Your Answer is CORRECT You answered: Marginal zone lymphoma

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presented by Edward G. Weir, M.D. The correct diagnosis is: Marginal zone lymphoma

Histology:

Lymph node histology is notable for an atypical nodular lymphoid proliferation and a paracortex that is largely replaced by fibrosis and adipocytes. Patent and occasionally distended lymph node sinuses can be appreciated. Some of the lymphoid nodules demonstrate germinal centers. Cytologically, the nodules are composed of a monomorphous population of small, slightly irregular lymphocytes with mature chromatin. In addition, the lymphocytes have moderately abundant clear cytoplasm, rendering them a monocytoid appearance. There is no evidence of plasmacytoid differentiation. The germinal centers comprise a polymorphous population of centrocytes, centroblasts and tingible body macrophages. By immunohistochemistry, the monomorphous lymphocytes are positive for CD20 and negative for both CD5 and CD10. The stain for CD5 highlights only the few paracortical T cells present, and the stain for CD10 highlights only the germinal center cells. Also, an immunostain for bcl-2 (not shown) is positive on the monomorphous population of lymphocytes and is negative in the germinal centers.

Discussion:

The monocytoid morphology of the malignant cells is a classic histologic manifestation of a low-grade marginal zone B cell lymphoma. The nodular growth pattern and apparent follicular colonization of the lymphoma underscores the marginal zone origin of the infiltrate. Furthermore, the lack of a prominent interfollicular expansion suggests an early stage of lymphoma development. The immunohistochemical studies clearly confirm that the lymphoma is of marginal zone and not mantle or follicular derivation. The lack of aberrant CD5 expression essentially excludes a diagnosis of mantle cell lymphoma as well as small lymphocytic lymphoma. A follicular lymphoma of low-grade histology should be positive for CD10 and should show germinal center reactivity for bcl-2. Most patients present with localized or generalized peripheral lymphadenopathy and a good performance status. Occasional bone marrow involvement is observed. The clinical course of nodal marginal zone lymphomas has not been well studied. Recent series suggest that patients respond to chemotherapy, but show a high early relapse rate. Nonetheless, the relatively long median survival in these patients is

consistent with an indolent biology.

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Case prepared by:

Bahram R. Oliai, M.D. boliai@jhmi.edu

Your Answer is CORRECT You answered: Small lymphocytic lymphoma

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presented by Edward G. Weir, M.D. The correct diagnosis is: Small lymphocytic lymphoma

Histology:

The nodal architecture is diffusely effaced by an abnormal lymphoid infiltrate. Lymph node sinuses are inapparent and cortical follicles are essentially absent. Numerous pale zones render the infiltrate a vague nodular appearance on low power examination. Cytologically, the infiltrate is predominantly comprised of a monomorphous population of small, mature lymphocytes. The pale zones are comprised of slightly larger lymphocytes with moderately abundant cytoplasm and prominent central nucleoli. Mitoses are few and there is no evidence of necrosis. By immunohistochemistry, the infiltrate is positive for CD20 and CD5, and negative for CD3 and CD10. Small lymphocytic lymphoma (SLL) is generally a disease of the elderly, and is the lymph node manifestation of chronic lymphocytic leukemia. Though occasional patients present with aleukemic nodal involvement at diagnosis, most patients will ultimately develop bone marrow and peripheral blood infiltration. Moreover, generalized lymphadenopathy and hepatosplenomegaly are not uncommon clinical manifestations. Furthermore, advanced stages of the disease are typically characterized by hypogammaglobulinemia and autoimmune phenomenon, often resulting in infectious complications, hemolytic anemia and thrombocytopenia. Like most indolent lymphomas, SLL is not considered to be curable with currently available therapy. However, treatment with alkylating agents, prednisone, and more recently, purine analogs has been found to be remarkably effective in producing longterm remissions. The extent of the disease at the time of diagnosis is the best predictor of survival. Lymph nodes involved by SLL usually demonstrate diffuse architectural effacement by a monomorphous proliferation of small, mature lymphocytes with sparse cytoplasm. The lymphocyte nuclei typically are round and have a condensed chromatin pattern. A very specific histomorphologic feature of SLL is the

Discussion:

presence of pseudofollicular growth centers, which renders the infiltrate a vaguely nodular appearance on low power examination. Unlike the B cell follicles of follicular hyperplasia and follicular lymphoma, growth centers have ill-defined margins and are cytologically comprised of predominantly prolymphocytes. Prolymphocytes are characterized as larger lymphoid cells with more abundant, slightly basophilic cytoplasm and a prominent central nucleolus. Immunophenotypically, the tumor cells demonstrate expression of B cell markers (CD20 and CD79a) and aberrant expression of the T-related markers, CD5 and CD43. They are negative for the T cell marker CD3 and the follicle center cell marker CD10. Among CD5-positive B cell lymphomas, the presence of CD23 reactivity distinguishes SLL from mantle cell lymphoma. Mantle cell lymphoma, which is not characterized by growth centers, is negative for CD23 but positive for the PRAD1 oncogene protein product CyclinD1. SLL is a low-grade lymphoma with few mitoses and a low proliferation index. Alternatively, Burkitts lymphoma is a very aggressive tumor characterized by numerous mitoses, macrophages engulfing apoptotic bodies, and necrosis.

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Case prepared by: Carol Allan, M.D. callan@jhmi.edu

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Your Answer is CORRECT You answered: T cell-rich B cell lymphoma

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presented by Edward G. Weir, M.D. The correct diagnosis is: T cell-rich B cell lymphoma

Histology:

Histologic sections of the lymph node demonstrate complete architectural effacement by a diffuse lymphoid infiltrate. Both lymph node sinuses and cortical follicles are absent. The infiltrate is comprised of numerous large, atypical cells surrounded by a background population of small, mature lymphocytes. Few plasma cells and granulocytes are identified. The atypical cells have abundant cytoplasm and complex nuclei; some cells appear to be binucleated. Many of the atypical cells are mitotically active. By immunohistochemistry, the large cells are positive for CD20, and negative for CD3, CD15 and CD30. Moreover, several of these large cells demonstrate kappa Ig light chain expression and none of them demonstrate lambda light chain expression. The vast majority of small lymphocytes in the background are positive for CD3, and negative for CD20 and CD57. Diffuse effacement of lymph node architecture by a dual population of large atypical cells and small mature lymphocytes is characteristic of many lymphoma types, including those listed above. Though these lymphomas may have unique but often subtle morphologic features, immunophenotypic studies are frequently necessary to establish a definitive diagnosis. A T cellrich large B cell lymphoma (TCRBCL) is cytologically notable for numerous large, atypical cells that typically have an unequivocally malignant appearance. These cells are very polymorphous, may have bizarrely-shaped nuclei, and are mitotically active. The small cells in the background, which usually predominate in number, are round and regular and represent host reactive T cells. This pattern is in contrast to a peripheral T cell lymphoma, which characteristically demonstrates a spectrum of atypicality from small-tointermediate-to-large lymphocytes. Also, unlike both mixed cellularity Hodgkins lymphoma and peripheral T cell lymphoma, there is a general paucity of plasma cells and granulocytes. Moreover, the large atypical cells in TCRBCL are immunophenotypically positive for the B cell marker CD20, and negative for the T cell marker CD3 and the Hodgkins markers CD15 and CD30. In addition, the lack of reactivity for CD30 differentiates TCRBCL from anaplastic large cell lymphoma, often referred to as Ki-1(CD30) lymphoma. It should be noted that TCRBCL may be difficult to distinguish from a diffuse variant of lymphocyte predominant Hodgkin lymphoma (LPHL), both morphologically and immunophenotypically. Like TCRBCL, LPHL is considered to be a B cell neoplasm. However, the malignant cells of TCRBCL lack the popcorn cytology of the L&H cells of LPHL. Furthermore, an immunostain for CD57 may be helpful since increased numbers of CD57positive T cells are commonly found in LPHL and are usually distributed in rings around the L&H cells. TCRBCL is considered to be a morphologic variant of diffuse large B cell lymphoma. It is an aggressive lymphoma but is amenable to cure with multiagent chemotherapy.

Discussion:

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Carol Allan, M.D.

callan@jhmi.edu

Your Answer is CORRECT You answered: Burkitts lymphoma

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presented by Risa Mann, M.D. The correct diagnosis is: Burkitts lymphoma

Histology:

A large abdominal mass is composed of a monotonous cellular proliferation infiltrating diffusely through adipose tissue. The neoplastic cells have a high mitotic rate and this is associated with the so-called starry sky pattern, which is due to the presence of benign appearing histiocytes scattered throughout the tumor mass. The neoplastic cells have relatively round nuclei with multiple medium sized nucleoli. The tumor has an extremely high proliferation rate with many mitotic figures. The nuclei of the tumor cells are approximately the same size as the nuclei of the benign starry sky histiocytes. The neoplastic cells have a small amount of basophilic cytoplasm. Although not visible on H&E stained slides, a touch prep of these tumor cells would demonstrate deep basophilic cytoplasm with numerous cytoplasmic lipid vacuoles. The dense infiltrate in the abdominal adipose tissue is easily recognized as a neoplastic lymphomatous process. The differential diagnosis involves the subclassification of this lymphoma. The starry sky pattern which is characteristic of any lymphoma with a high proliferation rate is commonly seen in Burkitt lymphoma but it may also be seen in other high grade lymphomas such as lymphoblastic lymphoma as well as large cell lymphomas. The size of the nuclei is helpful in further subclassifying this tumor. In Burkitt lymphoma the neoplastic cells have nuclei, which are about the same size of the nuclei of starry sky histiocytes. In contrast, the nuclei of lymphoblastic lymphoma cells are usually smaller than the nuclei of the benign histiocytes and the nuclei of large cell lymphomas are usually larger than the nuclei of the starry sky histiocytes. Lastly, most helpful in this differential diagnosis is the immunophenotype. The neoplastic cells of Burkitt lymphoma usually demonstrate membranous IgM with light chain restriction and B cell associated antigens such as CD19, CD20, CD22, CD10 and BCL6. The cells are negative for CD23, CD5 and TdT. Burkitt lymphoma has one of the highest proliferation rates of all lymphomas and nearly 100% of the cells are positive for Ki-67 staining. The tumor cells show clonal rearrangement of the immunoglobulin heavy and light chains and most cases have a translocation of MYC

Discussion:

from chromosome 8 to the IgG heavy chain region on chromosome 14 or less commonly to the light chain loci on chromosomes 11 or 22. Epstein Barr Virus (EBV) is identified in the majority of the neoplastic cells in endemic cases, however, the frequency of EBV association in sporadic Burkitt lymphoma is low. Sporadic Burkitt lymphoma occurs mainly in children and young adults but it can occur at any age. Patients usually present with bulky disease often presenting in extranodal sites.

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Case prepared by: Bahram R. Oliai, M.D. boliai@jhmi.edu

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Your Answer is CORRECT You answered: Follicular lymphoma

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presented by Edward G. Weir, M.D. The correct diagnosis is: Follicular lymphoma

Histology:

Histologic sections of lymph node demonstrate significant fatty replacement and an abnormal nodular proliferation of lymphocytes. The lymphoid nodules, which are round, discrete and fairly homogeneous in size, resemble B cell follicles. However, unlike normal B cell follicles, they lack well-defined mantle zones and polarized germinal centers. Furthermore, the abnormal lymphoid nodules are largely comprised of a monomorphous population of small, mature, cleaved lymphocytes and are notable for a conspicuous absence of tingible body macrophages. By immunohistochemistry, these lymphocytes are positive for CD20, CD10 and Bcl-2, and are negative for CD3, CD43 and CD5. The Ki-67 proliferation marker demonstrates

a low level of expression.

Discussion:

Follicular lymphoma is morphologically defined as a tumor comprised of follicle center cells, usually a mixture of small, cleaved centrocytes and larger, noncleaved centroblasts. Low-grade follicular lymphomas typically demonstrate a nodular growth pattern and a predominance of centrocytes, whereas more aggressive follicular lymphomas tend to be architecturally diffuse and show a greater proportion of centroblasts. Molecularly, follicular lymphomas are characterized by the t(14;18)(q32;q21) chromosomal translocation that has been identified in approximately 80% of cases using routine karyotyping methods. The t(14;18) is a reciprocal translocation that juxtaposes the bcl-2 oncogene on chromosome 18q21 with the IgH gene on 14q32. As a result, transcription of the bcl-2 gene is brought under the control of the IgH gene regulatory elements, most likely an enhancer region, leading to constitutive overexpression of the bcl-2 gene. The bcl-2 protein, which is localized to subcellular membranes such as the outer mitochondrial membrane, endoplasmic reticulum and nuclear envelope, plays a prominent role in protecting the cell from apoptotic death. Cells, which overexpress the bcl-2 protein, have a prolonged half-life, rendering these cells more susceptible to secondary genetic events that may result in transformation to a more aggressive phenotype. By immunohistochemistry, the neoplastic follicular cells are positive for the B cell markers CD20 and CD79a, as well as the germinal center cell marker CD10. Other low-grade B cell lymphomas lack CD10 expression. Also, unlike small lymphocytic lymphoma and mantle cell lymphoma, follicular lymphoma cells lack expression of CD5 and CD43. Lastly, the immunohistochemical expression of the bcl-2 protein is useful in distinguishing follicular lymphoma from follicular hyperplasia, since bcl-2 is absent from reactive processes.

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Case prepared by: Carol Allan, M.D. callan@jhmi.edu

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Your Answer is CORRECT You answered: Follicular lymphoma, mixed small cleaved and large cell type (WHO grade 2)
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presented by Risa Mann, M.D. The correct diagnosis is: Follicular lymphoma, mixed small cleaved and large cell type (WHO grade 2)

Histology:

This lymph node shows replacement of the normal nodal architecture by prominent nodular proliferation of lymphoid cells. The normal sinuses have been obliterated by this process. The germinal center-like structures proliferate within the lymph node in a back-to-back pattern with little intervening paracortical areas. The germinal center-like structures lack tingible body macrophages and lack obvious areas of polarization. At high power, the cellular proliferation within the germinal centers demonstrates a mixed cell population comprised predominantly of small cleaved lymphocytes admixed with larger centroblasts which demonstrate more cytoplasm and prominent nucleoli, sometimes opposed to the nuclear membrane. The major differential diagnosis in this case is between that of a florid reactive follicular hyperplasia and follicular lymphoma. A mantle cell lymphoma may grow in a vaguely nodular pattern, but rarely demonstrates this prominent follicular growth pattern. The germinal centers in this case proliferate in a back-to-back pattern within the lymph nodes, leaving very little intervening paracortical areas. This pattern is more typical of a neoplastic rather than a reactive process. Other features that morphologically favor a neoplastic follicular process include the lack of tingible body macrophages and the lack of polarization within the germinal centers. On closer examination the neoplastic proliferation within the germinal centers is composed predominantly of small cleaved lymphocytes admixed with larger atypical lymphocytes (centroblasts). The number of large cells seen at high power within the nodules is within the range accepted for a mixed small cleaved and follicular lymphoma (greater than 5 and less than 15 large cells per high powered field). Although the morphologic features described above are helpful in arriving at a diagnosis of follicular lymphoma, flow cytometry and/or immunoperoxidase stains may be helpful in further documenting the diagnosis. Flow cytometry in this case showed the phenotype typical of follicular lymphoma. The cells are CD10 positive B cells, which demonstrated light chain restriction. In addition, BCL2 stains could be performed on the paraffin embedded tissue, documenting the BCL2 positivity of the proliferating B cells within the neoplastic nodules. This observation correlates with the characteristic 14/18 translocation associated with follicular lymphomas.

Discussion:

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Case prepared by: Greg Seidel, M.D. gseidel@jhmi.edu

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Your Answer is CORRECT You answered: Small lymphocytic lymphoma/chronic lymphocytic leukemia transforming to diffuse large B cell lymphoma (Richter syndrome)
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presented by Michael Borowitz, M.D., Ph.D. The correct diagnosis is: Small lymphocytic lymphoma/chronic lymphocytic leukemia transforming to diffuse large B cell lymphoma (Richter syndrome)

Histology:

Much of the node shows characteristic changes of SLL/CLL, with architecture effacement by a pseudofollicular proliferation. Cells are round and outside the pseudofollicles the cells are mostly small. Cells in the pseudofollicles have more abundant cytoplasm and include many prolymphocytes and paraimmunoblasts with larger nuclei and more prominent nucleoli. Other parts of the node, however, show a very different pattern, with diffuse architectural effacement by a more monotonous population of large cells. Immunophentoypically these two areas are also different; both express CD20,

but there is loss of CD23 on the larger cells,

and a much higher expression of the proliferation marker Ki-67.

Flow cytometry plots also show this; while all cells are CD5+ B cells with clonal expression of kappa light chain, there is a distinct population of larger cells with much brighter CD20, FMC7, and loss of CD23.

Discussion:

The number of large cells can vary greatly in SLL/CLL, and their number alone is not sufficient to establish a diagnosis of transformation. It is particularly important not to over-interpret cases with unusually prominent pseudofollicles, some of which can even coalesce. True Richter transformation is invariably associated with a distinctly different architectural appearance from the background SLL/CLL.

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Case prepared by: Amy Duffield, M.D., Ph.D. aduffie1@jhmi.edu

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Your Answer is CORRECT You answered: Anaplastic large cell lymphoma

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presented by Andrea Subhawong, M.D. The correct diagnosis is: Anaplastic large cell lymphoma

Histology:

The biopsy is notable for large lymphoid cells which infiltrate in a cohesive pattern with a predilection for the nodal sinuses. Cytologically the nuclei are enlarged, often multinucleated, and have prominent nucleoli, which tend to be smaller and less eosinophilic than those observe in Hodgkin lymphoma. Some cells have nuclei which are eccentric and indented by a cytoplasmic light zone (hoff), and are thus defined as hallmark cells The morphologic findings are highly suggestive of ALCL. Immunohistochemical confirmation is made by intense and diffuse membranous and golgi staining with CD30 in the absence of B-cell markers.

Discussion:

In this context, ALK positivity confirms the diagnosis but is not positive in all cases and in fact becomes less frequent as a function of patient age.

In ALK negative cases, staining with CD4, CD2 and/or TIA-1 can be confirmatory in conjunction with appropriate morphology, however there appears to be no uniform criteria for separating ALK negative ALCL from peripheral T-cell lymphoma, NOS. The distinction is prognostically relevant as the survival decreases from ALCL ALK+ (best), ALCL ALK(intermediate), to PTCL NOS (worst). Isolated cutaneous ALCL has the best

prognosis of all. This is the last case for Week 470.

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Your Answer is CORRECT You answered: T cell/ histiocyte rich large B-cell lymphoma
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presented by Andrea Subhawong, M.D. The correct diagnosis is: T cell/ histiocyte rich large B-cell lymphoma

Histology:

The architecture is effaced by a diffuse lymphoid infiltrate. Most of the infiltrate is composed of small lymphocytes and histiocytes, but there are scattered large, atypical cells with abundant cytoplasm and complex nuclei; some cells appear to be binucleated. By immunohistochemistry, the large cells are positive for CD20, and negative for CD3, CD15 and CD30 (not shown). There is no residual nodularity in the background of the node. TCRBCL may be difficult to distinguish from a diffuse variant of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), both morphologically and immunophenotypically. Like TCRBCL, NLPHL is considered to be a B cell neoplasm. However, the malignant cells of TCRBCL lack the popcorn cytology of the atypical cells of NLPHL. Furthermore, an immunostain for CD57 may be helpful since increased numbers of CD57-positive T cells are commonly found in NLPHL and are usually distributed in rings around the popcorn cells. TCRBCL is

Discussion:

considered to be a morphologic variant of diffuse large B cell lymphoma. It is an aggressive lymphoma but is amenable to cure with multi-agent chemotherapy. This is the last case for Week 471.

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incorporated into any information retrievel system, electronic or mechanical, without the written permission of JHU.

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Discussion:

MALT lymphoma is characterized by a dense, monotonous population of centrocyte-like cells, lymphoepithelial lesions (infiltration of glandular epithelium by lymphocytes) and frequent follicular colonization. The tumor cells may also have plasmacytoid differentiation. Tumor cells are immunoreactive for B cell markers, including CD19, CD20, and CD79a, as well as bcl-10, with variable CD43 staining. They exhibit monoclonal light chain staining. This case demonstrated monoclonal heavy chain rearrangement by molecular studies.

Gastric MALT lymphomas are closely linked to Helicobacter pylori infection, and H. pylori eradication therapy produces a long term favorable outcome (Tohoku J Exp Med 2008;214:79)

Celiac disease, or gluten-sensitive enteropathy, is a T-cell mediated disease of genetically susceptible individuals, induced by ingesting proteins in wheat (gliadins), barley (hordeins) or rye (secalinin). Symptoms include episodic diarrhea, abdominal pain and distention and weight loss (Clin Med Res 2004;2:71), with clinical and microscopic improvement after dietary withdrawal. Microscopic changes include an increase in intraepithelial lymphocytes of 40+ lymphocytes/100 surface or upper crypt enterocytes, or early clustering of 12+ lymphocytes at the tip of villi and extending evenly down the sides of the villus (Mod Path 2003;16:342). There is also diffuse enteritis with marked atrophy or total loss of villi and elongated crypts. Definitive diagnosis requires these histologic findings plus positive serology and favorable clinical and serologic responses after dietary change. The differential diagnosis includes duodenal intraepithelial lymphocytosis with normal villous architecture, associated with H. pylori infection, but without any other features of celiac disease (Mod Path 2005;18:1134).

In this case, the presence of celiac sprue appears to be incidental. Celiac sprue is associated with an increased risk of malignant intestinal disease, but this is usually T cell intestinal lymphoma of the small bowel, not MALT lymphoma of the stomach. Celiac sprue does not appear to be associated with H. pylori gastritis (Am J Gastroenterol 2006;101:1880).

Additional references: PathologyOutlines.com chapters - small bowel, Lymphoma: B cell, Stomach

Nat Pernick, M.D., President PathologyOutlines.com, Inc. 30100 Telegraph Road, Suite 404 Bingham Farms, Michigan (USA) 48025 Telephone: 248/646-0325 Email: NatPernick@Hotmail.com Alternate email: NatPernick@gmail.com Discussion:

Primary diffuse large B-cell lymphoma of the central nervous system is a rare tumor that by definition, arises exclusively in the CNS with no obvious lymphoma elsewhere at diagnosis. It represents 5-10% of CNS neoplasms in patients ages 75+ (Hum Path 2003;34:1137). A majority of these neoplasms arise supratentorially within the white matter and in the periventricular area. They may be multifocal and may affect the leptomeninges, but primary leptomeningeal involvement is rare. At diagnosis, 20% have ocular involvement; and 8090% of these patients develop contralateral tumors and intraparenchymal CNS lesions, with invasion of the subretinal pigment epithelial space and vitreous. Dissemination to extraneural sites such as bone marrow is extremely rare.

Radiologically, these tumors are generally solitary, homogeneously contrast enhancing and usually have no ring enhancement, in contrast to glioblastoma multiforme and metastases.

Clinically, patients usually present with focal neurological deficits, signs of increased intracranial pressure or neuropsychiatric symptoms. Leptomeningeal involvement generally presents with a headache. Intraocular involvement may cause blurred vision or floaters.

Grossly, most central lymphomas are solid, grey, ill-defined, and usually deep-seated. Some travel along white matter tracts and transcend the corpus callosum, like infiltrating gliomas. Histologically, they are widely infiltrating with a perivascular predilection. Most are discohesive, but may occur in a glial meshwork within the CNS. Primary brain lymphomas have scant cytoplasm, high grade nuclei and multiple nucleoli, but less pleomorphism than other high grade CNS tumors. Most primary CNS lymphomas are diffuse large B cell subtype, and are immunoreactive for CD20, CD79a and CD22, but negative for CD3. However, nearly all tumors have a background of reactive T cells that may lead to an erroneous diagnosis of T cell lymphoma. The mitotic index is often > 50%.

Smears show single cells with discrete cell borders, vesicular nuclei, prominent nucleoli and frequent apoptosis.

Treatment includes high-dose methotrexate therapy with or without radiation. Chemotherapy has extended median survival in immunocompetent patients to 44 months (eMedicine). Although tumors can be classified by immunohistochemistry into germinal center and nongerminal center phenotypes, this does not appear to influence prognosis (Neuropathology 2009 Nov 18 [Epub ahead of print], J Ne

Discussion

Intravascular lymphoma is a rare subtype of diffuse large B cell lymphoma, with intravascular growth in the skin, CNS, and other sites. The presenting signs and symptoms are often complex, and include mental status changes, as in this case, and rapidly progressive dementia. Patients may present with a mass lesion (Pathol Int 2004;54:231), a skin

rash or fever of unknown origin.

Patients are typically elderly, with a median age of 71 years. Although chemotherapy may be effective (Ann Oncol 2004;15:1215), these tumors are often not diagnosed until autopsy, which typically shows involvement of most organs. In this case, the patient was 72 years old, and expired two weeks after the brain biopsy. A post-mortem examination revealed widespread disease, with involvement of the heart, lung, kidneys, adrenals, stomach, pancreas and spleen. No skin lesions were found.

Histologically, the tumor is composed of large centroblastlike lymphoid cells with prominent nucleoli within small vessel lumina, often capillaries. Mitotic figures are frequent, and there are often fibrin thrombi. Immunohistochemistry results are similar to diffuse large B cell lymphoma, with immunoreactivity for CD19, CD20, CD22 and CD79a. Tumors are usually bcl2 positive. Rarely, these tumors are T cell lymphomas with corresponding immunoreactivity.

Discussion

The initial flow cytometry showed CD20 and CD5 coexpression without CD23 expression, generating a differential diagnosis of atypical CLL (atypical since CD23 was not expressed), prolymphocytic leukemia (either de novo or secondary to CLL) and mantle cell lymphoma. A diagnosis of atypical CLL was favored based on the lack of organomegaly / lymphadenopathy, only moderately increased and stable WBC counts, prolymphocytes < 55% and lack of t(11;14). The subsequent lymph node biopsy had the characteristic CLL/SLL immunophenotype of CD5+, CD23+ B cells.

The paraimmunoblastic variant of SLL/CLL is a rare morphologic variant characterized by a diffuse to nodular

proliferation of paraimmunoblasts, the cells usually seen in pseudoproliferation centers of SLL. In classic SLL, the predominant population is small lymphocytes with scant cytoplasm, coarsely clumped chromatin and inconspicuous nucleoli. In the paraimmunoblastic variant, the predominant cells are slightly larger, with moderately abundant cytoplasm, more open/vesicular chromatin and a single prominent, central nucleolus. The paraimmunoblasts have the same staining pattern as classic CLL/SLL (i.e. expression of CD19, CD20, CD5 and CD23, negative for CD10 and FMC7). It is considered the tissue counterpart of a prolymphocytic transformation of CLL.

The paraimmunoblastic variant was first described by Pugh as an aggressive variant that presents with generalized lymphadenopathy, and occasionally splenomegaly (Am J Surg Pathol 1988;12:907). The term paraimmunoblast was first used by Lennert (Malignant Lymphomas other than Hodgkins disease. Berlin/Heidelberg: Springer-Verlag, 1978:111-36) to describe a mitotically active, medium-sized cell with weakly staining eosinophilic cytoplasm, irregular nuclear borders, vesicular chromatin and a single, prominent, central nucleolus. In contrast, immunoblasts are larger cells with moderate basophilic cytoplasm, large round nuclei and a similar prominent, central nucleolus. Centroblasts are larger cells with multiple basophilic, peripherally-placed nucleoli.

The differential diagnosis in this case includes a Richters transformation and blastoid variant of mantle cell lymphoma. Richters transformation of CLL/SLL usually presents with a single area of marked nodal growth, unlike the diffuse, symmetrical lymphadenopathy in this and other paraimmunoblast variant cases. The Richters node may show complete or partial involvement by sheets of centroblasts or immunoblasts with a proliferation fraction in transformed areas greater than 40% (Cancer J 2005;11:161).

Blastoid variant of mantle cell lymphoma also has a vaguely

nodular architecture and slightly larger cells with less clumped chromatin. However, cyclin D1 is overexpressed and t(11;14) is detected by FISH analysis.

The original flow cytometric examination demonstrated several features associated with a poor prognosis, including CD38 expression, a complex karyotype and p53 mutation (Jaffe: WHO Classification of Tumors, Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid System, Blood 1998;91:4342, Blood 2001;98:181). In addition, patients with the paraimmunoblastic variant of CLL/SLL have an aggressive clinical course (Hum Path 2002;33:1145).

Nat Pernick, M.D., President PathologyOutlines.com, Inc. 30100 Telegraph Road, Suite 404 Bingham Farms, Michigan (USA) 48025 Telephone: 248/646-0325 Fax: 248/646-1736