees of maturity

 

Pict. 29. This high-power microscopic view of a blood smear from a person with classical CML shows predominantly normal-appearing cells with intermediate maturity

 

Pict. 30. Low power view showing marked hypercellularity with a broad-spectrum of myeloid and erythroid cell types and marked myeloid hyperplasia

 

  TREATMENT    

A treatment program of CML includes:

· Cytostatic therapy (monotherapy, polychemotherapy).

· Treatment by alpha-interferonum

· Radial therapy.

· Leukocytoferesis.

· Splenectomy.

· Symptomatic therapy.

· Marrow transplantation.

Treatment of CML depends on disease stage and prognostic criterioa of lifetime at the moment of diagnosis establishment.

Attached to insignificant expressed clinicohematological features and satisfactory general state of patients common strengthen therapy is recommended, full value feeding, rich on vitamins, rational work and rest regime, clinical supervision.

In unroll stage of disease cytostatic therapy (mono or polychemotherapy). Is used in which appearance it was taken depends on prognostic factors of disease.

Monotherapy of CML. Agent of choice in treatment of CML is hydroxyurea (hedrea-litaliz). This agent inhibits one of key ferments into biosintesis of DNA – ribonuclease – diphosphatreductase and predominantey influences the pool of leukemis cells growing rapidly, block S and G-1 stages of mitotic cycle. Preparation isproduced in capsules on 0,5 g and is administrated in initial dose 20-40 mg/kg/ day, a sustaining dose is 15-30 mg/kg, and attached to progressing increas to 40-60 mg/kg on day.

Treatment effectiveness is values after 6 weeks, through treatment duration is not limited. As a rule,hydroxyurea is well carried, however there is possible development of dyspeptic phenomen, neurulogic violations, skin allergic reactions, rarely-stomatitis, leucopenia, trombocytopenia.

Contraindication of hydroxyurea:

–  leucopenia (amount of leucocites less than 3 х 10^⁹/l);

– thrombocytopenia (less than 100 х 10^⁹/l).

Attached to absence of the effect from hydroxyurea patient is prescribed mielosan (busulphan, mileran), that operates on predecessors-cell and stopes production of leukemic cells. It is prodused in pills on 0,002 g, usedin dependence on leucocytes level in daily dose 2-8 mg. Mielosan effect usually begins to appear not early than on 10- day from the beginning of aueption, and normalization of hemogram and decreasing of spleen size come on 3-6 treatment week after obtaining at general dose – 250-300 mg.

On obtaining remission and decreasing of leucocytes level less than18 х 10⁹/l, they switeh to sustaining doses on 2 mg 1-2 times a week.

For reaching more rapid effect mielobromolum is used 250 mg/day.

For fixing of remission combination of cytosar with hydroxyurea, methotrexate is recommended,thioguaninum, cyclophosfane and vincristinum, rubromicinum.

Polychemotherapy of CML:

Is pertormed at unroll stages of CML attached to presence of criterioa of high risk.

Advisible is application of scheme “7 + 3″ (cytosar in dose 100mg/m2 – 7 days, rubomicini in dose 45 mg/m2 – 3 days).

More frequently we used the AVAMP schemes and CVAMP (arabinosid (cytosin-arabinosid) -30 mg/m² i/v in 1 and 8 days; Vincrastinum 2 mg/m² i/v on 3- and 10- days, ametopretinum (metotrexatum) 20 mg/m² i/v on 2, 5 and 9 days, 6-mercaptopurinum – 60 mg/m² from 1 to 10 day; prednisolonum 40 mg/m² from 1-го to 10- day).

MEDICATION

 

The medications used for patients with chronic-phase CML include a myelosuppressive agent to achieve hematologic remission, which requires 1-2 months of treatment. Once the patient goes into hematologic remission, the goal of treatment is to suppress the Ph-positive hematopoietic clone in the bone marrow for a cytogenetic remission and, hopefully, a molecular remission. This entails the use of interferon alfa or a BMT.

Treatment is determined by:

(1) the age of the patient,

(2) the presence of an HLA-matched donor willing to donate bone marrow, and

(3) the Sokal score.

The 3 categories of the Sokal score are (1) low risk, which is less than 0.8; (2) intermediate risk, which is 0.8-1.2; and (3) high risk, which is greater than 1.2.

The Sokal score is calculated for patients aged 5-84 years by hazard ratio = exp (0.011 (age – 43) + 0 .0345 (spleen – 7.5 cm) + 0.188 [(platelets/700)2 – 0.563] + 0.0887 (% blasts in blood – 2.1).

The choice of treatment is determined by the prognosis and the age of the patient. Most patients have no matched donor or are too old for BMT; interferon alfa is the drug of choice in these patients.

–                    

 

 

 

Lymphoma classification (2001 WHO)

1.                 Non-Hodgkin Lymphomas:

–                     B-cell neoplasms

–                                           precursor

–                                           mature

–                     T-cell & NK-cell neoplasms

–                                           precursor

–                                           mature

2.                 Hodgkin lymphoma

Epidemiology of lymphomas

•                     5^th most frequently diagnosed cancer in both sexes

•                     males > females

•                     incidence

–                                           NHL increasing

–                                           Hodgkin lymphoma stable

Clinical manifestations

1.                 Variable

•                                                                     severity: asymptomatic to extremely ill

•                                                                     time course: evolution over weeks, months, or years

2.                 Systemic manifestations

•                                                                     fever, night sweats, weight loss, anorexia, pruritis

3.                 Local manifestations

•                                                                     lymphadenopathy, splenomegaly most common

•                                                                     any tissue potentially can be infiltrated

Other complications of lymphoma

•                     bone marrow failure (infiltration)

•                     CNS infiltration

•                     immune hemolysis or thrombocytopenia

•                     compression of structures (eg spinal cord, ureters)

•                     pleural/pericardial effusions, ascites

Staging defines how widespread the disease is and the locations of the disease in the body

Stage I – disease in single lymph node or lymph node region.

Stage II – disease in two or more lymph node regions on same side of diaphragm.

Stage III – disease in lymph node regions on both sides of the diaphragm are affected.

Stage IV – disease is wide spread, including multiple involvement at one or more extranodal (beyond the lymph node) sites, such as the bone marrow

Extranodal means ‘beyond nodal’ – sites are identified by the following notation:

N	= lymph nodes
E	= extranodal
H	= liver (hepatic)
L	= lung
B	= bone marrow
S	= spleen
P	= pleura (lung)
O	= bone
D	= skin (dermis)

A = without symptoms

B = with symptoms including unexplained weight loss (10% in 6 months prior to diagnosis,  unexplained fever, and drenching night sweats.)

Lymphoma Symptoms and Signs

Often, the first sign of lymphoma is a painless swelling in the neck, under an arm, or in the groin.

·                     Lymph nodes or tissues elsewhere in the body may also swell. The spleen, for example, often becomes enlarged in lymphoma.

·                     The enlarged lymph node sometimes causes other symptoms by pressing against a vein or lymphatic vessel (swelling of an arm or leg), a nerve (pain, numbness, or tingling), or the stomach (early feeling of fullness).

·                     Enlargement of the spleen may causeabdominal pain or discomfort.

·                     Many people have no other symptoms.

Symptoms of lymphoma may include the following:

·                     Fevers

·                     Chills

·                     Unexplained weight loss

·                     Night sweats

·                     Lack of energy

·                     Itching (up to 25% of patients develop this itch, most commonly in the lower extremity but it can occur anywhere, be local, or spreading over the whole body)

These symptoms are nonspecific.

The Ann Arbor classification (1971) is used most often for Hodgkin lymphoma. It classifies cases into the following 4 stages, principally on the basis of lymph node involvement:

·                     Stage I – a single lymph node area or single extranodal site

·                     Stage II – 2 or more lymph node areas on the same side of the diaphragm

·                     Stage III – denotes lymph node areas on both sides of the diaphragm

·                     Stage IV – disseminated or multiple involvement of the extranodal organs

Involvement of the liver or the bone marrow is considered stage IV disease. For staging classifications, the spleen is considered to be a lymph node area. Involvement of the spleen is denoted with the S suffix (ie, IIB_S).

A or B designations denote the absence or presence of B symptoms. A “B” designation includes the presence of 1 or more of the following:

·                     Fever (temperature >38°C)

·                     Drenching night sweats

·                     Unexplained loss of more than 10% of body weight within the preceding 6 months

An “A” designation is the absence of the above.

An “X” designation is sometimes used to indicate the presence of bulky disease.

Non-Hodgkin lymphomas (NHL)

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the spleen, the liver, and the GI tract. Presenting symptoms usually include peripheral lymphadenopathy. However, some patients present without lymphadenopathy but with abnormal lymphocytes in circulation. Compared with Hodgkin lymphoma, there is a greater likelihood of disseminated disease at the time of diagnosis.

Most  NHL are of B-cell origin.

B-NHL – are a heterogeneous group of malignancies that, with the exception of mantle cell lymphoma, arise by malignant transformation of B cells within the germinal center, (GC).

Epidemiology

NHL is the most prevalent hematopoietic neoplasm, representing approximately 4% of all cancer diagnoses and ranking seventh in frequency among all cancers. NHL is more than 5 times as common as Hodgkin disease.

Incidence varies with race; white people have a higher risk than black and Asian American people. In general, the incidence of NHL is slightly higher in men than in women, with a male-to-female ratio of approximately 1.4:1. The ratio may vary depending on the subtype of NHL, however; for example, primary mediastinal diffuse large B-cell lymphoma occurs more frequently in females than in males.

The median age at presentation for most subtypes of NHL is older than 50 years. The exceptions are high-grade lymphoblastic and small noncleaved lymphomas, which are the most common types of NHL observed in children and young adults. At diagnosis, low-grade lymphomas account for 37% of NHLs in patients aged 35-64 years but account for only 16% of cases in patients younger than 35 years. Low-grade lymphomas are extremely rare in children.

Etiology

The cause of NHL is unknown, although, as with the leukemias, substantial evidence suggests a viral cause (eg, human T-cell leukemia-lymphoma virus, Epstein-Barr virus, hepatitis C virus, HIV). Risk factors for NHL include immunodeficiency (secondary to posttransplant immunosuppression, AIDS, primary immune disorders, sicca syndrome, RA),Helicobacter pylori infection, certain chemical exposures, and previous treatment for Hodgkin lymphoma. NHL is the 2nd most common cancer in HIV-infected patients  and some AIDS patients present with lymphoma. C-myc gene rearrangements are characteristic of some AIDS-associated lymphomas.

Pathophysiology

Most (80 to 85%) NHLs arise from B cells; the remainder arise from T cells or natural killer cells. Either precursor or mature cells may be involved. Overlap exists between leukemia and NHL because both involve proliferation of lymphocytes or their precursors. A leukemia-like picture with peripheral lymphocytosis and bone marrow involvement may be present in up to 50% of children and in about 20% of adults with some types of NHL. Differentiation can be difficult, but generally patients with more extensive nodal involvement (especially mediastinal), fewer circulating abnormal cells, and fewer blast forms in the marrow (< 25%) are considered to have lymphoma. A prominent leukemic phase is less common in aggressive lymphomas, except Burkitt’s and lymphoblastic lymphomas.

Classification

Pathologic classification of NHLs continues to evolve, reflecting new insights into the cells of origin and the biologic bases of these heterogeneous diseases. The WHO classification is valuable because it incorporates immunophenotype, genotype, and cytogenetics, but numerous other systems exist (eg, Lyon classification). Among the most important new lymphomas recognized by the WHO system are mucosa-associated lymphoid tumors ; mantle cell lymphoma (previously diffuse small cleaved cell lymphoma); and anaplastic large cell lymphoma, a heterogeneous disorder with 75% of cases of T-cell origin, 15% of B-cell origin, and 10% unclassified. However, despite the plethora of entities, treatment is often similar except in certain T-cell lymphomas.

The WHO Classification  divides NHL  into INDOLENT and AGGRESSIVE groups based on morphology, tumour grade, and other prognostic factors.

Lymphomas are commonly also categorized as indolent or aggressive. Indolent lymphomas are slowly progressive and responsive to therapy but are not curable with standard approaches. Aggressive lymphomas are rapidly progressive but responsive to therapy and often curable.

In children, NHL is almost always aggressive. Follicular and other indolent lymphomas are very rare. The treatment of these aggressive lymphomas (Burkitt’s, diffuse large B cell, and lymphoblastic lymphoma) presents special concerns, including GI tract involvement (particularly in the terminal ileum); meningeal spread (requiring CSF prophylaxis or treatment); and other sanctuary sites of involvement (eg, testes, brain). In addition, with these potentially curable lymphomas, treatment adverse effects as well as outcome must be considered, including late risks of secondary cancer, cardiorespiratory sequelae, fertility preservation, and developmental consequences. Current research is focused on these areas as well as on the molecular events and predictors of lymphoma in children.

The clinical manifestations of non-Hodgkin lymphoma (NHL) vary with such factors as the location of the lymphomatous process, the rate of tumor growth, and the function of the organ being compromised or displaced by the malignant process.

The Working Formulation classification groups the subtypes of NHL by clinical behavior—that is, low-grade, intermediate-grade, and high-grade. Because the Working Formulation is limited to classification based upon morphology, it cannot encompass the complex spectrum of NHL disease, excluding important subtypes such as mantle cell lymphoma or T cell/natural killer cell lymphomas. However, it continues to serve as a basis for understanding the clinical behavior of groups of NHLs.

 References.

A – Main:

1. Davidson’s Principles and practice of medicine (21^st revised ed.) / by Colledge N.R., Walker B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.

2. Harrison’s principles of internal medicine (18^th edition) / by Longo D.L., Kasper D.L., Jameson J.L. et al. (eds.). – McGraw-Hill Professional, 2012. – 4012 p.

3. The Merck Manual of Diagnosis and Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 2011.

4. Web -sites:

a) http://emedicine.medscape.com/

b) http://meded.ucsd.edu/clinicalmed/introduction.htm

 

B – Optional:

a. Lawrence M. Tierney, Jr. et al: Current Medical Diagnosis and treatment 2000, Lange Medical Books, McGraw-Hill, Health Professions Division, 2000.

b. On Line Resources:

http://image.bloodline.net/category.html

http://www.merckmanuals.com/professional/hematology_and_oncology/anemias_caused_by_deficient_erythropoiesis/decreased_erythropoiesis.html

http://www.merckmanuals.com/professional/hematology_and_oncology/anemias_caused_by_hemolysis/overview_of_hemolytic_anemia.html?qt=&sc=&alt=

http://bestpractice.bmj.com/best–practice/monograph/94/treatment/guidelines.html