ONCOLOGY AND HEMATOLOGY
Approach to the Patient with Anemia
Inherited Disorders of Blood Coagulation
Approach to the Patient with Leukocytosis
Approach to the Patient with Lymphadenopathy
Sickle Cell Disease
Approach to the Patient with Splenomegaly
Approach to the Patient with Thrombocytopenia
Approach to the Patient with Thrombosis and Pulmonary Embolism
DEFINITIONS AND PATHOPHYSIOLOGY
Acute leukemia is caused by uncontrolled proliferation of a malignant clone of hematopoietic cells that does not differentiate and mature normally. Leukemic cells are introduced into the blood from the bone marrow. They may divide in the blood or infiltrate an organ, such as the spleen, liver, or lymph nodes, where they may also divide and then reenter the blood. In acute lymphocytic leukemia (ALL), the abnormal clone has characteristics of lymphoid cells. All other types of acute leukemia are classified as acute myeloid leukemia (AML). AML is subdivided according to cell type—myelocytic, promyelocytic, myelomonocytic, monocytic, erythroleukemic, and megakaryocytic.
Acute lymphocytic leukemia: Most patients are younger than 15 years. The median age of adult patients is 42 years. Men are affected more often than women.
Acute myeloid leukemia: The average patient is older than 55 years at diagnosis. The incidence increases with age. Ionizing radiation and some chemotherapeutic agents, especially alkylating agents, are associated with an increased incidence of AML.
Acute lymphocytic leukemia: Adults usually have the subacute onset of fatigue, lethargy, and anorexia. Petechiae or easy bruising may be found. An expanding bone marrow mass can cause bone pain. Most patients have palpable lymphadenopathy; the spleen is palpable in 50% of patients. About 15% of patients have a fever, which may be caused by occult infection. Signs of increased intracranial pressure or cranial nerve dysfunction caused by leukemic infiltration of the central nervous system may be evident. Anemia, granulocytopenia, and thrombocytopenia are almost always present at the time of diagnosis. For 85% of patients, the blood smear reveals lymphoblasts. The bone marrow biopsy specimen almost always is hypercellular with lymphoblastic predominance and a reduction in normal elements. Cerebrospinal fluid should be examined for leukemic cells. Serum lactate dehydrogenase and uric acid levels usually are elevated.
Acute myeloid leukemia: The features vary somewhat among the different subtypes. Adults usually have a vague history of progressive lethargy. However, as many as one-third of patients may come to medical attention with an acute illness due to infection. The patients usually have petechiae. Lymphadenopathy, splenomegaly, and hepatomegaly are unusual. The white blood cell (WBC) count is normal, elevated, or depressed with equal frequencies at diagnosis, although granulocytopenia is essentially universal. Anemia and thrombocytopenia usually are present. Blast cells are initially absent from the peripheral blood in about 15% of cases. The bone marrow usually is markedly hypercellular and has at least 50% to 75% leukemic cells. Uric acid levels generally are elevated.
Morphologic examination, histochemical reaction, cytogenetic and enzymologic studies and cell surface antigen identification are the principal laboratory tools for differentiating ALL from AML and for identifying clinically important subtypes of both.
PROGNOSIS AND MANAGEMENT
Acute lymphocytic leukemia: Prognosis is influenced adversely by advanced age, B-cell phenotype, greatly elevated WBC count at diagnosis, and a complex, abnormal karyotype. Most adults respond well to initial therapy, but unlike children with ALL, most adults ultimately die of the disease. Before chemotherapy is started, active infection must be controlled with antibiotics, and hyperuricemia with hydration and allopurinol. The standard induction regimens include drugs such as vincristine, prednisone, daunorubicin, and L-asparaginase. After the patient has achieved a complete remission and recovered from induction therapy, intensive postremission therapy with drugs not used during induction or with bone marrow transplantation is necessary to maximize the duration of the response. The median duration is 1 to 2 years; most relapses occur within 3 years. About 30% to 40% of patients live disease free for 5 years after treatment. Central nervous system involvement can be managed effectively with intrathecal methotrexate.
Acute myeloid leukemia: Remission therapy usually consists of only two drugs, cytarabine and daunorubicin or idarubicin. Almost all patients need prophylactic platelet transfusions and at least 90% need empiric broad-spectrum antibiotic therapy for fever while granulocytopenic. Complete remission is obtained among 70% or more of adults. All-trans retinoic acid induces remission of acute promyelocytic leukemia through induction of maturation and differentiation rather than by means of cytotoxicity. Intensive postremission therapy prolongs remission to a mean of 12 to 24 months. About 30% to 50% of patients with a complete response live disease free for at least 5 years after treatment. Late relapses occur but are rare.
Amyloidosis refers to a group of protein deposition diseases. Amyloid is a substance that consists of protein fibrils. Stained with Congo red and viewed with polarized light, it produces an apple-green birefringence.
EPIDEMIOLOGY AND ETIOLOGY
Approximately 2,500 cases occur annually in the United States; only 1% of patients are younger than 40 years. In primary amyloidosis, the fibrils consist of monoclonal k or l light chains. The condition is closely related to multiple myeloma. Secondary amyloidosis is associated with inflammatory processes such as rheumatoid arthritis and Crohn’s disease. The fibrils consist of protein A. Other varieties include familial amyloidosis, senile amyloidosis, and a b2 microglobulin amyloidosis associated with renal dialysis.
Primary amyloidosis: Weakness, fatigue, and weight loss are common, as are light-headedness, syncope, change in voice or tongue, dyspnea, and edema. Nephrotic syndrome, hepatomegaly, macroglossia, congestive heart failure, carpal tunnel syndrome, peripheral neuropathy, and orthostatic hypotension occur in 10% to 30% of cases.
Secondary amyloidosis: At diagnosis, more than 90% of patients have renal insufficiency or nephrotic syndrome. Gastrointestinal involvement often manifests as a malabsorption syndrome. Unlike primary amyloidosis, secondary amyloidosis rarely involves the heart and peripheral nerves.
LABORATORY STUDIES AND DIAGNOSTIC TESTS
Primary amyloidosis: Findings are those suggested by pattern of organ involvement. They may include azotemia and an echocardiogram that demonstrates increased ventricular wall thickness and an abnormal myocardial texture. Monoclonal protein is found in the serum and the urine of more than 70% of patients. The diagnosis depends on the demonstration of amyloid deposits. Findings at examination of an abdominal fat aspirate or rectal biopsy are abnormal more than 90% of the time.
Secondary amyloidosis: Most patients have azotemia and proteinuria. The diagnosis is made by means of biopsy of an affected organ.
PROGNOSIS AND MANAGEMENT
Primary amyloidosis: The median survival period ranges from 1 to 2 years. Therapy is unsatisfactory, but melphalan and prednisone prolong survival several months.
Secondary amyloidosis: The median survival time is approximately 2 years. Treatment depends on the underlying disease. Renal transplantation is helpful.
APPROACH TO THE PATIENT WITH ANEMIA
Anemia represents a reduction in the normal red blood cell (RBC) mass within the body as measured with peripheral blood hemoglobin level and hematocrit. The hematocrit of healthy men is 47% ± 7%; that of healthy women in 42% ± 5%.
The normal cycle of erythropoiesis requires coordination of erythropoietin stimulation with the necessary precursor cells and building blocks in a conducive microenvironment. RBC structure and extramedullary circumstances then determine the life span of the erythrocyte. Lesions in any component of this cycle can cause anemia.
Hyporegenerative versus hyperregenerative anemia: If shortened RBC survival causes anemia, as in bleeding or hemolysis, an erythropoietin surge leads to the release of increased numbers of reticulocytes (immature RBC precursors). An elevated reticulocyte count (more than 100,000 per microliter) thus indicates that the marrow is attempting to compensate for an extramedullary abnormality. A lower reticulocyte count suggests an abnormality within the marrow.
Categorization of anemia according to size of red blood cells: Anemia can be classified as microcytic, normocytic, or macrocytic (Table 211.2). Microcytic anemia originates in an iron or hemoglobin deficiency. Most cases of macrocytic anemia are caused by folate and vitamin B12 deficiencies. Normocytic anemia is a more heterogeneous group that includes most hemolytic disorders (Table 211.3).
HISTORY AND PHYSICAL EXAMINATION
Anemia often is asymptomatic unless it is severe, develops rapidly, or occurs in a patient with an underlying cardiopulmonary disorder. The symptoms include dyspnea on exertion, angina, and fatigue. Physical examination may reveal conjunctival and palmar pallor, tachycardia, and a systolic flow murmur.
Microcytic anemia: Patients with an iron deficiency may have overt hemorrhage or symptoms that suggest a source of occult bleeding. Result of stool tests for occult blood may be positive. Family history and ethnic background are useful in the diagnosis of thalassemia. History or examination findings of chronic inflammatory disease such as osteomyelitis or rheumatoid arthritis suggest anemia of chronic disease.
Normocytic hyporegenerative anemia: Findings of chronic inflammation suggest anemia of chronic disease. The symptoms of uremia may be elicited. Pancytopenia is suggested by a history of easy bruising or frequent infection. Hematologic malignant disease may be associated with fever, weight loss, lymphadenopathy, or splenomegaly.
Normocytic hyperregenerative anemia: The history may suggest hemolytic anemia (e.g., malaria among travelers or autoimmune hemolysis among patients with other symptoms of systemic lupus erythematosus). The history and physical examination may suggest a source of hemorrhage. However, hemorrhage causes a hyperproliferative anemia only if it has not caused a concomitant iron deficiency.
Macrocytic anemia: Hypothyroidism, alcoholism, and chronic liver disease may be apparent. Patients-with vitamin B12 deficiency, but not those with folate deficiency, often have a loss of vibratory and positional sense in the lower extremities.
LABORATORY STUDIES AND DIAGNOSTIC TESTS
In addition to reticulocyte count and cell size determination, the initial approach includes examination of a peripheral blood smear, white blood cell and platelet counts, and measurement of RBC distribution width (RDW), an indicator of the range of RBC sizes. An overall approach is outlined in Fig. 211.1.
Microcytic anemia: Iron deficiency is suggested by low serum levels of ferritin, a storage form of iron. The absence of bone marrow iron stores is considered the diagnostic gold standard, but a trial of iron therapy can be useful. In thalassemia, the RBCs are particularly microcytic for the degree of anemia; hemoglobin electrophoresis may help establish a diagnosis. Sideroblastic anemia shows iron accumulation in the mitochondria of developing RBCs within the marrow (ringed sideroblasts).
Normocytic hyporegenerative anemia: Results of bone marrow biopsy often are definitive. The anemia of renal failure has low erythropoietin levels; blood urea nitrogen and creatinine levels are elevated. Aplastic or hypoplastic processes affect the WBC and platelet counts. Marrow infiltration produces myelophthisis, in which the peripheral blood smear shows nucleated and teardrop-shaped RBCs and immature WBCs that have been extruded from the marrow.
Normocytic hyperregenerative anemia: Hemolysis may be associated with hyperbilirubinemia, low haptoglobin levels, and production of RBC autoantibodies. The peripheral blood smear may provide many diagnostic clues (e.g., schistocytes in microangiopathic processes that fragment RBCs and spherocytes in immune-mediated processes or hereditary spherocytosis).
Macrocytic anemia: Megaloblastic anemia is associated with exaggerated macrocytosis (mean corpuscular volume [MCV] more than 115 fL), a reduction in platelet and WBC counts, high levels of lactate dehydrogenase (LDH), and hypersegmentation of polymorphonuclear leukocytes on the peripheral blood smear. Serum vitamin B12 and RBC folate tests help identify the specific deficiency. The coexistence of iron deficiency anemia and megaloblastic anemias may yield a normal MCV but an elevated RDW. Nonmegaloblastic macrocytic anemia does not cause pancytopenia.
Anemia frequently is not the primary concern but is instead a clue to the presence of an underlying disorder that must be identified and treated (e.g., iron deficiency as a first manifestation of colon cancer). Management of the underlying disorder improves or resolves the anemia. If the degree of improvement is insufficient or there are acute symptoms of anemia, RBC transfusions can be performed.
DEFINITION, EPIDEMIOLOGY, AND ETIOLOGY
Aplastic anemia is a syndrome of bone marrow failure characterized by pancytopenia of the peripheral blood and hypocellularity of the bone marrow. Patients of all ages and both sexes are affected. It is caused by various pathophysiologic processes that affect the pluripotent stem cells. Most cases appear to be acquired, but approximately 50% have no identifiable cause and are called idiopathic. Recognized causes are listed in Table 230.1.
Two types of presentation are possible depending on the severity of pancytopenia. Some patients have a gradual onset of signs and symptoms of anemia, including fatigue, dyspnea, and pallor. Laboratory evaluation reveals variable but often mild pancytopenia and hypoplastic bone marrow. Other patients have signs and symptoms of thrombocytopenia and leukopenia in addition to those of anemia. They may have a sudden onset of high-spiking fevers and spontaneous petechiae and ecchymosis. In more severe cases, patients may have retinal hemorrhage, epistaxis, or oral mucosal bleeding. Except for evidence of bleeding, the physical examination findings generally are unremarkable. Lymphadenopathy and splenomegaly are not seen. In the absence of granulocytes, the findings associated with infection, such as pneumonia, may be minimal.
Laboratory evaluation should include studies that attempt to identify the cause of the aplasia, including tests for paroxysmal nocturnal hemoglobinuria, systemic lupus erythematosus, hepatitis, infectious mononucleosis, and pregnancy. Deficiency of vitamin B12 or folate should be excluded. Cytogenetic analysis may be helpful in identifying myelodysplastic syndromes and those with underlying chromosomal fragility states, such as Fanconi’s anemia.
PROGNOSIS AND MANAGEMENT
General supportive management: Drugs that interfere with platelet function should be avoided. Women of childbearing age should undergo menstrual suppression. Because of the need for frequent phlebotomy and transfusions, indwelling vascular catheters may be necessary. Fever and potential infection should be managed promptly and aggressively with cultures and antibiotics. Transfusions should be used judiciously. Active bleeding should be controlled with platelet transfusion if the platelet count is less than 20,000 per microliter. Prophylactic platelet transfusions need not be given until the platelet count is less than 5,000 to 10,000 per microliter. Transfusions should be leukocyte depleted, and family-derived transfusions should be avoided if bone marrow transplantation is being considered. Cytomegalovirus (CMV) antibody-negative patients should receive transfusions only from CMV antibody-negative donors.
Definitive treatment: Any possible offending exposures should be discontinued. Specific therapies include marrow stimulation (androgens, cytokines), immunosuppression (antithymocyte globulin, glucocorticoids, cyclophosphamide, cyclosporine), and bone marrow transplantation. The last should be considered primary treatment of patients younger than 40 to 45 years.
EPIDEMIOLOGY AND ETIOLOGY
The term breast cancer usually refers to adenocarcinoma, the most common malignant neoplasm of mammary tissue and, with lung cancer, one of the two most common cancers of women in the developed world. Risk factors include advanced age, history of breast cancer in a first-degree relative (especially if the lesions are bilateral or the relative is premenopausal), early onset of menarche (12 years of age or earlier), nulliparity or first pregnancy after 35 years of age, alcohol consumption, and prior radiation exposure. Current evidence suggests that use of oral contraceptives or postmenopausal estrogen replacement is associated with a slight increase in risk. Use of newer estrogens such as raloxifene may actually reduce risk. Germ-line mutations of the genes BRCA1 and BRCA2 are associated with a higher risk of both breast and ovarian cancer. Benign lesions such as cysts, mastitis, and most fibroadenomas are not predisposing conditions. The incidence of breast cancer among men is about 1% of the incidence among women.
PATHOPHYSIOLOGY, CLASSIFICATION, AND STAGING
Most adenocarcinomas of the breast are thought to arise from ductal epithelial cells. These cancers may be in situ or infiltrating (also called invasive). The in situ carcinomas are further classified as lobular carcinoma in situ (LCIS) or ductal carcinoma in situ (DCIS). LCIS and DCIS do not invade the parenchyma or stroma and have a very low potential for generating metastasis. DCIS lesions are usually regarded as a unilateral, very early, preinvasive form of true breast cancer. LCIS, in contrast, often is considered a marker of carcinogenic potential (equally shared with the uninvolved breast) rather than true cancer. Invasive adenocarcinoma, which does infiltrate into surrounding normal tissue, also has ductal and lobular types, the ductal types predominating. The most common sites of metastasis are the axillary lymph nodes. The number of nodes containing cancer is a good indicator of the propensity of the tumor to metastasize to more distant anatomic sites such as bone, lung, liver, and brain. About 15% of breast cancers have special histopathologic patterns, including mucinous and papillary types. Inflammatory breast cancer is an especially aggressive form of the disease characterized by diffuse breast swelling, erythema and warmth of the skin, breast pain, and peau d’orange edema of the skin.
Breast cancer is staged through assessment of tumor size (T), nodal involvement (N), and the presence or absence of distant metastases (M) and subsequent classification of the stage as 0, I, IIA, IIB, IIIA, IIIB, or IV. Proper staging requires pathologic examination of the breast tissue and axillary nodes, physical examination, chest radiography, and measurement of serum markers such as liver transaminases and alkaline phosphatase. Physical examination is not a reliable way of assessing axillary nodal involvement. With sentinel lymph node mapping, a radioactive tracer or a dye is introduced into the breast at tumor resection, and only the nodes that first take up the substance are dissected. If these nodes are free of cancer, it is extremely likely that the other axillary nodes will be free as well.
A review of breast symptoms is essential. The rest of the history should focus on indications of possible metastasis, such as bone pain and respiratory difficulties. The physical examination should include special emphasis on the breast, axilla, and supraclavicular areas. The presence of a supraclavicular node is an indication of metastatic disease and therefore alters prognosis and treatment.
A preoperative mammogram is useful in evaluating the rest of the abnormal breast and the contralateral breast for masses or calcifications before definitive surgery. A normal mammogram does not exclude the presence of a malignant lesion, however. A biopsy must be performed on a persistent mass regardless of the mammographic findings. Bone and liver scans are not performed routinely if laboratory values are normal. A complete blood cell count (CBC) and chemistry panel are recommended. After surgical treatment, a yearly mammogram is obligatory, and many oncologists obtain CBCs, hepatic enzymes, and alkaline phosphatase levels on a routine basis.
PROGNOSIS AND MANAGEMENT
DCIS and LCIS: DCIS can manifest as a mass, but it is more commonly found by means of biopsy of abnormal calcifications detected with a mammogram. Optimal management is not yet established. Most patients undergo radiation therapy after local excision. Although there is no established role for systemic chemotherapy because of the very small likelihood of metastasis, tamoxifen may decrease the risk of invasive breast cancer among patients treated with lumpectomy and radiation. Because LCIS usually is not palpable and is invisible at mammography, the diagnosis is commonly incidental to breast biopsy performed for another reason. Because the presence of LCIS is an indicator of a propensity for development of breast cancer and because both breasts are at equal risk, treatment options include observation alone or bilateral simple, prophylactic mastectomy. There is no role for radiation therapy. Recent data have demonstrated a 50% reduction in the risk of infiltrating breast cancer among patients with a history of LCIS who are treated with tamoxifen.
Infiltrating tumors: Adverse prognostic factors include a greater number of positive axillary nodes, larger tumor size, poorly differentiated histologic features, and the absence of receptors for estrogen and progesterone in the cancer cells. Most patients with stage I cancers, many with stage II cancers, and some with stage III cancers can be cured with local therapy. Patients with more advanced stage III cancers and with stage IV disease cannot be cured with surgery alone and need systemic therapy. Local therapy consists of surgery (now often breast sparing rather than mastectomy or radical mastectomy), axillary dissection, and radiation therapy. Adverse effects include disfigurement (breast reconstruction can be performed) and lymphedema (which may occur less often when sentinel lymph node–mapping techniques are used). Systemic drug therapy is used in the following three settings: (a) as an adjunct to local therapy to limit micrometastatic disease, (b) in the management of overt metastatic disease, and (c) as primary therapy for locally advanced breast cancer to render the local disease amenable to surgical and radiotherapeutic approaches. Cyclophosphamide, methotrexate, 5-fluorouracil, paclitaxel, and docetaxel are the chemotherapeutic drugs used most commonly. The first three often are combined into the CMF regimen. The drug most commonly used in hormonal therapy for breast cancer is tamoxifen (usually 20 mg by mouth per day), which acts as an antiestrogen in breast tissue. Tumor estrogen receptors are required. The most common toxicities are hot flashes, irregular menses, and depressed mood. Increased risk of uterine cancer has also been found.
Metastatic disease: In addition to systemic treatment, some metastatic processes may necessitate special therapy. For example, bony metastases leading to intractable pain or to skeletal instability may necessitate radiation therapy or even surgery. Malignant pleural effusions may necessitate repeated thoracentesis or pleurodesis with a sclerosing agent. Morbidity from central nervous system metastasis can be minimized by use of glucocorticoids and radiation therapy. Hypercalcemia generally responds to immediate intravenous hydration followed by the administration of a biphosphonate such as pamidronate.
Chronic leukemia is a group of heterogeneous proliferative disorders involving lymphoid or myeloid cells that retain some capability of differentiation and maturation. The group includes chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), and hairy cell leukemia (HCL).
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
Chronic lymphocytic leukemia: CLL is caused by malignant expansion of a clone of lymphocytes. Most patients in the United States have the B-cell subtype. T-cell CLL is more common in Japan. CLL occurs primarily among older persons and is equally distributed between men and women.
Chronic myelocytic leukemia: CML is a myeloproliferative disorder of the stem cells common to bone marrow cells and B lymphocytes. Abnormalities of red blood cell (RBC), and platelet production accompany the increase in granulocytes. All of the cells have the Philadelphia (Ph) chromosome, which reflects reciprocal translocation of material between chromosomes 9 and 22. The key event is translocation of the ABL gene. CML usually is diagnosed in midlife or later.
CLINICAL FINDINGS AND DIAGNOSIS
Chronic lymphocytic leukemia: About half of patients come to medical attention with lymphadenopathy in addition to lymphocytosis (usually more than 15,000 cells per microliter). Splenomegaly also may be present. Anemia and thrombocytopenia usually are late features unless an autoimmune process has supervened. Fever and painful lymphadenopathy are uncommon and suggest infection. The bone marrow usually is diffusely displaced by small, mature lymphocytes. A few patients have abdominal tumors with the histologic features of large cell lymphoma (Richter’s syndrome). Associated autoimmune phenomena, such as hemolytic anemia, can develop at any time and do not influence prognosis. Death usually is related to infection. The T-cell variety tends to involve the skin and to respond less well to therapy.
Chronic myelocytic leukemia: Initially, patients are asymptomatic, though complaints related to splenomegaly may be offered. The WBC count usually is 2 to 4 times the upper limit of normal, and the blood smear discloses the immaturity of the granulocyte series (myelocytes, metamyelocytes). The platelet count is normal or elevated, and anemia does not occur early in the course. Leukocyte alkaline phosphatase activity is low or absent and helps to differentiate CML from other causes of granulocytosis, such as infection and polycythemia vera. The bone marrow is hypercellular, primarily because the granulocyte compartment is expanded and immature (but not blastic). There often is an accelerated phase or blastic phase within 3 to 4 years of presentation.
PROGNOSIS AND MANAGEMENT
Chronic lymphocytic leukemia: CLL usually is an indolent disease with a median survival period of 3 to 10 years, depending on presenting stage. Therapy is palliative and does not influence survival. No therapy is needed for asymptomatic lymphocytosis with minimal lymphadenopathy and normal RBC and platelet counts. In time, progressive lymphadenopathy or hepatosplenomegaly may necessitate therapy with an alkylating agent such as chlorambucil with or without prednisone. Splenectomy or splenic irradiation may benefit patients with hypersplenism. Lymphomatous transformation necessitates parenteral combination chemotherapy.
Chronic myelocytic leukemia: An adverse prognosis is associated with higher degrees of leukocytosis, the presence of blasts in the peripheral blood, and greater splenomegaly and thrombocytosis. Oral hydroxyurea is used to treat the chronic form of the disease. Recombinant interferon-a also is effective. These treatments are palliative, and it is uncertain that they delay the blastic phase, which may necessitate intensive antileukemic chemotherapy. Allogeneic bone marrow transplantation in the chronic phase can cure about half of patients.
DEFINITION AND PATHOPHYSIOLOGY
Hodgkin’s disease is a B-cell lymphoid neoplasm. The diagnosis is based on the recognition of Reed–Sternberg cells interspersed among a reactive mixed-cell population of lymphocytes, eosinophils, histiocytes, plasma cells, and neutrophils.
EPIDEMIOLOGY AND ETIOLOGY
The incidence of Hodgkin’s disease is higher among men than women and higher among blacks than whites. The rate increases through early life, peaks in the third decade, declines until 45 years of age, and steadily increases thereafter. There is evidence of both an infectious cause (Epstein–Barr viral genomes are found in 18% to 50% of persons with Hodgkin’s disease) and a genetic susceptibility. The disease also is associated with a variety of defects in cellular immunity.
Four histologic types have been described, based on the appearance and relative proportions of Reed–Sternberg cells and the histologic background—lymphocyte predominance, nodular sclerosis, mixed cellularity, and lymphocyte depletion. The nodular sclerosis type is most common among young adults. The mixed cellularity type predominates among children and the elderly.
The most common presentation is an unexplained mass or swelling in the superficial lymph nodes, especially in the neck. The nodes are characteristically nontender and have a rubbery consistency. About two-thirds of patients have intrathoracic disease at diagnosis. Mediastinal lymphadenopathy and splenic involvement are common. Constitutional symptoms, called B symptoms, include fever in excess of 38°C, drenching night sweats, and weight loss exceeding 10%. The presence of the rare Pel–Ebstein fever (a cyclic pattern of high fevers for 1 to 2 weeks alternating with afebrile periods of similar lengths) almost confirms the diagnosis of Hodgkin’s disease. Unexplained, generalized pruritus may occur. Pain in involved lymph nodes immediately after the ingestion of alcohol is almost pathognomonic for Hodgkin’s disease.
LABORATORY STUDIES, DIAGNOSTIC TESTS, AND STAGING
The diagnosis of Hodgkin’s disease is made by means of biopsy. Baseline studies should include a complete blood cell count, liver and renal chemical analysis, and measurement of calcium. Cytopenia may occur as a result of marrow involvement, hypersplenism, or autoimmune destruction. An elevated erythrocyte sedimentation rate correlates with advanced disease and a worse prognosis. The evaluation also includes computed tomography of the chest, abdomen, and pelvis. Bone marrow biopsy is not a routine procedure. The use of staging laparotomy and splenectomy has become increasingly selective. The anatomic distribution of Hodgkin’s disease in contiguous lymphatic structures is predictable and nonrandom. These patterns from the basis for the Ann Arbor staging classification (Table 3), which has been shown to correlate well with prognosis.
TABLE 3. ANN ARBOR STAGING CLASSIFICATION FOR HODGKIN’S DISEASE
PROGNOSIS AND MANAGEMENT
Hodgkin’s disease is one of the most highly curable malignant diseases. About 80% of patients with newly diagnosed disease are cured, and fewer than 10% will die directly of the disease. Tumor burden and older age are adverse prognostic factors. Additional prognostic variables include histologic type, sex, the presence of B symptoms, the number of disease sites, and the presence of bone marrow involvement.
Primary therapy: Stage I or II supradiaphragmatic disease is controlled with extended-field radiation therapy, chemotherapy, or both. Cure rates greater than 90% have been reported with combination therapy, such as radiation therapy and chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine. For extensive mediastinal disease, a combination of radiation therapy and chemotherapy can cure 70% to 80% of patients. Sixty-five percent to 70% of patients with stage III or IV disease treated with chemotherapy regimens containing doxorubicin hydrochloride (Adriamycin) are free of disease after 5 years.
Relapse: Relapse after radiation therapy responds very well to chemotherapy. Relapse after primary chemotherapy or combination therapy has a less favorable outcome. The initial remission duration after primary chemotherapy greatly affects response to subsequent treatment. High-dose therapy with stem cell rescue is the favored treatment when primary induction fails or when there is a brief initial remission.