Wintrobe's Atlas of Clinical Hematology, 1st Edition

Chapter 5.Lymphoproliferative Disorders

Jan V. Hirschmann MD

Denis J. Bailey MD, FRCPC

Douglas C. Tkachuk MD, FRCPC

Among lymphoid tumors, the World Health Organization (WHO) classification has three major divisions: (1) B-cell neoplasms, (2) T- and NK-cell neoplasms, and (3) Hodgkin lymphoma. These categories include both lymphomas, traditionally identified as proliferative lymphoid tissue masses, and leukemias, indicating widespread bone marrow involvement, usually associated with circulating tumor cells. The distinction is arbitrary, and some “lymphomas” have extensive marrow involvement and circulating neoplastic cells initially, or they evolve into “leukemias” with progressive disease.

The classification of these disorders attempts to identify the tumors' putative cells of origin and their apparent maturity. The B and T/NK categories are divided into two types: precursor neoplasms, in which the cells are in the earliest stages of differentiation, and the peripheral neoplasms, which consist of cells in the later stages of maturation. Sometimes the cell of origin is apparent on morphologic criteria, but many are identified via immunophenotyping that identifies characteristic antigens on the cell surface. About 80% to 85% of lymphoid neoplasms are of B-cell origin; nearly all the rest derive from T cells. Tumors arising from NK cells are rare.

The entire B-cell line originates from precursor B lymphoblasts in the bone marrow that differentiate into naïve B cells that have surface immunoglobulin. The lymphoblasts are the putative cells of origin of precursor-B acute lymphoblastic leukemia and lymphoma. The naïve marrow B cells are the source of small lymphocytic lymphoma and chronic lymphocytic leukemia. The naïve B cells leave the marrow to circulate in the blood and travel to the cortex of lymph nodes, where they occupy primary follicles (those without germinal centers) and secondary follicles (those with germinal centers) in the mantle zone, which surrounds the germinal centers. These cells are the source of mantle cell lymphoma. When naïve B cells encounter antigen, they transform into blasts and travel to the center of primary follicles, forming the germinal center, where the cells are called centroblasts. These large cells, whose vesicular nuclei contain nucleoli, are thought to be the source of most large B-cell lymphomas and Burkitt lymphoma. The centroblasts mature to centrocytes, which are medium-sized, cleaved cells with inconspicuous nucleoli from which follicular lymphomas are thought to arise. The centrocytes mature into: (1) antibody secreting plasma cells, from which plasma cell myeloma and Waldenström macroglobulinemia originate, and (2) memory B cells, which are found in the areas around follicles (marginal zone) and are the putative origin of marginal-zone lymphomas of the spleen, lymph nodes, and mucosa-associated tissue (MALT).

The earliest T cells reside in the thymus, and these are considered the source of precursor T-cell lymphoblastic leukemia/lymphoma. The circulating mature T cells are the source of peripheral (i.e., outside the thymus) T-cell neoplasms. The mature T-cell lymphomas account for about 12% of non-Hodgkin lymphomas. The most common subtypes are peripheral T-cell lymphoma and anaplastic large-cell lymphoma, which together constitute about half of all cases.

Mature B-Cell Neoplasms

The clonal proliferation of cells in mature B-cell neoplasms ranges in differentiation from naïve B cells—resting lymphoid cells that have surface immunoglobulin but have not yet encountered antigens—to mature plasma cells, which produce immunoglobulins in response to previous antigen exposure. The classification of these disorders, which account for >80% of lymphoid neoplasms, generally depends on morphologic characteristics, immunophenotyping of the cells, and anatomic involvement (i.e., whether the process is primarily disseminated [often leukemic], extranodal, or nodal). The disseminated disorders, which are usually indolent, typically involve the bone marrow and commonly affect the blood, lymph nodes, and spleen. This group includes chronic lymphocytic leukemia, Waldenström macroglobulinemia, hairy cell leukemia, splenic marginal-zone lymphoma, and plasma cell leukemia. The primary mature B-cell extranodal neoplasm is marginal zone B-cell lymphoma of MALT. Common primary nodal mature B-cell lymphomas are follicular-center lymphoma and mantle cell lymphoma. Diffuse large B-cell lymphoma, the most common lymphoma worldwide, and Burkitt lymphoma may be nodal, extranodal, or disseminated. Most patients have no predisposing factors, but some have severe immunocompromise from infection with human immunodeficiency virus (HIV), primary immunodeficiencies, and immunosuppressive medications.

Chronic Lymphocytic Leukemia (CLL)

Chronic lymphocytic leukemia is a clinically heterogeneous disease consisting of monoclonal small B-cell lymphocytes expressing CD19, CD5, and CD23. The excessive number of cells occurs because of both increased proliferation and accumulation of cells with an increased lifespan. Most patients are asymptomatic at the time of diagnosis, their median age is about 65, and the male:female ratio is approximately 2:1. When symptoms occur, they commonly include weakness and fatigue, related to anemia from bone marrow replacement or immune-related hemolysis caused by a warm-reactive polyclonal IgG, which occurs in about 10% to 25% of patients during the course of disease. Other complaints may include fever, weight loss, and bleeding. The physical examination is often unremarkable, but common findings are hepatosplenomegaly and enlarged, nontender, firm, mobile lymph nodes in the cervical, axillary, and inguinal areas.

The diagnostic criteria for CLL are: (1) an absolute lymphocytosis ≥5 × 109/L; (2) ≥30% lymphocytosis in a normocellular or hypercellular bone marrow; and (3) monoclonal B cells with low levels of surface immunoglobulins and CD5 positivity. The blood smear shows an increased number of mature small lymphocytes with little cytoplasm and dense, clumped chromatin. Nucleoli are not usually visible, and many cells, being more fragile than normal lymphocytes, disrupt during the preparation of the smear, producing “smudge cells,” in which the cytoplasm is lost and the nucleus spread out. Some cells may be prolymphocytes, which are larger than mature lymphocytes, possess nucleoli, and have more cytoplasm. In a variant, CLL with increased prolymphocytes, a clinically more aggressive disease than CLL, prolymphocytes represent 10% to 55% of the lymphocytes. (When prolymphocytes are >55%, the diagnosis is B-cell prolymphocytic leukemia.) Bone marrow lymphocytes may assume one or more patterns: nodular—tightly packed aggregates of cells; interstitial—lymphocytes intermixed with other hematopoietic cells; or diffuse—extensive lymphocytic infiltration throughout the marrow. Rare hematologic findings include immune thrombocytopenia and pure red cell aplasia.

Several factors influence prognosis, but one especially important feature is whether somatic mutations exist in the specific immunoglobulin heavy-chain region (IgVH) genes of the malignant lymphocytes. DNA sequences in which these genes in the B cells differ from those in the germ line by ≥2% are considered “mutated,” and CLL with this feature, which constitutes about 50% to 60% of cases, is much more indolent than that with unmutated genes. The presence of many cells that are CD38+ or express ξ-chain-associated protein 70 (ZAP-70) also correlates with more aggressive disease.

Nonhematologic complications of CLL include infections related to hypogammaglobulinemia, decreased cell-mediated immunity, or neutropenia caused by CLL or its treatment. Paraneoplastic pemphigus, a blistering disorder of the skin and mucous membranes, rarely occurs. About 5% of patients with CLL develop Richter syndrome: The disease transforms into a non-Hodgkin lymphoma, usually diffuse large B-cell type. Characteristic features include fever, weight loss, rapid increase in lymph node size, and elevated serum lactic dehydrogenase (LDH).

B-Cell Prolymphocytic Leukemia

This rare disorder predominantly affects older adults (median age, 70), with a male:female ratio of 1.6:1. Most patients have marked splenomegaly without enlarged peripheral lymph nodes. By definition, prolymphocytes constitute >55% of the circulating lymphoid cells, but in most cases they exceed 90%. About half of patients have anemia and thrombocytopenia. The prolymphocytes are twice the size of small lymphocytes and possess a small amount of pale blue cytoplasm and round nuclei, which contain moderately condensed chromatin and a conspicuous central nucleolus. The bone marrow shows diffuse infiltration with these abnormal cells.

Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma)

This clonal disorder is characterized by the production of monoclonal IgM in association with bone marrow infiltration by small lymphocytes showing plasmacytoid or plasma cell differentiation. The median age is about 65, and males slightly outnumber females. Some patients are asymptomatic, but most have problems related to: (1) tissue infiltration by the malignant cells; (2) circulating IgM; (3) IgM tissue deposition; (4) auto-antibody formation; (5) amyloid; and (6) constitutional symptoms of fever, weight loss, and night sweats. About one-third of patients have enlargement of lymph nodes, liver, or spleen from tumor infiltration. Uncommon sites of involvement include lungs (masses, nodules, pleural effusion) and skin (papules or nodules), although virtually any organ can be affected.

Circulating IgM, which usually exceeds 30 g/L, forms aggregates and binds water, sometimes resulting in hyperviscosity, which has several clinical manifestations. The level of IgM does not necessarily correlate well with clinical manifestations. Ophthalmologic features include visual blurring and decreased acuity, associated with retinal hemorrhages, exudates, and dilated, tortuous veins with segment of widening (“sausage links” or “boxcars”). The increase in plasma volume can cause congestive heart failure. The impaired blood transit through the microvasculature can cause neurologic symptoms of dizziness, headache, deafness, confusion, nystagmus, vertigo, and ataxia. The combination of damage to vessel walls from the diminished blood flow and the interaction of monoclonal IgM with clotting factors and platelets can lead to bleeding, such as epistaxis, oral mucosal hemorrhage, and cutaneous ecchymoses. The IgM can precipitate on cooling, creating a type I cryoglobulinemia in up to 20% of patients, but <5% have symptoms related to it, such as cutaneous vasculitis, Raynaud phenomenon, or cold urticaria.

Deposition of IgM in the kidneys can lead to proteinuria and renal insufficiency. Firm, flesh-colored papules and nodules can form from IgM in the dermis, and occasional patients can develop gastrointestinal problems of diarrhea, malabsorption, and bleeding from monoclonal protein present in the intestinal wall. Monoclonal light chains can form amyloid, which is clinically evident in about 2% of patients with Waldenström macroglobulinemia. The organs most commonly affected include the heart, peripheral nerves, kidney, liver, and lungs. The monoclonal IgM also can behave as an autoantibody, and up to 20% of patients have a peripheral neuropathy from antibodies against glycoproteins in the nerves. It is usually a distal, symmetrical, chronic demyelinating process. The macroglobulins also may interact with red cell antigens at temperatures <37°C, causing a chronic hemolytic anemia called cold-agglutinin disease.

A normocytic, normochromic anemia is common and can arise from bone marrow infiltration, hemolysis, dilution by increased plasma volume, and hemorrhage. On peripheral blood smear, rouleaux formation is common, and sometimes red-cell agglutination leads to clumping of erythrocytes. Increased numbers of small lymphocytes, some resembling plasma cells (“plasmacytoid lymphocytes”) with abundant basophilic cytoplasm, are common. Plasma cells also may be visible.

The bone marrow shows lymphoid aggregates, a diffuse interstitial infiltrate, or a mixed nodular-diffuse pattern of the small lymphocytes, plasmacytoid lymphocytes, and plasma cells.

Hairy Cell Leukemia

The median age of patients with this disease is approximately 55 years, and the male:female ratio is about 4:1. In most patients, the neoplastic B-lymphoid cells affect primarily the bone marrow and spleen, causing splenomegaly and decreased circulating cells, including monocytes and neutrophils, in most patients. About 50% have pancytopenia at the time of diagnosis. The disease, which accounts for about 2% of adult leukemias, predisposes to bacterial infections because of neutropenia, but also causes diminished cell-mediated immunity. The result is an increased susceptibility to non-tuberculous mycobacteria, fungi, Listeria monocytogenes, Toxoplasma gondii, Pneumocystis pneumonia, and various viruses. Hairy cell leukemia is also the most common cause of paraneoplastic vasculitis, whose features are fever, nodular skin lesions, palpable purpura, and arthritis. Some patients have other rheumatologic disorders, including systemic sclerosis, polymyositis, and polyarteritis nodosa. Nearly all patients with this disease have palpable splenomegaly, often to gargantuan size, and about 40% have hepatomegaly.

In addition to reduction in one or more cell lines, peripheral smears in about 85% of cases reveal the hairy cells—small- to medium-sized lymphoid cells that possess a round, kidney-shaped, oval or bilobed, and commonly eccentric, nucleus with ground-glass chromatin, but absent or inconspicuous nucleoli, and abundant, pale-blue cytoplasm with numerous irregular, thin projections resembling hairs. Because of associated reticulin fibrosis, aspirating a bone marrow specimen may be difficult or impossible but, if successful, usually discloses conspicuous hairy cells. Bone marrow biopsies are usually hypercellular and demonstrate patchy, diffuse, or interstitial infiltration with mononuclear cells possessing abundant cytoplasm and prominent cell borders, creating a “fried-egg” appearance. The reticulin fibrosis produces a net-like pattern affecting areas of hairy cell infiltration. Hairy cells have acid phosphatase activity that is resistant to tartrate and, in >95% of cases, a tartrate-resistant acid phosphatase stain (TRAP) is positive. In the rare variant form of hairy cell leukemia, however, the TRAP stain is usually negative, the white count is elevated, neutropenia and monocytopenia are absent, and the hairy cells have prominent nucleoli, similar to the cells of prolymphocytic leukemia.

Multiple Myeloma (Plasma Cell Myeloma)

Multiple myeloma is a clonal proliferation of plasma cells that occurs in older adults (median age at diagnosis is about 70 years), and it has a greater incidence in blacks than in whites. Exposure to ionizing radiation is a predisposing condition. The clinical features relate to: (1) marrow or other organ infiltration by plasma cells; (2) the production of a monoclonal protein in blood or urine, which occurs in 99% of patients; or (3) immune deficiency from inadequate immunoglobulin production from the normal plasma cells. Bone marrow infiltration by the plasma cells can cause several lytic bone lesions, from which the term multiple myeloma (tumor of the bone marrow) arises. These are often painful. Because the plasma cells produce substances that both resorb bone and impair its formation, diffuse osteopenia can develop, which can be painful when pathologic fractures occur, especially in the vertebrae and ribs. Sometimes, extramedullary aggregates of plasma cells—plasmacytomas—develop, especially in the skin, lymph nodes, liver, and spleen. Anemia is present in about 70% of patients with multiple myeloma, in part from impaired erythropoiesis caused by bone marrow replacement with plasma cells. Another consequence of bony involvement is hypercalcemia, which can lead to lethargy, confusion, polyuria, constipation, nausea, and vomiting. The polyuria can lead to renal insufficiency.

Reduced kidney function also arises from the effects of monoclonal protein, which is IgG in about 60% of cases of multiple myeloma, IgA in 20%, and light chains alone (κ in about two-thirds, λ in about one-third) in 20%. About 80% of patients of excrete light chains (Bence-Jones protein) in the urine, and their precipitation in the tubules can cause renal insufficiency. It also may occur when circulating light chains are deposited in the glomeruli. In about 35% of patients with multiple myeloma, excess light chains form AL amyloid, causing proteinuria most commonly, but sometimes renal insufficiency. Amyloidosis also may cause the carpal tunnel syndrome and, less frequently, cardiomyopathy, macroglossia, or periorbital ecchymoses. Some monoclonal proteins injure the peripheral nerves, producing a symmetrical, sensorimotor, demyelinating polyneuropathy, especially in the context of POEMS syndrome, an acronym for a disorder that includes in various combinations polyneuropathy, organomegaly, endocrinopathies, M (monoclonal) protein, and skin changes. The organomegaly is enlargement of the spleen and liver; the endocrinopathies may be diabetes, thyroid disease, gonadal, or adrenal disorders; and the skin changes typically include diffuse hyperpigmentation, hypertrichosis, and cutaneous thickening. Fewer than 10% of patients with multiple myeloma, usually IgA type, develop hyperviscosity, characterized by bleeding, mental changes, visual blurring and decreased acuity, and congestive heart failure.

Decrease immunoglobulin production increases the risk of bacterial infections, especially from encapsulated organisms, such as Streptococcus pneumoniae and Haemophilus influenzae. Infections from gram-negative bacilli are also common, typically a complication of neutropenia from therapy or progressive disease.

The diagnosis of multiple myeloma depends on a concurrence of features, and several different diagnostic criteria have been proposed. Perhaps the most common scheme requires fulfilling one major and one minor criterion or three minor criteria. The major criteria are: (1) marrow plasmacytosis >30%; (2) plasmacytoma on biopsy; and (3) M-component (monoclonal protein) in the serum of IgG >3.5 g/dL or IgA >2 g/dL or in the urine >1 g/24h of Bence-Jones protein. Minor criteria are: (1) marrow plasmacytosis of 10% to 30%; (2) M component, but less than the values of the major criteria; (3) lytic bone lesions; and (4) immunoglobulins <50% of normal: IgG <600 mg/dL, IgA <100 mg/dL, IgM <50 mg/dL.

The peripheral blood smear may appear more basophilic than normal because of the presence of the acidic paraproteins, which also cause the red cells to adhere, resulting in rouleaux, stacks of erythrocytes, in areas where they would normally be separated. The red cells are usually normochromic and normocytic. Sometimes, leukoerythroblastosis, the presence of nucleated red cells and immature white cells, is apparent, indicating disruption of the bone marrow from the infiltrating plasma cells. Occasional plasma cells may be visible. When plasma cells are >2,000/mm3 (2 × 109/L) or constitute >20% of the circulating white cells, the term plasma cell leukemia is used. It can occur as the presentation of multiple myeloma or as a complication of a previously diagnosed case.

On bone marrow aspiration, the plasma cells may appear normal or may demonstrate altered maturation, such as a normal cytoplasm with a diffuse nuclear chromatin pattern, nucleoli, lobulated or multilobed nuclei, mitoses, and a high nuclear:cytoplasm (N:C) ratio. Immunoglobulins can appear in the cytoplasm as multiple small vacuoles (creating Mott cells), as large homogeneous spheres (Russell bodies), or as crystalline rods. The cytoplasmic margins may be eosinophilic, producing “flame cells.” Inclusions present in the nucleus are called Dutcher bodies. On bone marrow biopsy, the pattern of plasma cells may be: (1) interstitial—intermixed with normal hematopoietic cells; (2) nodular—discrete aggregates of plasma cells; or (3) packed—with plasma cells occurring in sheets, replacing the normal fat and hematopoietic cells and obliterating the normal marrow architecture. As in aspirates, Russell bodies, Mott cells, crystals, and Dutcher bodies may be visible.

Splenic Marginal-Zone Lymphoma

This rare disorder, previously called splenic lymphoma with villous lymphocytes, is a B-cell neoplasm in which small lymphocytes replace the white pulp germinal centers of the spleen. The mantle zone of B lymphocytes that ordinarily surrounds the germinal center, and with it constitute the follicle, may be intact or effaced, and the marginal zone beyond that layer contains larger cells, including blasts. Most patients are >50 years old, and it affects both genders equally. The major clinical feature is splenomegaly. Some patients have immune thrombocytopenia or hemolytic anemia, but enlarged peripheral lymph nodes are uncommon, and extranodal disease is rare. About one-third of patients have a monoclonal gammopathy. Most patients have marrow involvement, but the peripheral blood usually shows only modestly increased numbers of pleomorphic small lymphocytes. Some are “villous” lymphocytes, which have a round or oval nucleus with moderately condensed chromatin, sometimes a small nucleolus, and basophilic cytoplasm, with short, thin projections, characteristically at one pole of the cell. Small numbers of plasmacytoid lymphocytes and plasma cells also may be present. In the bone marrow, the same combination of cells are present in a diffuse or nodular pattern.

Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma)

This neoplasm, usually an adult disease with a median age of about 60 years, constitutes about 8% of non-Hodgkin lymphomas. It often occurs in disorders associated with chronic lymphocytic inflammation, such as Sjögren disease, Hashimoto thyroiditis, and gastritis caused by Helicobacter pylori. The gastrointestinal tract is the most common site of disease, especially the stomach, and this neoplasm constitutes about 50% of all primary gastric lymphomas. Other common sites are the lungs, salivary glands, eye, skin, and thyroid. Bone marrow involvement is uncommon, and lymph nodes are variably affected, depending in part on the site of extranodal disease. In the involved tissue, the lymphoma cells are heterogeneous in appearance and include small lymphocytes, monocytoid B cells, sometimes plasma cells, and cells primarily residing in the marginal zone outside the lymphoid follicles. These cells look like centrocytes in being small to medium in size and having irregular nuclei with dispersed chromatin, inconspicuous nucleoli, and generous, pale cytoplasm. Large cells resembling centroblasts are usually present, but not predominant. When they involve the epithelium, marginal-zone cells typically accumulate in aggregates and distort or destroy it. In lymph nodes, the lymphoma cells occupy the marginal zone.

Follicular Lymphoma

Follicular lymphoma constitutes about 40% of non-Hodgkin lymphoma in the United States, affecting primarily adults, with a median age of about 60 years and equal gender distribution. Most patients have widespread disease at diagnosis, with diffuse lymph node enlargement, bone marrow involvement in about 40% of patients, and circulating neoplastic cells in about 10%. In 25% to 35% of cases the disease transforms into a large B-cell lymphoma, usually diffuse.

The lymphoma is called “follicular” because the neoplastic cells are those normally present in the germinal centers of lymphoid follicles—centrocytes and centroblasts—and because in affected tissue the cells maintain at least partially the follicular pattern of discrete aggregates rather than diffuse involvement. The predominant cells, the centrocytes, are small to medium in size, have scant pale cytoplasm, inconspicuous nucleoli, and nuclei that are twisted, elongated, or cleaved. The centroblasts are large, have noncleaved, round to oval nuclei with nucleoli, and possess sparse, basophilic cytoplasm. The proportion of centroblasts determines the grade of lymphoma based on microscopic examination of 10 neoplastic follicles at 40× high-power magnification: Grade 1 has 0 to 5 centroblasts/high-power field (hpf); Grade 2 has 6 to 15 centroblasts/hpf; Grade 3a has >15 centroblasts/hpf with centrocytes also present; Grade 3b has >15 centroblasts/hpf without centrocytes. In peripheral blood smears, the neoplastic cells are commonly smaller than normal lymphocytes, have very sparse cytoplasm, and possess cleft nuclei. In patients with bone marrow involvement, the process is typically focal and paratrabecular in location and, as in lymph nodes, the predominant cells are the centrocytes, which are small lymphocytes with cleaved nuclei. Larger cells—either large centrocytes, with irregular or cleft nuclei, or centroblasts, with round or oval, noncleaved nuclei and prominent nucleoli—also are present.

Mantle Cell Lymphoma

This lymphoma, which constitutes about 5% to 10% of non-Hodgkin lymphoma, occurs primarily in adults, with a median age at diagnosis of about 60 years and a male predominance of at least 2:1. The disease is usually widespread, affecting lymph nodes, liver, spleen, and bone marrow. Some patients have gastrointestinal disease, with numerous lymphomatous polyps anywhere in the alimentary tract. The neoplastic cell closely resembles centrocytes, appearing as small- to medium-sized lymphocytes with sparse cytoplasm and irregular or cleaved nuclei containing moderately dispersed chromatin and inconspicuous nucleoli. In some cases, the cells tend to surround the germinal centers of lymph nodes in the mantle zone. The cell of origin is thought to be naïve B cells normally present in the mantle zone. Some cytologic variants occur, including a blastoid type in which cells resemble lymphoblasts with dispersed chromatin. Bone marrow involvement in mantle cell lymphoma includes interstitial, focal, paratrabecular, and diffuse patterns. The cells are small lymphocytes with irregular and cleaved nuclei, resembling centrocytes. Centroblasts are not present.

Diffuse Large B-Cell Lymphoma

This disorder accounts for about 40% of non-Hodgkin lymphomas. It occurs at all ages, but the median age at diagnosis is about 60 years. Patients typically have a rapidly enlarging mass at the sites of disease, which include lymph nodes, stomach, ileocecal region of the intestinal tract, and a wide variety of other extranodal areas. Bone marrow involvement, however, is rare. The histologic pattern is diffuse replacement of the normal tissue with large neoplastic cells of various morphologies that are at least twice the size of normal lymphocytes. The most common is the centroblastic type, in which the cells have oval to round vesicular nuclei with two to four nucleoli and sparse basophilic cytoplasm. In the immunoblastic variant, >90% of cells have a single, central nucleolus in the nuclei and abundant basophilic cytoplasm. In the T-cell/histiocytic-rich type, most cells are normal T cells and histiocytes, with <10% being large neoplastic B cells. The anaplastic variant has very large cells with bizarre, pleomorphic nuclei.

Mediastinal Large B-Cell Lymphoma

This is a subtype of diffuse large B-cell lymphoma in which the proposed cell of origin is a B cell normally present in the medulla of the thymus. It especially occurs in adolescents and young adults: The median age at diagnosis is in the third decade. Most patients are female. The clinical scenario is a rapidly enlarging anterior mediastinal mass, often producing the superior vena cava syndrome and airway obstruction. Extranodal involvement is uncommon initially, but disease can spread to various sites, including brain, skin, liver, kidneys, and adrenals. The neoplastic cells resemble those of other large B-cell lymphomas, with varying sizes and nuclear shapes, but usually with abundant basophilic cytoplasm.

Burkitt Lymphoma

This rapidly growing neoplasm commonly involves extranodal areas and occurs in three different settings. Endemic Burkitt lymphoma affects young children in equatorial Africa and Papua, New Guinea, typically causing masses in the jaw and other facial bones. Other common sites of involvement are the distal ileum, cecum, omentum, ovaries, kidneys, and breasts. Evidence of Epstein-Barr viral infection is present in all patients, and co-infection with malaria may predispose to the development of lymphoma. Sporadic Burkitt lymphoma occurs worldwide, affecting predominantly children and young adults, with a male:female ratio of about 3:1. In the United States, this neoplasm causes about 30% of childhood non-Hodgkin lymphoma. The commonest presentation is with abdominal tumors involving the ileocecal area and peritoneum, but ovaries, kidneys, and breasts often are affected. Evidence of Epstein-Barr virus in tumor cells is <30%. Immunodeficiency-associated Burkitt lymphoma occurs primarily in people infected with the human immunodeficiency virus (HIV), but it can occur in other immunosuppressed patients, such as organ transplant recipients. The presentation is similar to that of patients with the sporadic form, but nodal, bone marrow, and meningeal involvement is more common. Epstein-Barr virus is found in 25% to 40% of the neoplasms.

The relatively uniform, medium-sized neoplastic cells diffusely infiltrate the affected areas and show numerous mitotic figures and spontaneous cell death (apoptosis). They have round nuclei with clumped chromatin and multiple, central nucleoli. The basophilic cytoplasm usually contains lipid vacuoles. The benign histiocytes ingesting the dead cells have a clear cytoplasm, and their presence in the dark background of the abundant lymphoma cells gives the appearance of a “starry sky.” Two variants are Burkitt lymphoma with plasmacytoid differentiation and atypical Burkitt/Burkitt-like lymphoma. Both have more pleomorphic nuclear sizes and shapes. In the former, some tumor cells contain a single nucleolus and a monotypic immunoglobulin in eccentric basophilic cytoplasm. In the latter, the nucleoli are more prominent and fewer in number than they are in typical Burkitt lymphoma.

Mature T-Cell and NK-Cell Neoplasms

The classification of these neoplasms depends on combining histologic, immunophenotypic, genetic, and especially, clinical features because morphologic and immunophenotypic abnormalities may be diverse in a specific disorder and yet similar among different diseases. As a group, these disorders have specific geographic foci (especially Asia), have infrequent lymph node involvement, demonstrate cell death (apoptosis) and necrosis, are accompanied by an increased incidence of the hemophagocytic syndrome, and often are associated with viral infections, especially with the Epstein-Barr virus.

T-Cell Prolymphocytic Leukemia

This disorder accounts for about 2% of adult small lymphocytic leukemias and is primarily a disease of people >50 years old, with most patients having impressive splenomegaly. Generalized lymph node enlargement and hepatomegaly are common. Skin nodules or diffuse papular rashes occur in about 25% of cases, pleural effusions or ascites in about the same number. The major laboratory finding is a very high white count, exceeding 200×109/L in about two-thirds of patients. Anemia and thrombocytopenia are also common. The diagnosis is established on peripheral blood films, where most cells are prolymphocytes, with a well-defined central nucleolus and a deeply basophilic cytoplasm that often demonstrates blebs or protrusions. These cells are larger than normal small lymphocytes, but in 20% of cases of T-cell prolymphocytic leukemia (the small-cell variant), the cells are small, with more condensed nuclear chromatin and no apparent nucleolus, which, however, is apparent on electron microscopy.

Bone marrow aspirates show the same cells that are present on blood smears. Bone marrow biopsies show heavy infiltration that can be interstitial, nodular, diffuse, or mixed. The number of reticulin fibers is increased.

T-Cell Large Granular Lymphocytic Leukemia

The median age of patients with this disorder is about 60 years, and many have clinical and serologic evidence of rheumatoid arthritis. About 40% are asymptomatic at the time of diagnosis. The most prominent clinical feature is splenomegaly, present in about 50%; lymph node enlargement is rare. The white cell count is elevated because of an increased number of large granular lymphocytes, which usually appear normal and have round or oval, eccentric nuclei with condensed chromatin and abundant basophilic cytoplasm containing small or large purplish granules. To fulfill diagnostic criteria these cells should exceed 2 × 109/L for at least 6 months without an alternative explanation. Severe neutropenia, sometimes associated with bacterial infections, is present in about 50% of patients, and a few have pure red cell aplasia. Bone marrow involvement is variable and often minimal, the typical pattern being interstitial or diffuse, but rarely nodular. Patients with neutropenia usually have normal immature granulocytes but decreased neutrophils (maturation arrest), and patients with thrombocytopenia characteristically demonstrate adequate or increased megakaryocytes. Anemia may be accompanied by red cell aplasia or hypoplasia.

Aggressive NK-Cell Leukemia

This disorder typically occurs in adolescents or young adults and is more common in Asians than in whites. The clinical features are usually fever and hepatosplenomegaly, associated with anemia, thrombocytopenia, and neutropenia. The peripheral blood film shows the leukemic cells, which may be sparse or numerous, as slightly bigger than normal large granular lymphocytes, some with irregular, hyperchromatic nuclei and coarser or more open chromatin. In the abundant pale or light-blue cytoplasm are fine or coarse azurophilic granules. The bone marrow demonstrates minimal to pronounced infiltration with neoplastic cells, sometimes accompanied by erythrophagocytic histiocytes (hemophagocytosis). Evidence of Epstein-Barr virus infection detected by in situ hybridization is present in most cases.

Adult T-Cell Leukemia/Lymphoma

This disorder, caused by infection with the retrovirus human T-cell leukemia virus type 1, is endemic in Japan, the Caribbean, and parts of central Africa. Most patients have acquired the infection at an early age through breast milk or exposure to blood, and the lifetime cumulative risk of later developing leukemia or lymphoma, which occurs at a median age of about 55 years, is approximately 2%. The typical clinical features include generalized lymph node enlargement, hypercalcemia, hepatosplenomegaly, and skin lesions, which can be nodules, papules, or a diffuse scaly rash. Four clinical patterns occur. Most common is the acute variant, which includes constitutional symptoms, diffuse lymph node enlargement, skin rash, hepatosplenomegaly, hypercalcemia with or without lytic bone lesions, high numbers of circulating leukemic cells, and an elevated serum lactic dehydrogenase (LDH). Some patients have opportunistic infections from decreased cell-mediated immunity. The lymphomatous variant consists of generalized lymph node enlargement without circulating leukemic cells. Hypercalcemia and elevated LDH may be present. The chronic variant has prominent skin lesions, mostly an exfoliative process, but no hypercalcemia. The white count is elevated, with >10% being leukemic cells. Serum LDH is slightly increased. The smoldering variant has a normal white cell count with <3% neoplastic cells, normal serum calcium and LDH, and no enlargement of lymph nodes, spleen, or liver. Pulmonary involvement and skin rashes may be present.

On peripheral smear the leukemic cells are markedly pleomorphic. The chromatin is coarsely clumped, nucleoli are present, and the nuclei often have numerous lobes that resemble flowers or clover. The cytoplasm is deeply basophilic. A small number of cells may resemble blasts, with dispersed nuclear chromatin. The bone marrow pattern may be patchy, interstitial, or diffuse. Cell size varies from small to large but, in most cases, the nuclei are pleomorphic in shape, lobulation, and chromatin appearance. Nucleoli are usually prominent. In the chronic and smoldering variants, small cells with minimal cellular abnormalities may be present. Osteoclasts and bone marrow resorption commonly are increased, sometimes even when neoplastic cells are not apparent.

In some patients with early or smoldering disease the lymph nodes resemble Hodgkin lymphoma in having diffuse paracortical infiltrates of small- to medium-sized lymphocytes and interspersed Reed-Sternberg–like cells (large cells with multiple nuclei containing prominent nucleoli) and giant cells with convoluted or lobulated nuclei. These cells, which express CD30 and CD15, are EBV-positive B lymphocytes, thought to proliferate in this disease because of the immunodeficiency that the T-cell neoplasm causes.

Extranodal NK-/T-Cell Lymphoma, Nasal Type

This disorder, virtually always associated with Epstein-Barr virus when it involves the nose, is more common in males than females and is more frequent in Asia and Latin America than elsewhere. It may develop in immunocompromised patients, including organ transplant recipients. The disease typically occurs in adults and originates as a mass or diffuse neoplastic infiltration causing nasal obstruction, pain, or bleeding. The process can extend to neighboring structures, causing swelling or destruction of the affected tissues. From these areas, it can disseminate to distant sites, such as the gastrointestinal tract, cervical lymph nodes, and the skin, where nodules and ulcers may form. When the disease originates outside the nasal cavity, systemic symptoms can occur, and multiple sites, such as skin and alimentary tract, often are involved.

The lymphoma cells commonly are intermingled with numerous benign cells, such as small lymphocytes, histiocytes, eosinophils, and plasma cells, making the disease often appear inflammatory rather than neoplastic. The process is destructive, typically causing ulceration and necrosis. It tends to occur around vessels, which it destroys. The cells are diverse in size and appearance. They may have irregular and elongated nuclei, often undergoing mitosis, with granular chromatin. The cytoplasm is commonly pale.

The peripheral blood film rarely discloses neoplastic cells, which have azurophilic cytoplasmic granules. Similarly, the bone marrow rarely is involved with neoplastic cells.

Hepatosplenic T-Cell Lymphoma

This rare disorder typically occurs in adolescents and young adults, affecting males much more frequently than females. Some patients have had previous solid organ transplants. The main clinical feature is marked hepatosplenomegaly, usually accompanied by thrombocytopenia. Lymph nodes usually are not enlarged. Anemia, sometimes from hemolysis, and leukocytosis also may occur. The peripheral blood film rarely shows neoplastic cells, but they usually are present on the bone marrow aspirate as medium-sized lymphocytes with dispersed chromatin and mildly basophilic cytoplasm. The marrow biopsy shows interstitial or intrasinusoidal infiltration with medium- to large-sized lymphoid cells with a rim of pale cytoplasm.

Mycosis Fungoides and Sézary Syndrome

This disorder occurs most commonly in adults, with a male:female ratio of about 2:1. It is a T-cell cutaneous lymphoma that begins as flat areas of scaling and erythema that may be asymptomatic or pruritic. At varying intervals, but typically after several years, it may progress to cause dusky red to violaceous plaques—sharply demarcated lesions that are elevated above the surrounding normal skin. Sometimes, lymph nodes are enlarged, but biopsies commonly show a reactive pattern, rather than neoplastic infiltrates. If the disease continues to advance, the next stage is the formation of cutaneous tumors. Only then does the lymphoma tend to spread to extracutaneous sites, typically, lymph nodes, spleen, liver, and lungs.

Confident pathologic diagnosis of mycosis fungoides can be very difficult, especially in the early stages, and numerous skin biopsies, sometimes taken over intervals of months to years, may be necessary before the characteristic findings are clearly present. The diagnostic abnormality consists of dermal and epidermal infiltration of small- to medium-sized T cells with irregular nuclei whose convolutions resemble the brain (cerebriform nuclei). In the dermis, infiltrates typically are present at the epidermal border and consist of small lymphocytes, eosinophils, and the neoplastic cells. Single or small numbers of the neoplastic cells may be present in the epidermis, but sometimes many aggregate there to form Pautrier's abscesses. Enlarged lymph nodes commonly represent dermatopathic lymphadenopathy, which consists of numerous histiocytes expanding the paracortical areas. A few cerebriform lymphocytes may be present, but not in clusters. This Grade I disease is considered to be uninvolved by neoplasm. Early involvement with mycosis fungoides (Grade II) shows focal disruption of lymph node architecture by aggregates of atypical cerebriform lymphocytes. Grade III lymph nodes have complete replacement of the lymph node by diffuse infiltrates of atypical cerebriform cells. One variant of mycosis fungoides is pagetoid reticulosis, in which a chronic solitary plaque is present, and the neoplastic cells are located only in the epidermis. Another is follicular mucinosis, in which the lymphoma cells are present only in hair follicles, where they cause mucinous degeneration. Clinically, the lesions are indurated papules or plaques, which in hairy areas can cause alopecia.

Sézary syndrome may be another variant of mycosis fungoides or, at least, closely resembles it. It occurs in adults and is defined by erythroderma (cutaneous redness and scaling involving nearly all the skin surface), generalized lymph node enlargement, and the presence of circulating neoplastic cells. Pruritus is typically present, and the disease may cause alopecia. As in mycosis fungoides, the skin shows dermal and epidermal infiltration with cerebriform lymphocytes. Lymph nodes show Grade II or III involvement. The peripheral blood film has numerous small or large neoplastic cells with cerebriform nuclei containing condensed chromatin. The N:C ratio is large. Because these cells may appear in small numbers in both benign skin diseases and early stages of mycosis fungoides, most criteria require that their level exceed 1,000/mm3. Because mycosis fungoides can cause erythroderma, some experts distinguish it from Sézary syndrome according to this hematologic criterion.

Peripheral T-Cell Lymphoma, Unspecified

This category includes about 50% of the peripheral T-cell lymphomas in Western countries. Most cases occur in adults, and the disease usually presents with nodal involvement, but disseminated disease is common, often with circulating neoplastic cells and affected extranodal sites, especially the skin. Constitutional symptoms, such as weight loss, fever, and fatigue, are frequent.

These lymphomas cause diffuse infiltration of lymph nodes with neoplastic cells that are variable, but most commonly medium- to large-sized cells with irregular, pleomorphic nuclei and prominent nucleoli. Vascular proliferation in the lymph node is common, and often a mixed inflammatory reaction is prominent, including eosinophils, plasma cells, small lymphocytes, and epithelioid histiocytes. Multinucleated cells resembling Reed-Sternberg cells and “clear cells” with very pale cytoplasm may be present. Two rare subtypes are the T-zone and lymphoepithelioid cell variants. The former has small- to medium-sized neoplastic cells in intact follicles. The latter has small cells and numerous clusters of epithelioid histiocytes.

Anaplastic Large-Cell Lymphoma

This disorder causes about 3% of adult non-Hodgkin lymphoma and about 10% to 30% in childhood. The usual clinical features are generalized lymph node enlargement and constitutional symptoms, including fever. The disease is commonly widespread at the time of diagnosis, typically involving such extranodal sites as skin, bone, lung, and liver. The neoplastic cells are pleomorphic, but despite this lymphoma's having three variants—common, lymphohistiocytic, and small-cell—all cases include some characteristic cells called “hallmark cells” because they are present in all types. These have eccentric nuclei shaped like horseshoes or kidneys, sometimes with a perinuclear eosinophilic area. They are usually, but not always, large. In the common variant, which accounts for about 70% of cases, large hallmark cells typically predominate, and they possess abundant cytoplasm that is clear, basophilic, or eosinophilic. Multiple nuclei may occur, the chromatin usually is dispersed, and nucleoli are prominent. Sometimes, the hallmark cells are less numerous than the large neoplastic cells with rounded nuclei. In the lymphohistiocytic variant, which constitutes about 10% of cases, the numerous histiocytes coexist with and may outnumber the neoplastic cells, which may be smaller than in the common variant and tend to aggregate around vessels. The histiocytes may demonstrate erythrophagocytosis. In the small-cell variant, which accounts for about 5% to 10% of cases, the major neoplastic cells are small to medium in size and have irregular nuclei. Hallmark cells tend to aggregate around blood vessels. Neoplastic cells are rarely visible in the peripheral blood film, where they are large and pleomorphic. On bone marrow aspirates, they are also usually sparse. Bone marrow biopsies may show the large, pleomorphic, and sometimes multinucleated lymphoma cells in an interstitial, focal, or diffuse pattern.

Hodgkin Lymphoma

Hodgkin lymphomas constitute about 30% of all lymphomas. The characteristic tumor cells, which have single (Hodgkin cells) or multiple nuclei (Reed-Sternberg cells), intermingle with inflammatory cells and other non-neoplastic cells. The WHO classification divides this disorder into two major categories: nodular lymphocyte–predominant Hodgkin lymphoma and classical Hodgkin lymphoma, which has four subtypes—nodular sclerosis, mixed-cellularity, lymphocyte-rich, and lymphocyte-depleted Hodgkin lymphoma.

Hodgkin lymphoma is classified according to Stages I through IV.

·     Stage I: Single lymph node region or lymphoid organ (spleen, thymus, Waldeyer ring) is involved.

·     Stage II: ≥ 2 lymph node regions involved on same side of diaphragm, with number of anatomic sites indicated by suffix (e.g., II3).

·     Stage III: Lymph node regions or structures involved on both sides of the diaphragm:

·     III1: with or without splenic, hilar, celiac, or portal nodes

·     III2: with paraaortic, iliac, or mesenteric nodes

·     Stage IV: Involvement of extranodal sites beyond those designated E.

·     E: Involvement of a single extranodal site or contiguous with or proximal to nodal diseases site.

Other qualifying designations include the presence or absence of specific constitutional symptoms: A: no symptoms; B: fever, drenching sweats, or weight loss. The presence of bulky disease, X, is defined by greater than one-third mediastinal widening at T5–T6 or a nodal mass >10 cm.

The neoplastic cells rarely appear in the peripheral blood smear. Even with marrow involvement, they are also uncommon in the bone marrow aspirate, where they appear as large cells with two nuclei and prominent nucleoli. On bone marrow biopsy, neoplastic cells are present in about 10% of cases and usually exist in a mixture of small lymphocytes, eosinophils, and macrophages. The pattern can be either focal or diffuse. Variations include the presence of numerous Reed-Sternberg cells with few other cells, a fibrotic marrow with few neoplastic cells, and a hypocellular marrow with scattered foci of neoplastic and reactive cells.

Nodular Lymphocyte–Predominant Hodgkin Lymphoma

This monoclonal B-cell disorder accounts for about 5% of Hodgkin lymphoma and typically occurs in adults 30 to 50 years of age, with males more commonly affected than are females. It usually causes localized lymph node enlargement in cervical, axillary, and inguinal lymph nodes. These nodes are replaced partly or completely by a nodular or diffuse infiltrate of small lymphocytes, histiocytes, and large neoplastic cells that are variants of Reed-Sternberg cells, known as popcorn or L&H (lymphocytic and histiocytic) cells. These usually have a single, large nucleus that often is folded or multilobulated, with several basophilic nucleoli, and sparse cytoplasm.

Classical Hodgkin Lymphoma

This group accounts for 95% of cases of Hodgkin lymphoma and tends to occur in two age groups: between 15 and 35 years and a second, smaller group in the sixth decade. Most patients present with localized lymph node enlargement affecting cervical, mediastinal, axillary, or para-aortic regions. The spleen often is affected, but primary extranodal involvement is rare, as is bone marrow infiltration, except in advanced disease. The diagnosis requires finding neoplastic cells. One type is Reed-Sternberg cells, which are large with multiple nuclei or nuclear lobes and prominent eosinophilic nucleoli, at least two in two separate nuclear lobes to be diagnostic. Similar, but mononuclear, cells are called Hodgkin cells. These cells are thought to originate nearly always from mature B cells in the germinal center. Rarely, they derive from peripheral T cells. Accompanying and far outnumbering these neoplastic cells are reactive, non-neoplastic cells, whose identity varies according to the histologic subtype.

Nodular Sclerosis Hodgkin Lymphoma

This type accounts for about 70% of classical Hodgkin lymphoma, with a median age of 28 and equal gender distribution. Most patients present with stage II disease, and about 40% have B symptoms. The most common site of involvement is the mediastinum. The affected lymph nodes demonstrate the presence of collagen bands that divide the lymphoid tissue into nodules. The neoplastic cells, which occur in a mixture of small lymphocytes, plasma cells, eosinophils, and macrophages, tend to have nuclei with more lobules and smaller nucleoli than in other types of classical Hodgkin lymphoma. In formalin-fixed tissue sections, a clear space surrounds these Reed-Sternberg cells because of cytoplasmic retraction, giving them the name of lacunar cells, because they seem to rest in lacunae.

Mixed-Cellularity Hodgkin Lymphoma

This type accounts for about 25% of cases of classical Hodgkin lymphoma, is more common in males, sometimes occurs in patients with HIV infection, and has evidence of genomes of Epstein-Barr virus in the tissue in at least 70% of cases. The average age is about 35 to 40 years. Patients commonly have advanced disease and B symptoms, with widespread enlargement of peripheral lymph nodes. The spleen is involved in 30% of patients. The internal structure of the lymph nodes is effaced by diffuse infiltration with a combination of small lymphocytes, plasma cells, eosinophils, macrophages, and numerous neoplastic cells, including both Reed-Sternberg cells and mononuclear variants.

Lymphocyte-Rich Classical Hodgkin Lymphoma

In this disease, which constitutes about 5% of classical Hodgkin disease, peripheral lymph node enlargement is the main feature, and patients usually have stage I or II disease without B symptoms. About 70% of patients are males. The lymph nodes can show a diffuse or nodular pattern with numerous small lymphocytes, no neutrophils or eosinophils, and scattered neoplastic cells that can either be characteristic Reed-Sternberg and Hodgkin cells or resemble L&H cells. About 40% have evidence of infection with Epstein-Barr virus.

Lymphocyte-Depleted Classical Hodgkin Lymphoma

This type, which accounts for <5% of classical Hodgkin lymphoma, often is associated with HIV infection. The median age is 37 years, and about 75% of patients are male. Peripheral lymph nodes are less commonly involved than are retroperitoneal lymph nodes, abdominal organs, and bone marrow. Most patients have advanced disease with B symptoms. The lymph nodes have a relative paucity of lymphocytes compared with neoplastic cells. Sometimes, diffuse fibrosis is present, and the neoplastic cells may be pleomorphic. Evidence of Epstein-Barr infection is common.

 

Table 5.1 World Health Organization classification of lymphoproliferative disorders

B-cell Neoplasms
Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma
Mature B-cell neoplasms
Chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Splenic marginal-zone B-cell lymphoma
Hairy cell leukemia
Plasma cell myeloma
Monoclonal gammopathy of undetermined significance
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Primary amyloidosis
Heavy-chain diseases
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
Nodal marginal zone B-cell lymphoma
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
Primary effusion lymphoma
Burkitt lymphoma/leukemia
B-cell proliferations of uncertain malignant potential
Lymphomatoid granulomatosis
Posttransplant lymphoproliferative disorder, polymorphic
T-cell and NK-cell Neoplasms
Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma
Mature T-cell and NK-cell neoplasms
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Aggressive NK-cell leukemia
Adult T-cell leukemia/lymphoma
Extranodal NK-/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides
Sézary syndrome
Primary cutaneous anaplastic large cell lymphoma
Anaplastic large cell lymphoma
Angioimmunoblastic T-cell lymphoma
Peripheral T-cell lymphoma, unspecified
T-cell proliferation of uncertain malignant potential
Lymphomatoid papulosis
Neoplasm of uncertain lineage and stage of differentiation
Blastic NK-cell lymphoma
Hodgkin lymphoma
Nodular lymphocyte predominance
Classical
   Nodular sclerosis
   Lymphocyte-rich
   Mixed cellularity
   Lymphocyte depletion

NK, natural killer.
Adapted with permission from Wintrobe's Clinical Hematology, 11th Edition, page 2304.

 

Table 5.2 Selected antibodies that are useful in immunophenotypic analysis of non-hodgkin lymphomas

Clusters of Differentiation (CD)

Number

Antibodies

Reactivity

CD1

Leu-6, T6, and OKT6

Thymocytes, dendritic cells, and epidermal Langerhans cells

CD2

Leu-5, T11, and OKT11

T cells and natural killer cells

CD3

Leu-4, T3, OKT3, UCHT-1, and poly-CD3

T cells

CD4

Leu-3, T4, and OKT4

Helper and inducer T cells, monocytes, and macrophages

CD5

Leu-1, T1, OKT1, and UCHT-2

T cells and B-cell subset

CD7

Leu-9 and 3A1

T cells and natural killer cells

CD8

Leu-2, T8, OKT8, and UCHT-4

T-cytotoxic and -suppressor cells and natural killer cells

CD10

CALLA, J5, and BA-3

Progenitor B lymphocytes and B-cell subset (follicular center cells)

CD11b

Leu-15 and Mo-1

Granulocytes, monocytes, natural killer cells, T-cell subset

CD11c

Leu-M5 and Ki-M1

Monocytes and macrophages, granulocytes, natural killer cells, and B-cell subset (hairy cell leukemia and monocytoid B cells)

CD14

Leu-M3, Mo2, MY4, and UCHM-1

Monocytes, granulocytes, and epidermal Langerhans cells

CD15

Leu-M1 and MY1

Granulocytes, monocytes, Reed-Sternberg cells, activated lymphocytes, and some epithelial cells

CD16

Leu-11

Natural killer cells, granulocytes, macrophages, and T-cell subset

CD19

Leu-12 and B4

B cells

CD20

Leu-16, B1, and L26

B cells

CD21

B2

B-cell subset and follicular dendritic cells

CD22

Leu-14

B-cell subset

CD23

Leu-20 and B6

Activated B cells and follicular mantle B cells

CD24

BA-1

B cells and granulocytes

CD25

IL2R and Tac

Activated T and B cells and activated macrophages

CD30

Ki-1 and Ber-H2

Activated T and B cells and Reed-Sternberg cells

CD38

Leu-17 and T10

Plasma cells, thymocytes, and activated T cells

CD43

Leu-22, MT1, and DFT1

T cells, B-cell subset, granulocytes, and monocytes and macrophages

CD45

T29/33, HLe-1, and T200

Leukocytes

CD45RA

Leu-18 and 4KB5

B cells, T-cell subset, granulocytes, and monocytes

CD45RB

LCA and PD7/26/16

B cells, T-cell subset, granulocytes, and monocytes and macrophages

CD45RO

UCHL1 and A6

T cells, B-cell subset, granulocytes, and monocytes and mocrophages

CD56

Leu-19 and NKH1

Natural killer cells and T-cell subset

CD57

Leu-7 and HNK1

Natural killer cells and T-cell subset

CD68

KP1, Ki-M6, and KiM7

Monocytes and macrophages

CD71

T9 and OKT9

Activated T and B cells, macrophages, and proliferating cells

CD74

LN2

B cells, monocytes and macrophages, and Reed-Sternberg cells

CDw75

LN1

B cells and some epithelial cells

CD79a

mb-1

B cells

CD103

HML-1

Intestinal intraepithelial T cells

CD138

Syndecan

Plasma cells and plasmablasts

 

IgG, A, M, D, and E

Immunoglobulin heavy chains

 

κ, λ

Immunoglobulin light chains

 

Anti-TCR αβ, βF1

αβ T cells

 

Anti-TCR γσ

γσ T cells

 

HLA-DR and LN3

Activated T and B cells, monocytes, and macrophages

 

Anti-TdT

Lymphoblasts and some myeloblasts

 

Anti-lysozyme

Monocytes, macrophages, and granulocytes

 

MAC 387

Macrophage subset

 

EMA

Epithelial cells, plasma cells, and some lymphoid neoplasms, including lymphocyte predominant Hodgkin lymphoma and anaplastic large cell lymphoma

 

Ki-67, PCNA

Nuclear proliferation antigens

 

Antiperforin, antigranzymes A, B, and C; and anti-TIA-1

Cytolytic granule-associated proteins in natural killer cells and cytotoxic T cells

 

 

Table 5.3 Staging of non-hodgkin lymphoma

Staging System

Stage

Definition

Ann Arbor

I

Involvement of a single lymph node region or a single extranodal organ or site (stage IE).

II

Involvement of two or more node regions on the same side of the diaphragm or localized involvement of an extranodal site or organ (stage IIE) and one or more lymph node regions on the same side of the diaphragm.

III

Involvement of lymph node regions on both sides of the diaphragm that may also be accompanied by localized involvement of an extranodal organ or site (stage IIIE) or spleen (stage IIIS), or both (stage IIISE).

IV

Diffuse or disseminated involvement of one or more distant extranodal organs with or without associated lymph node involvement.

B symptoms

Fever >38°C, night sweats, or weight loss >10% of body weight in the 6 mo preceding admission, or a combination of these, is defined as a systemic symptom.

National Cancer Institute Modified Staging System

I

One or two nodal sites or one extranodal site of disease without poor prognostic features.

II

More than two nodal sites of disease or one or more localized extranodal sites plus draining nodes with none of the following poor prognostic features: performance status ≤70, B symptoms, any mass >10 cm in diameter (particularly abdominal), serum lactate dehydrogenase >500 IU/dl, bone marrow involvement, three or more extranodal sites of disease.

III

Stage I or II plus any poor prognostic features.

International Prognostic Index

Adverse factors

Risk group

Number of factors

   Performance status ≥2a

   Low

   0, 1

   Lactate dehydrogenase > normala

   Low-intermediate

   2

   Extranodal sites ≥2

   High-intermediate

   3

   Stage III and IV diseasea

   High

   4, 5

   Age >60 yr

aAge-adjusted factors.
Reprinted with permission from Wintrobe's Clinical Hematology, 11th Edition, page 2374.

 

Table 5.4 Pathologic features in the differential diagnosis of small B-cell lymphomas

 

Immunophenotype

 

 

Growth Pattern

Cytology

CD5

CD23

CD10

Surface Ig

Cytogenetics

B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma

Diffuse effacement with proliferation centers

Small round nuclei, scant cytoplasm

+

+

-

Weak IgM and IgD

Trisomy 12 dels: 17p13, 11q22, 13q14

Lymphoplasmacytic lymphoma

Diffuse or interfollicular

Small lymphocytes, plasma cells, and plasmacytoid lymphocytes

-

-

-

Moderate IgM

t(9;14) (p13;q32)

Mantle cell lymphoma

Diffuse or vaguely nodular

Irregular nuclei, scant cytoplasm, and few large cells

+

-

-

Moderate IgM and IgD
Lambda > kappa

t(11;14) (q13;q32)

Follicular lymphoma

Follicular

Irregular cleaved nuclei (centrocytes) and admixed large cells (centroblasts)

-

-

+

Bright IgM > IgG > IgA

t(14;18) (q32;q21) > 85%

Nodal marginal zone B-cell lymphoma

Interfollicular and perisinusoidal

Small, round, and folded nuclei and abundant cytoplasm ± plasma cells

-

-

-

Moderate IgM

Trisomy 3

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue

Diffuse

Small, round, and folded nuclei and abundant cytoplasm plasma cells

-

-

-

IgM

Trisomy 3 t(11;18) (q21;q21)

Ig, immunoglobulin; +, positive; -, negative.
Adapted with permission from Wintrobe's Clinical Hematology, 11th Edition, page 2304.

 

Table 5.5 Immunophenotype of CLL and other chronic B-cell disorders

Condition

smIg

CD5

CD10

CD11c

CD19

CD20

CD22

CD23

CD25

CD43

CD79b

CD103

FMC7

Chronic lymphocytic leukemia

Dim

++

-

-/+

++

Dim

-/+

++

+/-

+

-

-

-/+

Waldenström macroglobulinemia

++

-

-

-/+

++

++

+

-

-/+

+

++

-

+

Prolymphocytic leukemia

+++

-/+

-/+

-/+

++

+++

++

++

-/+

+

++

-

+

HCL

+++

-

-

++

+++

+++

+++

-

+++

+

+

+++

+++

HCL variant

+++

-

-

++

+++

+++

+++

-

-

+

+

+++

+++

Splenic lymphoma with villous lymphocytes

++

-/+

-/+

+/-

++

++

++

+/-

-/+

+

++

-/+

++

Marginal-zone B-cell lymphoma

++

-

-

+/-

++

++

+/-

+/-

-

-/+

++

-

++

Mantle cell lymphoma

++

++

-/+

-

++

++

++

-

-

+

++

-

+

Follicular lymphoma

++

-/+

++

-

++

++

++

-/+

-

-

++

-

++

-, not expressed; -/+, usually is not expressed; +/-, usually is expressed; + to +++, varying degrees of strength of expression; HCL, hairy cell leukemia; smIg, surface membrane immunoglobin.
Reprinted with permission from Wintrobe's Clinical Hematology, 11th Edition, page 2438.

 

Diagram 5.1.

Reprinted with permission from Wintrobe's Clinical Hematology, 11th Edition, page 2327.

 

Diagram 5.2.

Figure 5.1 Generalized lymphadenopathy in chronic lymphocytic lymphoma/small lymphocytic lymphoma (CLL/SLL). Bilateral axillary lymphadenopathy and hepatosplenomegaly are present in a patient with advanced stage CLL/SLL. (Courtesy Dr. D. Amato.)

 

Figure 5.2 Generalized lymphadenopathy in CLL/SLL. Axial computed tomography (CT) scans from a case of CLL/SLL. Left panel: Upper thorax shows prominent bilateral axillary lymphadenopathy (long arrows) and some small mediastinal lymph nodes (short arrow). Middle panel: Lower thorax/upper abdomen reveals prominent retrocrural lymphadenopathy (arrow). Enlarged retroperitoneal (long arrow) and multiple prominent mesenteric lymph nodes (short arrows) are present in the right panel.

Figure 5.3 Top panel: Erysipelas in a patient with CLL. (Courtesy Dr. P. Galbraith.) Herpes Simplex I gingivostomatitis (middle panel) and varicella-zoster shingles (bottom panel) in two patients with CLL. (Courtesy Dr. I. Quirt.)

 

Figure 5.4 Enlarged lymph nodes. Gross lymph nodes specimens have been cut to show characteristic homogenous pattern (“fish flesh” appearance) of a lymph node diffusely involved by CLL/SLL on the left, as compared with the nodular, heterogeneous appearance of a lymph node involved with metastatic cancer on the right.

Figure 5.5 CLL in blood smear. A low-power view of a blood smear shows lymphocytosis with smudge cells (left panel). A higher-power view demonstrates the typical appearance of the CLL cell: a small mature lymphocyte with condensed, clumpy chromatin pattern (“soccer ball” pattern) and regular nuclear contours (right panel). CLL cells can be difficult to distinguish from normal circulating lymphocytes.

 

Figure 5.6 Mature B-cell neoplasms in peripheral blood. Low- and high-power views on the left and right sides of the figure, respectively, show the four common mature B-cell lymphoproliferative disorders in blood: CLL, chronic lymphocytic leukemia; MCL, Mantle cell lymphoma; HCL, hairy cell leukemia; SLVL, splenic lymphoma with villous lymphocytes (splenic marginal zone lymphoma).

Figure 5.7 Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). An internal mammary node is diffusely effaced by a proliferation of small, mature lymphocytes with high N:C ratios and condensed chromatin. Inconspicuous proliferation centers are composed of prolymphocytes and immunoblasts—larger cells with paler-staining nuclei and nucleoli, which are delineated by arrows at the boundary of the proliferation centers.

 

Figure 5.8 CLL/SLL. The lymph node is diffusely replaced by small mature lymphocytes with high N:C ratios and condensed chromatin. Coalescent proliferation centers consisting of prolymphocytes and immunoblasts surround the smaller, mature-appearing CLL cells.

Figure 5.9 Diffuse marrow involvement by CLL/SLL. A blood smear demonstrates mature lymphocytosis (upper panel) and various magnified views of a marrow biopsy are shown (lower panels). The biopsy shows a diffuse pattern of involvement of marrow by CLL, with total effacement of the architecture by small, mature lymphoid cells possessing regular nuclear contours.

 

Figure 5.10 Patterns of marrow involvement by CLL. Low- and higher-power views of bone marrow biopsies are shown on the left and right, respectively, demonstrating the three patterns commonly seen in marrow involvement by CLL: nodular, interstitial, and diffuse. Nodular infiltration indicates the presence of foci of lymphoma cells separated by unaffected bone marrow and is typically distributed in a mid-paratrabecular pattern in CLL (upper panels). Interstitial infiltration is marked by diffuse, patchy bone marrow invasion by individual CLL cells interspersed between hematopoietic and fat cells. Diffuse infiltration, associated with a poorer prognosis, involves complete effacement of bone marrow architecture by sheets of lymphoma cells.

 

Figure 5.11 FISH in CLL. Cytogenetic abnormalities such as del(17)(p13.1) and del(11)(q22) portend rapid disease progression and poor survival, whereas del(13)(q14.3) as the sole abnormality has good prognosis in CLL. The significance of trisomy 12 is undetermined. The loss of p53 function predicts poor survival in this disease. This slide shows results from an interphase FISH panel performed on CLL cells. A. Deletion of the ATM gene (red) at 11q22.3 compared with a centromere 11 control (green). B. Trisomy 12 as indicated by three centromere 12 signals. C. Deletion of the 13q14.3 region (red) as compared to the LAMP1 gene (green) at 13q34. D. Deletion of the p53 gene (red) at 17p13 as compared with a centromere 17 control (green).

Figure 5.12 Spleen in CLL. CLL involvement of organs is often diffusely infiltrative, but with retention of the underlying architecture. In this gross specimen, the spleen is homogeneously enlarged by diffuse infiltration of the red pulp.

 

Figure 5.13 CLL in the stomach. This figure is an example of CLL causing stomach ulceration (arrow) and diffusely infiltrating the stomach wall and extending into the adjacent liver. Note the small nodules of CLL in the hepatic parenchyma.

Figure 5.14 Prolymphocytic leukemia (PLL). A blood smear demonstrates large, nucleolated lymphoid cells in a case of PLL transformed from CLL. For comparison, a normal small lymphocyte is present in the upper left corner of the figure.

 

Figure 5.15 Richter syndrome. This lymph node is diffusely effaced by a dual population of small CLL/SLL and large B-lymphoma cells. Different areas of the lymph node are composed exclusively of either the smaller CLL/SLL or larger B-cell lymphoma cells as shown in the left and right lower panels, respectively.

 

Figure 5.16 B-cell prolymphocytic lymphoma (PLL). Sheets of monomorphic large lymphoid cells with prominent single nucleoli diffusely efface a lymph node.

Figure 5.17 Lymphoplasmacytic lymphoma (LPL). This figure demonstrates a right flank mass in a patient suffering from recurrent Waldenström macroglobinemia.

 

Figure 5.18 Waldenström macroglobinemia. This lymph node is completely effaced by diffuse sheets of monotonous-appearing plasma cells, some showing intranuclear inclusions of monoclonal immunoglobin in the form of Dutcher bodies (arrows).

Figure 5.19 Waldenström macroglobinemia. Bone marrow biopsy sections in the upper three panels show diffuse replacement of the marrow by a small lymphocytic/plasma cell population that exhibits restricted IgM expression by immunohistochemistry. The bottom panel demonstrates a mixed population of lymphocytic/plasmacytoid cells in a marrow aspirate smear.

 

Figure 5.20 Massive splenomegaly in a patient with hairy cell leukemia. (Courtesy of The Crookston Collection.)

Figure 5.21 Splenomegaly in HCL. An axial CT scan with oral and intravenous contrast shows prominent splenomegaly with no focal lesions in a case of HCL.

 

Figure 5.22 Spleen in HCL. The spleen is diffusely enlarged, and the red pulp is infiltrated, by uniformly, well-spaced lymphoid cells possessing regular nuclear contours and condensed chromatin. (Courtesy Dr. D. Amato.)

 

Figure 5.23 HCL in blood smears and bone marrow biopsies. This is a composite figure from four cases of HCL. These examples illustrate the variability in the appearance of HCL cells in blood smear (top panels). HCL cells are small to medium in size with mature chromatin and display ample, neutral-staining cytoplasm that may form hair-like villous projections. The distinctive “fried egg” appearance of HCL in biopsy specimens is shown in the bottom panels. HCL usually is associated with extensive reticulin fibrosis that results in failed attempts to obtain cellular aspirate smears (dry taps).

Figure 5.24 Electron micrographs of HCL. Transmission electron micrographs of cells from a case of hairy cell leukemia show numerous cytoplasmic villous projections at low magnification (top panel), and at higher power (lower panel), the characteristic ribosomal-lamella complexes composed of concentrically arranged sheets of membranes alternating with rows of ribosomes are seen.

 

Figure 5.25 Multiple myeloma. An unusually advanced case of myeloma shows the anterior extension of a rib tumor into subcutaneous tissues, forming a large nodular mass.

Figure 5.26 Multiple myeloma involving the skin. This figure shows two cases of myeloma involving the skin. Extramedullary sites of involvement at diagnosis or during the course of multiple myeloma are rare.

 

Figure 5.27 AL type of amyloidosis. Amyloidosis occurs in approximately 5% to 10% of patients with myeloma and is related to the deposition of monoclonal immunoglobulin light-chain components that are synthesized by neoplastic plasma cells. This form of amyloidosis mainly affects the heart, kidneys, gastrointestinal tract, liver, and central nervous system. Skin involvement occurs in about 30% to 40% of patients. Amyloid of the tongue can cause it to become enlarged, woody, and indurated (top panel, courtesy Dr. I. Quirt). Direct skin infiltration with amyloid can produce the featureless tightening and thickening appearance of scleroderma (middle panel). Amyloid is identified grossly by a staining reaction with iodine similar to that of starch (hence the term “amyloid,” meaning “starch-like”). Autopsy kidneys stained with iodine are shown in the lower panel, with an amyloid kidney on the left and a normal kidney on the right. (Courtesy Dr. I. Wanless.)

Figure 5.28 Amyloidosis of spleen. A freshly cut splenectomy specimen displaying the wax-like appearance of amyloid deposits. (Courtesy Dr. D. Driman.)

 

Figure 5.29 Top panel: Post-vaccination necrosis in a myeloma patient. Vaccinations with live attenuated viruses are contradicted in patients suffering from myeloma and other conditions leading weakened immune systems. Widespread skin necrosis at the vaccination site (progressive vaccinia/vaccinia necrosum) may occur, as in this patient. (Courtesy Dr. I. Quirt.) Skull radiograph showing multiple punched out lesions affecting the skull, from a patient with multiple myeloma (bottom panel, courtesy Dr. P. Galbraith).

 

Figure 5.30 Lytic boney lesions in myeloma. This lateral view of the cervical spine shows lytic lesions mainly involving the vertebral bodies of the cervical spine in case of myeloma (arrowleft upper panel). Sagittal MRI of the cervical spine in same patient discloses myeloma replacing mid-cervical vertebral bodies (arrow) causing anterior spinal cord compression (right upper panel). Gross specimens of vertebral columns with multiple, punched-out, hemorrhagic, lytic lesions from myeloma (middle panels) are compared to normal (lower panels).

Figure 5.31 Background staining and rouleaux formation in myeloma. The excessive immunoglobins produced by the neoplastic plasma cells in myeloma are acidic and take up the basophilic stains used in blood smears. The consequence is an increase in background bluish staining in blood smears in myeloma patients (slide on right in upper panel) compared with normal (slide on left). The abnormal immunoglobins also cause the RBCs to adhere. This resulting rouleaux (“stacking of coins”) formation may be visible on those portions of the smear where erythrocytes are normally apart (lower panel).

 

Figure 5.32 Serum electrophoresis. Albumin (Alb.) is the largest peak and closest to the positive electrode and the next peaks are globulins: α-1, α-2, β, and γ. The γ-peak is closest to the negative electrode. The presence of a monoclonal protein is characterized by a sharp, well-defined “M spike” with a single heavy chain and a similar band with a κ- or λ-light chain. A broad diffuse band with one or more heavy chains and κ- and λ-light chains characterizes a polyclonal protein.

 

Figure 5.33 Serum and urine electrophoresis with immunofixation. The composition of monoclonal abnormalities (M spikes) are analyzed by immunofixation to determine the identities of the heavy-chain and light-chain types. Several examples of normal and abnormal results from immunofixation electrophoresis are shown here. (Courtesy Dr. P. Y. Wong.)

Figure 5.34 Cytogenetics in myeloma. Certain cytogenetic abnormalities are associated with poor prognosis in myeloma. These include translocations involving the IgH locus on 14q32: t(11;14), t(4;14), t(14;16); chromosome 13 deletions that are detected by conventional cytogenetics; and loss of 17p13 demonstrated best by interphase FISH. A multiple myeloma karyotype with del(13)(q14;q22) and a derivative 14 chromosome from a t(11;14)(q13;q32), along with other trisomies is shown in the upper panel. The lower panel illustrates another myeloma case with t(11;14)(q13;q32) along with other structural aberrations.

 

Figure 5.35 Bone marrow morphology in myeloma. Myeloma usually involves the bone marrow in a widespread, but patchy manner. A low- and high-power view of a biopsy is shown in the upper two panels, showing focal involvement by myeloma. The lower panel shows an aspirate smear composed almost exclusively of plasma cells.

Figure 5.36 The diverse morphology of myeloma. Plasma cells, from 16 different cases of myeloma, are displayed here.

 

Figure 5.37 Appearance of myeloma on bone marrow biopsy. High-power views of biopsy specimens from six different cases of myeloma cases are shown here. Intranuclear (Dutcher bodies) and intracytoplasmic (Mott cells) inclusions of abnormal immunoglobin appear in neoplastic plasma cells in the left and right upper panels, respectively.

Figure 5.38 Myeloma and bone formation. Upper panel: A low-power view of a marrow biopsy shows areas of thickened bone associated with a hypercellular focus of myeloma (left side of biopsy core). The bottom two panels display foci of new bone formation associated with irregular lamellar bone and increased numbers of osteoblasts. The latter are easily confused with plasma cells.

 

Figure 5.39 Amyloid in marrow. A bone marrow biopsy is diffusely infiltrated by eosinophilic, proteinaceous material that accumulates in and around blood vessels. The characteristic apple-green birefringence can be demonstrated after Congo-red staining.

Figure 5.40 Crystal-storing histiocytosis in myeloma. Abnormal proteins can precipitate and form crystals in myeloma and other hematopoietic malignancies, such as lymphoplasmacytic lymphoma and granulocytic sarcoma.

 

Figure 5.41 Myeloma of the skull. A CT scan of the head with bone windows and a radiograph (upper two panels and middle panels, respectively) showing lytic skull lesions, with the largest measuring 4 cm by 1.8 cm. These finding are consistent with myeloma. The lower panel is a photomicrograph from a biopsy demonstrating sheets of highly atypical plasma cells. (Courtesy Dr. J. Bilbao.)

 

Figure 5.42 Myeloma of the spine. A contrast-enhanced CT scan of the abdomen for image-directed biopsy of a lytic vertebral lesion discloses destruction and soft-tissue replacement of the right aspect of the vertebral body, extending into the vertebral canal (red arrow). The other panels contain photomicrographs of the biopsy consisting exclusively of plasma cells with both intranuclear Dutcher bodies (arrows, middle panel) and cytoplasmic (Mott cells, arrowslower panel) inclusions of monoclonal immunoglobin. (Courtesy Dr. J. Bilbao.)

Figure 5.43 Plasma cell leukemia. A. Low-power examination of blood smear shows leukocytosis and rouleaux formation. B. Higher-power view shows that the leukocytosis is due exclusively to circulating plasma cells. The “atypical” appearance of normal circulating lymphocytes associated with high levels of serum immunoglobins is shown in C. Cytoplasmic vacuolation and the resulting appearance of the nucleus pushed to one side can lead to mistaking this for plasma cell leukemia.

 

Figure 5.44 Splenic marginal zone lymphoma (SMZL). This figure demonstrates the gross appearance of a splenectomy specimen from a case of SMZL. Multiple small (1 to 3 mm) discrete nodules of expanded white are diffusely distributed throughout the splenic parenchyma.

 

Figure 5.45 Splenic marginal-zone lymphoma with hilar lymph node involvement. The spleen is diffusely infiltrated by macroscopically visible nodular expansions of white pulp. Perivascular nodules made up of monotonous-appearing, well-spaced, medium-sized lymphoid cells are shown.

Figure 5.46 SMZL in blood smear. The typical cells in this disease are mature-appearing, medium-sized lymphocytes with ample cytoplasm that forms villous projections. A normal small lymphocyte is seen in the right upper corner.

 

Figure 5.47 Marrow involvement SMZL. Marrow biopsies show a mostly sinusoidal pattern of marrow involvement by lymphoma. High-power views show small-sized lymphoma nuclei (compared with the larger endothelial nucleus, arrow in right upper figure), which possess a condensed chromatin pattern and regular nuclear contours. Low- and high-power views of CD20 immunostained biopsy sections accentuate the sinusoidal pattern of marrow involvement characteristic of this lymphoma.

Figure 5.48 MALT lymphoma of sclera. Clinical photograph of eye showing fleshy “salmon-color patch” of the superficial ocular surface.

 

Figure 5.49 This gastrectomy specimen shows a thickened stomach wall (arrow) from MALT lymphoma with a well-demarcated ulcer (bottom panel).

Figure 5.50 Extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). This gastric biopsy demonstrates extensive involvement by well-spaced, medium-sized lymphoid cells that invade and destroy glands to form lymphoepithelial lesions.

 

Figure 5.51 MALT lymphoma of small bowel mesenteric lymph nodes. This gross specimen from a small bowel resection shows a large (20 cm) obstructing mass involving numerous small-bowel mesenteric lymph nodes.

 

Figure 5.52 MALT lymphoma of small bowel. This MALT lymphoma involves a very well-defined segment of small bowel. Note the circumferential and transmural involvement of the bowel wall.

Figure 5.53 Extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). This partial gastrectomy specimen demonstrates a MALT lymphoma ulcerating through the muscularis mucosae. Uniformly, well-spaced, medium-sized lymphoid cells invade and destroy glands to form lymphoepithelial lesions (right lower panel).

 

Figure 5.54 MALT lymphoma of right parotid gland. An axial CT scan through the lower jaw reveals an enhancing soft-tissue mass in the region of the right parotid gland.

 

Figure 5.55 Extranodal MALT lymphoma of parotid gland. A lymph node and subjacent parotid gland demonstrate a vaguely nodular proliferation of well-spaced monocytoid lymphocytes invading germinal centers (left middle panel) and glandular structures to form lymphoepithelial lesions (right middle panel). Nodules of MALT lymphoma are seen filling sinuses (left lower panel), and these exhibit a characteristic uniformly well-spaced pattern reminiscent of the so-called “fried egg” appearance of hairy cell leukemia involving the bone marrow (right lower panel).

Figure 5.56 Axillary lymphadenopathy in a case of extranodal MALT lymphoma.

 

Figure 5.57 Lymph node involvement by extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). A cervical lymph node from a case of MALT lymphoma of the parotid gland shows diffuse involvement by uniformly well-spaced, medium-sized lymphoid cells. Islands of MALT lymphoma are visible in the medium-power photomicrograph in the right upper corner (arrows).

 

Figure 5.58 Extensive bilateral cervical and axillary lymphadenopathy in a patient with advanced-stage follicular lymphoma at presentation.

Figure 5.59 Ulcerating, enlarged axillary lymph nodes with follicular lymphoma.

 

Figure 5.60 Follicular lymphoma involving the scalp.

Figure 5.61 Follicular lymphoma of the left tonsil. Lymphoma is the most common tumor of the tonsils in children; however, in adults lymphomas appear clinically similar to the more common tonsillar tumor, squamous cell carcinoma.

 

Figure 5.62 Follicular lymphoma in spleen. This gross splenectomy specimen shows tiny macroscopically visible neoplastic nodules of follicular lymphoma diffusely involving the entire spleen.

 

Figure 5.63 Follicular lymphoma. This gross specimen of a freshly resected lymph node is cut to reveal the macroscopically visible neoplastic follicles in follicular lymphoma.

Figure 5.64 Reactive follicular hyperplasia. An enlarged submandibular lymph node shows numerous follicles of varying size that do not appear crowded. Focally (blue arrow), the lymphoid tissue extends outside the capsule into adjacent adipose tissue. This extracapsular tissue, however, contains reactive follicles similar to the follicles inside the capsule. The follicles contain prominent, well-defined germinal centers that have a reactive appearance, with frequent tingible body macrophages (black arrows) and a brisk mitotic rate (red arrow). Undisrupted, well-demarcated, broad mantle zones surround the follicles. Immunohistochemistry was negative for bcl-2 protein.

 

Figure 5.65 Follicular lymphoma, Grade 1. Fibroadipose tissue is involved by crowded, diffusely distributed, uniformly sized aggregates composed almost exclusively of well-spaced centrocytes with cleaved nuclear contours. For comparison, the right corner of the bottom right panel shows benign centrocytes with regularly contoured nuclei and condensed chromatin (arrows).

 

Figure 5.66 Follicular lymphoma, Grade 1. This lymph node is replaced by regularly distributed, uniformly sized aggregates consisting almost exclusively of centrocytes with cleaved nuclear contours. The lymph node appears to be replaced by expanding sheets of monotonous small-cleaved follicular center cells. Only occasional, larger nucleolated cells are seen (arrows) in this example of low-grade follicular lymphoma.

Figure 5.67 Follicular lymphoma, Grade 2. The lymph node architecture is completely effaced by uniform, crowded follicles, some of which merge into each other. Focal invasion into the capsule, without extension into perinodal tissue, is present. The neoplastic follicles consist of small cleaved (centrocytes) and large noncleaved (centroblasts, red arrows) cells. An average of nine large noncleaved cells was present in 10 high-power fields. A rare follicular dendritic cell (fdc) is also visible among the lymphoma cells. Immunophenotype (by immunohistochemistry and flow cytometry) of the lymphoma cells revealed: CDs 20+/10+/23+/5-/11c-/bcl2+/ bcl6+. MIB-1 staining showed positivity in approximately 25% of the follicular lymphoma cells. DNA analysis revealed a low S-phase fraction of 1%.

 

Figure 5.68 Follicular lymphoma, Grade 3. This lymph node shows numerous uniformly spaced and sized nodules composed almost exclusively of large nucleolated centroblasts. Squeezed between the malignant nodules of centroblasts are linear arrays of centrocytes.

Figure 5.69 Follicular lymphoma, Grade 3 (3b subtype). A retroperitoneal lymph node is replaced by numerous, back-to-back lymphoid follicles that often merge together. The follicles consist of monotonous, intermediate-to-large cells with irregular nuclei, vesicular chromatin, small distinct nucleoli, and scanty, basophilic cytoplasm. The proliferation extends through the lymph node capsule into surrounding adipose tissue (arrow). Immunophenotype of the lymphoma cells reveals: CDs 20+/10+/20+/23+/5-/11c-, and bcl6+. DNA analysis revealed that 60% of lymphoma cells had an aneuploid DNA content, with a DNA index of 1.18 and an S-phase fraction of 10%, the last consistent with intermediate grade.

 

Figure 5.70 Follicular lymphoma cells in aspirate smear. Medium-sized atypical lymphoid cells with cleaved nuclei are present in this aspirate from a marrow replaced by follicular lymphoma.

Figure 5.71 Marrow involvement by non-Hodgkin lymphoma (NHL), follicular type. This bone marrow biopsy demonstrates extensive involvement by NHL, follicular type, with the multiple paratrabecular lymphoid aggregates closely hugging bony trabeculae. As shown in the lower panel, closer inspection reveals that the lymphoid infiltrate consists primarily of small lymphocytes with close chromatin pattern and irregular nuclear contours.

 

Figure 5.72 NHL, follicular type involving marrow. Medium-power views of biopsy from a case of NHL, follicular type, show the characteristic paratrabecular aggregates. Paratrabecular collections of CD20+/CD10+/bcl2+ small lymphoid cells are typical when this disease affects the bone marrow. Note the nuclear staining pattern for bcl2 (insetlower panel).

Figure 5.73 Nuclear morphology of CLL, follicular lymphoma, and large B-cell lymphoma cells in biopsy. Although lymphomas should not be classified based on appearance in bone marrow, this composite figure highlights the differences in nuclear morphology among these three different B-cell lymphoproliferative disorders.

 

Figure 5.74 Detection of clonal B cells by PCR. Malignant B- or T-cell proliferations are clonal, which helps to distinguish them from reactive polyclonal proliferations. PCR is a sensitive assay used to detect abnormal clonal B- and T-cell populations in which JH primers are used to amplify the V and J regions in the IGH gene. The internal control is a region of the dystrophin gene. Lane 1 is the negative control, 2 is a positive patient, 3 is a negative patient, 4 is positive control, 5 is positive control diluted to 1:1,000, 6 is without input RNA, and 7 is a 100-bp DNA ladder. In a polyclonal population of B cells, a variety of PCR products are produced, resulting in a mixed population of DNA fragments that differ slightly in size and result in a very faint or undetectable smear when run on gels (patient-). In B-cell lymphoma, a single PCR product is produced resulting a discrete band (patient+ and control+ lanes). (Courtesy Dr. S. Kamel-Reid.)

Figure 5.75 Detection of clonal T cells by PCR. The faint DNA smears between the 50- and 100-bp marker on this gel indicates that no clonal T-cell population is detectable in the four patient samples analyzed. Clonal T-cell receptor rearrangement is not lineage specific and not uncommonly detected in B-cell and other neoplasms. (Courtesy Dr. S. Kamel-Reid.)

 

Figure 5.76 Detection of clonal B cells by Southern blot. Southern blot is a specific assay and regarded as the gold standard to detect abnormal clonal B-cell populations. Clonal populations are detected by the appearance of new bands (arrows) following digestion of extracted tumor DNA by enzymes (restriction endonucleases) that cleave DNA in a sequence-specific manner. Compared with PCR, Southern blot is a time-consuming test that requires more tissue. (Courtesy Dr. S. Kamel-Reid.)

Figure 5.77 Low S-phase fraction in low-grade lymphomas. S-phase fraction, an index of cellular proliferation measured by DNA flow cytometry, of less than 5% is typically seen in low-grade follicular lymphoma. (Courtesy J. Davidson.)

 

Figure 5.78 The t(14;18)(q32;q21) rearrangement. The ideograms of chromosomes 14, 18, and the respective derivative chromosomes are to the left in color. The corresponding G-banded chromosome pairs are to the right. The arrows indicate the breakpoints on the respective chromosomes. Most cases of follicular lymphoma have a t(14;18) reciprocal chromosomal translocation. This results in overexpression of the BCL-2 gene and, ultimately, increased production of the antiapoptotic protein bcl-2. Bcl-2 protein is not detected in high amounts in benign, reactive germinal-center cells.

Figure 5.79 FISH of the IGH/BCL2 fusion gene. The BCL2 gene at 18q21 (red) and the IGH gene at 14q32 (green) co-localize to generate yellow signals, indicating a reciprocal translocation involving these loci.

 

Figure 5.80 Mantle cell lymphoma. This middle-aged man has extensive lymphadenopathy, including prominent right supraclavicular lymph nodes from recurrent Mantle cell lymphoma (MZL).

Figure 5.81 Mantle cell lymphoma, nodular type, and mantle-zone pattern. Neoplastic nodules of medium-sized lymphoid cells with slightly irregular nuclear contours efface the lymph node architecture. Some of the nodules retain a distinctly mantle-zone pattern, in which expanded collars of mantle zones surround germinal centers (arrows). The high-power view on the bottom panel shows cytologic detail of the mantle lymphoma cells with a histiocyte nucleus (H) for size comparison.

 

Figure 5.82 Mantle cell lymphoma (multiple lymphomatous polyposis). Sections from the jejunum show widespread polypoid lesions composed of submucosal nodules of small lymphoid cells that were cyclin D1+/CD5+/CD20+ B-cells by immunohistochemistry.

Figure 5.83 Mantle cell lymphoma, nodular type. This lymph node is effaced by a nodular expansion of medium-sized lymphoid cells with a closed chromatin pattern and fairly regular nuclear contours. The low-power view of a reticulin-stained lymph node section in the right upper panel highlights the nodular pattern of involvement. Admixed with the mantle lymphoma cells are occasional follicular dendritic cells, one delineated by an arrow showing classic “kissing” nuclei.

 

Figure 5.84 Marrow involvement by non-Hodgkin lymphoma, mantle cell. Low- and high-power views of bone marrow biopsies from two cases of Mantle cell lymphoma are shown here. The pattern of marrow involvement and the cytologic appearance of Mantle cell lymphoma can be quite variable. Two different cases are demonstrated here, with one revealing a nodular pattern of infiltration (top panels) and the other displaying a diffuse pattern (lower panels). High-power views in both show small- to medium-sized (endothelial nuclei for comparison are delineated by arrows) lymphoma nuclei with condensed chromatin pattern and slightly irregular nuclear contours.

Figure 5.85 The t(11;14)(q13;q32) rearrangement in Mantle cell lymphoma. The diagnostic t(11;14) of Mantle cell lymphoma is depicted here. The ideograms of chromosomes 11, 14, and the respective derivative chromosomes are illustrated on the left in color, and the corresponding G-banded chromosome pairs are on the right. The arrows indicate the breakpoints on the respective chromosomes. The t(11;14) is detectable in almost all cases of Mantle cell lymphomas. This translocation juxtaposes the immunoglobulin heavy chain (IGH) and the cyclin D1 gene (CCND1), resulting in overexpression of cyclin D1.

 

Figure 5.86 FISH of the IGH/ CCND1 fusion gene in Mantle cell lymphoma. A standard FISH assay that is used to detect the t(11;14) in either formalin-fixed/ paraffin embedded or fresh tissues is illustrated here. The CCND1 gene at 11q13 (red) and the IGH gene at 14q32 (green) co-localize to generate yellow signals, indicating a reciprocal translocation involving these loci. The t(11;14)(q13;q32) occurs in 95% of cases by FISH, although it may not be readily detectable by standard cytogenetics.

 

Figure 5.87 Diffuse large B-cell lymphoma (DLBL) of the thyroid. Any extranodal location can be a primary site for diffuse large B-cell lymphoma.

Figure 5.88 Diffuse large B-cell lymphoma involving the skin and subcutaneous tissues of knee.

 

Figure 5.89 Diffuse large B-cell lymphoma involving the skin and subcutaneous tissues of abdominal wall.

Figure 5.90 Diffuse large B-cell lymphoma involving the inferior aspect of a testis.

 

Figure 5.91 Diffuse large B-cell lymphoma involving the skin and subcutaneous tissues of back.

Figure 5.92 Diffuse large B-cell lymphoma involving left inguinal lymph nodes.

 

Figure 5.93 Diffuse large B-cell lymphoma involving lymph node. This lymph node shows the homogenous, fish-flesh appearance of lymphoma totally replacing the entire lymph node.

Figure 5.94 Gallium uptake scan showing two prominent discrete areas of increased uptake in the spleen in a case of DLBL extensively involving the spleen.

 

Figure 5.95 An axial CT of abdomen with oral and intravenous contrast. The spleen is enlarged and heterogeneous, with multiple hypodense lesions (arrow). The latter may represent necrotic tumor. The large spleen indents the body of the stomach. (Same case as shown in Fig. 5.94.)

Figure 5.96 Diffuse large B-cell lymphoma involving spleen. Multiple large discrete tumors are visible in this gross splenectomy specimen.

 

Figure 5.97 Generalized lymphadenopathy from diffuse large B-cell lymphoma. On the left is an axial thoracic CT scan with contrast that reveals soft-tissue masses in the right axillary region at the level just inferior to the aortic arch. On the right is an abdominal CT scan at the level of the left renal vein showing large retroperitoneal soft-tissue masses. The largest mass displaces the left kidney laterally.

 

Figure 5.98 Diffuse large B-cell lymphoma involving cerebral spinal fluid (CSF). This CSF sample stained with Wright-Giemsa demonstrates numerous large, pleomorphic cells with multilobulated nuclei and a high mitotic rate.

Figure 5.99 Diffuse large B-cell lymphoma involving bone marrow. As with many of the mature B-cell lymphomas, the appearance of DLBL in the marrow is highly variable, and classifying these diseases based solely on the morphologic appearance in the marrow is discouraged. Shown here are mid-trabecular aggregates composed almost exclusively of atypical, large lymphoid cells with the characteristic vesicular (or “glassy”) chromatin pattern and one to two prominent nucleoli of DLBL. An aspirate smear from the same case shows a pleomorphic population of highly atypical, large lymphoid cells (right lower panel).

 

Figure 5.100 Marrow involvement by DLBL, T-cell rich type. Low-, medium-, and high-power views (top to bottom panels, respectively) demonstrate numerous large, poorly circumscribed, mid-trabecular aggregates made up of a heterogeneous population of large, atypical lymphoid cells with vesicular nuclei admixed with small mature lymphocytes. CD20-immunostained biopsy sections accentuate the nodular pattern of marrow involvement by the minor subpopulation of large malignant-appearing B cells that are admixed with benign reactive small T cells. This case could be mistaken for marrow involvement by Hodgkin lymphoma.

 

Figure 5.101 Diffuse large B-cell lymphoma (centroblastic, with multilobated cells). This lymph node shows marked sclerotic thickening of its capsule, with complete effacement of the architecture by extensive, noncohesive sheets of monotonous, large cells. A high mitotic rate with tripolar mitotic figure (white triangle) and multilobed nuclei (small black triangle) is seen, as well as numerous apoptotic bodies (small arrowsright lower panel). Immunophenotype of the lymphoma cells by flow cytometry and immunohistochemistry reveals a CDs 20+/10+/bcl6+/kappa+ immunophenotype.

Figure 5.102 Mediastinal large B-cell lymphoma. An axial CT scan through upper thorax at the level of the aortic arch shows a large mass (arrow) mostly involving the anterior mediastinum.

 

Figure 5.103 Mediastinal large B-cell lymphoma. This autopsy specimen with transversely cut lungs and mediastinum at the level of the aortic arch demonstrates a large infiltrative mass encasing the entire aortic arch and extending into adjacent lung.

Figure 5.104 Diffuse large B-cell lymphoma (immunoblastic and centroblastic). A biopsy from the base of the tongue shows necrosis and extensive infiltration of tissue with atypical large lymphoid cells composed of immunoblasts with large, single, central nucleoli (open arrows) and centroblasts with multiple smaller nucleoli situated near the nuclear membrane (closed arrows).

 

Figure 5.105 A and B. B-cell NHL associated with t(14;18) and t(8;14), leukemic phase. These blood smears show circulating, large nucleolated blasts, some with clefted nuclear contours. For comparison, mature small lymphocytes are present near the lower left corners of both figures. C. The bone marrow biopsy is totally replaced by sheets of poorly preserved, malignant cells that display extensive crush artifact. FISH for (14;18) and c-myc rearrangement were positive in this case. These “double hit” lymphomas, as well as diffuse large B-cell lymphoma, when confined to blood and marrow; at time of diagnosis, are easily misdiagnosed as precursor B-cell lymphoblastic leukemia/lymphoma.

Figure 5.106 Intravascular large B-cell lymphoma. This gastric biopsy from a 45-year-old man shows normal overall architecture, but higher magnification in lower panel reveal a vessel filled with highly atypical large CD20+ B-cell lymphoma cells.

 

Figure 5.107 Angiocentric diffuse large B-cell lymphoma (lymphomatoid granulomatosis). The left panel is a magnetic resonance image (MRI) axial T1-weighted image with intravenous contrast showing multiple enhancing lesions at the gray–white junctions of the cerebral cortex. The figure on the right is from the autopsy brain of the same case, showing atypical lymphoid cells invading cerebral blood vessels and causing fibrinoid necrosis. (Courtesy Dr. J. Bilbao.)

 

Figure 5.108 Angiocentric diffuse large B-cell lymphoma (lymphomatoid granulomatosis). An autopsy lung from a patient with lymphomatoid granulomatosis reveals extensive involvement with multiple necrotizing lesions.

Figure 5.109 Angiocentric diffuse large B-cell lymphoma (lymphomatoid granulomatosis), grade 3/3. Lung biopsy showing large lymphoid cells restricted to blood vessels and displaying a vasculitic pattern of involvement, with fibrinoid necrosis and angioinvasion. Commonly EBV-positive, this large B-cell lymphoma variant often is accompanied with a predominant T-cell background and usually manifests as pulmonary or paranasal sinus involvement.

 

Figure 5.110 Intravascular large B-cell lymphoma. Sections of cerebrum from autopsy brain specimen reveal widespread involvement of small vessels by large atypical lymphoid cells, that by immunostains are CD20+ B cells. The lymphoma cells extend through the walls of the vessels but do not invade brain parenchyma. Other names for this disease are malignant angioendotheliomatosis and angiotropic large-cell lymphoma.

Figure 5.111 Diffuse large B-cell lymphoma, ALK-positive. A supraclavicular lymph node biopsy shows dense fibrous tissue and extensive coagulative tumor necrosis intimately associated with sheets of large, malignant lymphoid cells. The malignant cells have giant-sized, eosinophilic staining nucleoli (closed arrow) and a high mitotic rate (open arrow). Immunostains for ALK-1 show strong granular staining with focal enhancement in the Golgi region. Additional immunostains revealed the lymphoma cells were CD138+/EMA+ and negative for B-cell and T-cell markers. In this case, approximately 50% of the lymphoma cells were positive for the proliferation marker MIB1.

 

Figure 5.112 Top panel: Burkitt's lymphoma, endemic type. A large tumor involves the mandible of a young girl. (Courtesy of The Crookston Collection.) Bottom panel: Burkitt's lymphoma of the large intestine, nonendemic type. Burkitt lymphoma presenting as a large polypoid mass of the large intestine. (Courtesy Dr. Bill Geddie.)

Figure 5.113 Burkitt lymphoma. The biopsy of an abdominal mass shows, at low-power, the classic “starry sky” appearance of rapidly proliferating malignant cells intermixed with larger histocytes actively engulfing tumor debris (upper panel). The lower panel shows intermediate-sized cells that are uniform in size and shape, with multiple small basophilic nucleoli. FISH for c-myc translocation was positive in this case.

 

Figure 5.114 Burkitt lymphoma involving bone marrow. This bone marrow biopsy demonstrates total replacement by rapidly growing tumor cells, some of which exhibit apoptosis that are admixed with “starry-sky” histocytes engulfing tumor debris.

Figure 5.115 Burkitt's leukemia. This blood smear reveals L3-type lymphoblasts with multiple nucleoli and basophilic staining, vacuolated cytoplasm.

 

Figure 5.116 c-myc translocations in Burkitt lymphoma/leukemia. Translocations of c-myc including t(8;14), t(2;8), and t(8;22) have been reported in nearly all cases of Burkitt lymphoma. The t(8;14)(q24.1;q32) rearrangement is the most common and is found in 60% to 70% of cases. The ideograms of chromosomes 8, 14, and the respective derivative chromosomes are to the left in color; the corresponding G-banded chromosome pairs are to the right. The arrows indicate the breakpoints on the respective chromosomes.

 

Figure 5.117 FISH for c-myc translocations in Burkitt's lymphoma/leukemia. FISH of a c-MYC rearrangement. The region centromeric to the c-MYC gene is labeled with a red fluor and the region ~ 1 Mb telomeric to the c-MYC gene is labeled with a green fluor. When a translocation occurs involving the c-MYC gene, the red and green signals split apart. A yellow fusion signal indicates an intact c-MYC gene. This approach can detect the t(8;14), t(2;8), and t(8;22) involving the c-MYC locus at 8q24.

Figure 5.118 DNA content in Burkitt lymphoma. A high S-phase fraction, an index of cellular proliferation measured by DNA flow cytometry, of greater than 20% is typically seen in Burkitt lymphoma. (Courtesy J. Davidson.)

 

Figure 5.119 Atypical Burkitt/Burkitt-like lymphoma. This breast mass in a 23-year-old woman shows sheets of large, pleomorphic cells infiltrating in a sinusoidal pattern that is associated with necrosis and scattered individual debris-laden macrophages, creating a “starry sky” appearance (lower panels). Lymphoma cells are large, display multiple prominent nucleoli, contain moderate amounts of cytoplasm, and have a high mitotic rate. FISH for c-myc translocations are negative.

 

Figure 5.120 Plasmablastic lymphoma involving soft palate.

Figure 5.121 Plasmablastic lymphoma. This figure shows fragments of a solitary nasal tumor from an HIV-negative patient with no evidence of paraproteinemia. The tumor contains sheets of atypical plasmacytoid cells with a high mitotic rate.

 

Figure 5.122 T-cell lymphoproliferative disorders in blood smear. This figure displays the morphologic appearance of four T-cell lymphoma/leukemia disorders in blood: precursor T-cell lymphoblastic leukemia/lymphoma (T-ALL); T-cell prolymphocytic leukemia (T-PLL); Sézary syndrome/mycosis fungoides; and adult T-cell leukemia/lymphoma (ATLL).

Figure 5.123 Adult T-cell leukemia/lymphoma (ATLL). This blood smear from a case of ATLL shows a pleomorphic population of large cells with polylobated nuclei (“flower cells”). By flow cytometry, these cells were CD3+/CD4+/CD2+/CD7-/CD25+. Serology for HTLV-1 was positive.

 

Figure 5.124 Acute adult T-cell leukemia/lymphoma, (ATLL). Large atypical lymphoid cells, “flower cells” with convoluted nuclei, are seen circulating in blood (top left figure) and in involved lymph nodes (all other figures). ATLL cells are typically CD4+/CD25+ (bottom two panels) and Tdt negative.

Figure 5.125 Extranodal NK-/T-cell lymphoma, nasal type. A nasal NK-/T-cell lymphoma in a middle-aged women of Asian descent (top two panels). An axial CT through the level of the orbit demonstrates increased density in the left ethmoid sinus (lower panel). A large soft-tissue mass is present anterior and lateral to the right orbit (arrow).

 

Figure 5.126 Extranodal NK-/T-cell lymphoma, nasal type. Ethmoid sinus tissue fragments from a 38-year-old woman show extensive necrosis and an angiocentric, pleomorphic population of large atypical lymphoid cells mixed with some histiocytes, small lymphocytes, and rare plasma cells. The lymphoma cells were positive for T-cell markers, CD56 and EBV.

Figure 5.127 Hepatosplenic T-cell lymphoma. Top panel: An axial CT scan of the upper abdomen reveals a homogeneously enlarged liver. The spleen is absent. The middle panel is a blood smear showing medium-sized lymphoid cells with pale rims of cytoplasm and slightly irregular nuclear contours. The lymphoma cells typically express the γ/δ T-cell receptor, as shown in the flow cytometric scattergram (arrowbottom panel).

 

Figure 5.128 Mycosis fungoides. Generalized erythrodermic type.

Figure 5.129 Mycosis fungoides involving the lower extremities with hyperkeratosis and fissuring of soles.

 

Figure 5.130 Mycosis fungoides and Sézary syndrome. Plaques, ulceration, and lymphadenopathy are present in a case of stage T3 mycosis fungoides with necrotic and ulcerated tumors.

 

Figure 5.131 Sézary syndrome involving the bone marrow. In the top panel is a blood smear showing large Sézary cells with characteristic convoluted (“cerebriform”) nuclei. Poorly defined nodules of Sézary cells are visible in these plastic-embedded bone marrow sections (bottom two panels).

Figure 5.132 Mycosis fungoides. The figure shows epidermal involvement with single-cell exocytosis and individual large, atypical lymphoid cells with convoluted nuclear contours (arrow) infiltrating the epidermis (epidermotropism). The lymphoma cells in this particular case by immunohistochemistry, displayed an abnormal T-cell phenotype: CD4+ T-cells with aberrant loss of CD7.

 

Figure 5.133 Peripheral T-cell lymphoma involving skin of hands and feet.

Figure 5.134 Peripheral T-cell lymphoma presenting in gums.

 

Figure 5.135 Angioimmunoblastic T-cell lymphoma (angioimmunoblastic lymphadenopathy). An enlarged lymph node is completely effaced by a polymorphic proliferation of small lymphocytes (Ly), histiocytes (Hi), eosinophils (Eo), plasma cells (Pc), and transformed nucleolated T-cell lymphoma cells (red arrows). This infiltrate is accompanied by a profuse increase in small, thin-walled vessels lined by plump endothelial cells (En). The nucleolated T-cell lymphoma cells expressed an aberrant transformed T-cell phenotype CDs 3+/5-/7-/38+ and HLADR+ by immunohistochemistry. Monomorphic sheets of transformed T cells were not present in this case.

Figure 5.136 Angioimmunoblastic T-cell lymphoma. The normal lymph node architecture is effaced by a mixed-cell infiltrate consisting of small lymphocytes, scattered plasma cells, eosinophils, and transformed lymphocytes. The infiltrate is accompanied by a marked increase in arborizing thin-walled blood vessels lined by plump endothelial cells. Clusters of atypical, transformed lymphocytes with abundant clear cytoplasm are present (left lower panel). There is a background increase in CD3+ small T cells (upper small panel) with large atypical clear lymphoid cells strongly CD10+ (lower small panel). The atypical clear lymphoid cells by flow cytometry and immunohistochemistry were CD10 positive, CD3 positive T cells with loss of CD7. PCR studies were negative for B-cell clonality, Epstein-Barr virus, and Human Herpes Virus 8 in this case.

 

Figure 5.137 Enteropathy-type T-cell lymphoma. This figure shows sections near a small-bowel fistula from a 53-year-old man with history of celiac disease. A large ulcerating lesion with transmural extension into the surrounding serosa is associated with necrosis and an extensive multifocal infiltrate composed mostly of atypical large lymphoid cells with vesicular nuclei that were positive for T-cell markers CDs 3, 2 and 5 with aberrant loss of CD7 by immunohistochemistry.

Figure 5.138 Peripheral T-cell lymphoma. The lymph node architecture is disrupted by a diffuse interfollicular proliferation of clusters of “clear” lymphoid cells admixed with centrocytes. The morphologic spectrum for this disease entity is broad, with this particular case composed primarily of large cells.

 

Figure 5.139 Subcutaneous panniculitis-like T-cell lymphoma (large cell variant). A subcutaneous neck nodule shows adipose tissue infiltrated by a heterogeneous population of fibroblasts, histiocytes, and atypical lymphoid cells. The large atypical lymphoid cells stained positively for T-cell markers such as CD8 (inset of lower panel).

Figure 5.140 Precursor T-lymphoblastic leukemia/lymphoma. This lymph node is diffusely replaced by sheets of rapidly proliferating malignant cells interspersed by debris-laden histiocytes creating the typical “starry sky” appearance at low-power (upper panel). Medium-sized lymphoma cells with high N:C ratios, finely reticulated (“open”) chromatin patterns, and high mitotic rate are characteristic of this disease (see Figs. 2.96 and 2.97).

 

Figure 5.141 Lymphomatoid papulosis on the skin of the forearm. The lesions in this case of lymphomatoid papulosis spontaneously regressed without treatment. Lymphomatoid papulosis and CD30+ cutaneous lymphoma are part of a spectrum of diseases characterized by large CD30+ lymphoma cells. Lymphomatoid papulosis lesions are typically rapidly growing but self-healing nodules, whereas CD30+ cutaneous lymphoma (see Fig. 5.142) can have a similar clinical feature at presentation but does not spontaneously regress.

Figure 5.142 Primary cutaneous anaplastic CD30+ large-cell lymphoma. This figure shows two cases involving skin and underlying tissues of the upper extremity.

 

Figure 5.143 Anaplastic CD30+ large-cell lymphoma involving spleen. Nodules of lymphoma are seen near the capsule (arrows).

 

Figure 5.144 Primary cutaneous anaplastic CD30+ large-cell lymphoma. This skin biopsy from the upper arm of a 54-year-old woman reveals deep infiltration into subcutaneous tissue by poorly defined nodules of large, anaplastic cells with multilobulated nuclei. Many of the cells are “hallmark cells,” with lobulated nuclei forming horseshoe or wreath-like configurations. Immunostains were positive for T-cell markers and CD30.

Figure 5.145 Anaplastic CD30+ large-cell lymphoma, ALK-1 positive. This inguinal lymph node from a 19-year-old man displays a sinusoidal pattern of involvement by large pleomorphic CD30+/ALK-1+ T cells. The diffuse pattern of sinusoidal spread, similar to metastatic carcinoma, preserves nodal architecture.

 

Figure 5.146 Anaplastic CD30+ large-cell lymphoma, ALK-1 positive. Nests of large malignant CD30+/ALK1+ cells fill sinuses throughout this lymph node. The arrow in the left middle panel shows a lymphoma cell with an atypical multilobed or horseshoe-shaped (wreath-like) nucleus. Numerous mitotic figures are present. The t(2;5) associated with anaplastic large-cell lymphoma results in the expression of a ALK-1 fusion protein that can be detected either by immunohistochemistry (left bottom panel) or FISH (Fig. 5.147).

Figure 5.147 t(2;5)(p23;q35) by cytogenetics and FISH in diffuse anaplastic large-cell lymphoma. Approximately one-third of anaplastic CD30+ large-cell lymphomas harbor the t(2;5) which is associated with favorable outcome in this disease. The upper panel shows ideograms of chromosomes 2, 5, and the respective derivative chromosomes are to the left in color. The corresponding G-banded chromosome pairs are to the right. The arrows indicate the breakpoints on the respective chromosomes. Lower panel: FISH of an ALK rearrangement. The region telomeric to the ALK gene is labeled with a red fluor, and the region centromeric to the ALK gene is labeled with a green fluor. When a translocation occurs involving the ALK gene, the red and green signals split apart. A yellow fusion signal indicates an intact ALK gene.

 

Figure 5.148 Hodgkin lymphoma with axillary lymph node involvement causing edema and enlargement of the right breast (top panel, courtesy Dr. P. Galbraith). Bottom panel: Rash in Hodgkin lymphoma. Hodgkin lymphoma in this young woman was accompanied by a generalized, pruritic macular papular rash at the time of diagnosis.

Figure 5.149 Hodgkin lymphoma of spine. A coronal MRI reveals a diffuse low signal through a lumbar vertebral body (arrow). This is the MRI equivalent of an “ivory vertebra,” a term used to describe isolated, diffuse sclerosis of a vertebral body on radiographs. The differential diagnoses include non-Hodgkin and Hodgkin lymphoma, metastases, and Paget disease.

 

Figure 5.150 Hodgkin lymphoma of spleen. An axial CT scan with intravenous contrast shows a very large spleen with large, complex, hypodense masses. The low-density regions centrally within the masses likely represent areas of necrosis.

 

Table 5.6 Relative incidence of each stage for each histopathologic subtype of Hodgkin disease

 

Histologic subtype

Stage

Lymphocyte-Predominant (%)

Nodular Sclerosis (%)

Mixed- Cellularity (%)

Lymphocyte-Depleted (%)

IA and IB

47

8

12

9

IIA and IIB

38

52

34

14

IIIA and IIIB

14

29

41

41

IVA and IVB

1

11

13

36

Total

100

100

100

100

Modified from Kaplan HS, Hodgkin's disease, 2nd ed. Cambridge: Harvard University Press, 1980.
Reprinted with permission from Wintrobe's Clinical Hematology, 11th Edition, page 2525.

Figure 5.151 Right cervical lymphadenopathy in a case of Hodgkin lymphoma (top panel). Recurrent Hodgkin lymphoma of anterior mediastinum eroding through anterior chest wall (bottom panel, courtesy Dr. P. Galbraith).

 

Figure 5.152 Herpes zoster in a patient presenting with Hodgkin lymphoma. (Courtesy Dr. I. Quirt.)

Figure 5.153 Finger warts (verruca simplex) in a patient presenting with Hodgkin lymphoma. (Courtesy of The Crookston Collection.)

 

Figure 5.154 Gross appearance of a group of resected lymph nodes matted together by nodular sclerosis Hodgkin lymphoma. A vague nodular appearance can be discerned.

Figure 5.155 Hodgkin lymphoma of spleen. Multiple small nodules of Hodgkin lymphoma are distributed throughout the splenic parenchyma.

 

Figure 5.156 Nodular lymphocyte-predominant Hodgkin lymphoma. This lymph node is effaced by a small lymphocyte/histiocyte infiltrate and occasional “L&H” (popcorn) cells that are large cells with multilobulated nuclei and very fine neutral-staining nucleoli (bottom panel). In this disease, distinct from classical Hodgkin disease, these cells are typically CD45+/CD20+/BCL6+/CD30-/CD15-.

Figure 5.157 Nodular sclerosis Hodgkin lymphoma, grade 1. A spinal accessory node from a 31-year-old woman shows a thickened capsule with the architecture distorted by broad bands of collagenous fibrosis interspersed with nodular aggregates composed primarily of small lymphocytes, scattered histiocytes, occasional eosinophils, plasma cells, and classic Reed-Sternberg cells.

 

Figure 5.158 Nodular sclerosis Hodgkin lymphoma, grade 2 (syncytial variant). A scalene node from a 32-year-old woman is distorted by wide bands of collagen sclerosis and nodules consisting mostly of highly atypical, large, multinucleated cells that stain positively for CD30 (right lower panel) and CD15.

Figure 5.159 Gross appearance of a group of resected lymph nodes contiguously involved by mixed-cellularity Hodgkin lymphoma.

 

Figure 5.160 Mixed-cellularity Hodgkin lymphoma. This lymph node from 37-year-old woman displays diffuse proliferation of small lymphocytes, eosinophils (Eo), plasma cells (Pc), and histiocytes (H) admixed with occasional classic Reed-Sternberg (RS) cells, which are characterized by a bilobed nucleus, vesicular chromatin, and prominent, dual, eosinophilic nucleoli. In addition, mononuclear RS variants (mononuclear RRS) actually are often easier to find in this and other subtypes of Hodgkin lymphoma.

 

Figure 5.161 Lymphocyte-rich classical Hodgkin lymphoma. An enlarged lymph node is replaced by a vaguely nodular proliferation of small lymphocytes interspersed with classical RS cells (right upper panel), L&H cells (left middle panel), clusters of histiocytes (right middle panel), and immunohistochemistry showing the typical RS phenotype in classical Hodgkin lymphoma, namely positive for CD30 and CD15 and negative for CD45.

Figure 5.162 Lymphocyte-depleted Hodgkin lymphoma. This axillary lymph node is totally replaced by a primarily large-cell infiltrate accompanied by some small mature lymphocytes. Numerous classic Reed-Sternberg cells (CDs 30+/15+/45-) were present in addition to bizarre forms with multilobulated nuclei mimicking wreath cells of anaplastic large-cell lymphoma.

 

Figure 5.163 Hodgkin lymphoma, interfollicular pattern. An enlarged axillary lymph node from a 39-year-old woman shows expansion of the interfollicular area by nodules invading germinal centers (triangles) and composed of a mixture of small lymphocytes, histiocytes, and occasional classic bilobed and mononuclear variants of Reed-Sternberg cells.

 

Figure 5.164 Hodgkin lymphoma involving the bone marrow. A dense fibrosclerotic process totally replaces the marrow and is composed of a heterogeneous mixture of inflammatory cells including small lymphocytes, histiocytes, plasma cells, eosinophils and occasional large CD30+ mononuclear Reed-Sternberg cell variants (arrow and inset).

Figure 5.165 Progressive transformation of germinal centers (PTGC). Large, expanded, and partially obliterated follicles (arrows) are being invaded by small mantle cells. This condition often is seen in the same lymph nodes involved by nodular lymphocyte-predominant Hodgkin lymphoma.

 

Figure 5.166 Large B-cell lymphoma mimicking nodular sclerosis Hodgkin lymphoma. This retroperitoneal lymph node reveals extensive fibrosis, associated with nodules composed mostly of small mature lymphocytes and occasional large, highly atypical multinucleated large B-cell lymphoma cells. The latter, by immunostains, were CDs 45+/30-/15-/20+. Many displayed bilobed nuclei with a vesicular (open or uncondensed) chromatin pattern, with two eosinophilic staining nucleoli that could easily, in the absence of immunohistochemistry, be confused with Reed-Sternberg cells.



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