The authors report a localized (primary) conjunctival marginal zone B-cell lymphoma (mucosa-assoc... more The authors report a localized (primary) conjunctival marginal zone B-cell lymphoma (mucosa-associated lymphoid tissue (MALT)-type), with amyloid deposition with relapse in the stomach, 14 months after the initial diagnosis. Ocular adnexal marginal zone B-cell MALT lymphoma is often localized at diagnosis; some relapse in typical MALT sites. There are few reports of localized conjunctival lymphoma with a relapse in the stomach. The authors suggest that all patients with localized ocular adnexal lymphoma be followed for an extended period.
Archives of Pathology & Laboratory Medicine, Apr 1, 2008
Lymphomas arising in extranodal sites are intriguing. The types of lymphomas encountered vary wid... more Lymphomas arising in extranodal sites are intriguing. The types of lymphomas encountered vary widely from one extranodal site to another. For many types of extranodal lymphomas, there are distinctive clinicopathologic features, sometimes including association with an underlying immunodeficiency syndrome, autoimmune disease, infection, or other immunologic disorder, or a predilection to affect patients of certain ethnic origins. Presented below is a review of lymphomas that are encountered most often in extranodal sites.
The American Journal of Surgical Pathology, Jul 1, 2007
Primary testicular lymphomas typically occur in patients over 60 years of age. Most are diffuse l... more Primary testicular lymphomas typically occur in patients over 60 years of age. Most are diffuse large B-cell lymphomas with frequent dissemination and a poor prognosis. Primary follicular lymphoma of the adult testis has not been well characterized. However, a small number of primary testicular follicular lymphomas have recently been described in children. These showed stage 1E disease, a lack of BCL2 gene rearrangement and Bcl-2 protein expression, and a good clinical outcome. Here, we describe 5 cases of primary follicular lymphoma of the testis and epididymis in adults. These presented as unilateral testicular masses 12 to 40 mm in diameter and were characterized histologically by small neoplastic follicles in a sclerotic background. The neoplastic cells expressed CD10 and Bcl-6, but not Bcl-2 and lacked t(14;18)(q32;q21)/ IGH-BCL2 and BCL6 gene rearrangements. Four of the five patients were 35 years old or younger, and 4 presented with stage 1EA disease. Although follow-up is 12 months or less in 2 of the 5 patients, to date each has followed an indolent clinical course. These features are different from those of most adult nodal follicular lymphomas but are very similar to those of the pediatric primary testicular follicular lymphomas. Together, the pediatric and adult cases represent a discrete clinicopathologic entity of t(14;18)(q32;q21)/IGH-BCL2-negative primary follicular lymphoma of the testis and epididymis, which typically present as clinically indolent localized disease in young males and should be distinguished from the diffuse large B-cell lymphoma more frequently seen in the testes of older adults.
IgG4 is the least common of all the IgG subclasses. In recent years an uncommon systemic disease ... more IgG4 is the least common of all the IgG subclasses. In recent years an uncommon systemic disease characterized by variable manifestations that may include the presence of tumour-like sclerosing lesions in a variety of extranodal sites, lymphadenopathy, presence of increased numbers of IgG4þ plasma cells in affected tissues, elevated serum IgG4 level, frequent presence of autoantibodies and often, a good response to steroid therapy or Rituximab has been described. The disorder has been called IgG4-related sclerosing disease, IgG4-related systemic disease and IgG4-related autoimmune disease; currently the preferred designation is IgG4-related disease (IgG4-RD). In addition to other changes that may be found in association with IgG4-RD, some investigators have suggested that IgG4-RD may serve as a substrate for the development of lymphoma. This review focuses on lymphadenopathy associated with IgG4-RD and also explores the significance of isolated lymphadenopathy with increased numbers of IgG4þ plasma cells. Emerging data on lymphomas arising in association with IgG4-RD and the possibility of an increased risk of lymphoma in patients with IgG4-RD are also discussed.
The American Journal of Surgical Pathology, Nov 1, 2008
Rare cases of CD20+ T-cell lymphoma (TCL) have been reported, but the clinicopathologic spectrum ... more Rare cases of CD20+ T-cell lymphoma (TCL) have been reported, but the clinicopathologic spectrum of this disorder is not known. We identified 9 cases of CD20+ TCL diagnosed at our institution and 26 additional cases through a search of the English language literature. Among current cases, there were 7 men (ages 71 to 81, median 75 y) and 2 women (ages 36 and 37 y). Five patients presented with predominantly nodal disease (localized in 3 and widespread in 2 cases) and 4 patients presented with purely extranodal disease involving the parotid glands, skin, or small intestine. CD20 was uniformly and strongly expressed in 5 cases and dimly expressed or present on a subset of neoplastic cells in 4 cases. The proportion of CD20+ T cells changed over time in 3 cases. Three cases fulfilled diagnostic criteria for clinicopathologically defined subtypes of TCL (2 mycosis fungoides; 1 enteropathy-type TCL), whereas 6 were peripheral TCL unspecified with variable cytomorphology, T-cell immunophenotype, and sites of involvement. In 8 of 9 cases, a clonal T-cell population was identified by molecular genetic analysis. Among 8 cases with clinical follow-up, 5 behaved aggressively with death from disease within 3 years of diagnosis in 4 cases (median survival: 11 mo, range: 1 to 35 mo), and recurrent disease at 10 months in 1 case; 1 patient died of an EBV+ B-cell lymphoma (BCL) 66 months after the original diagnosis; in the remaining 2 cases, patients were alive and undergoing treatment (follow-up: 4 and 18 mo). Historical cases showed similar clinicopathologic variability. CD20+ TCL is rare, and clinically and pathologically heterogeneous. When CD20 expression is present in TCL, it may be dimmer than that of normal B cells, suggesting neoplastic transformation of a normal CD20dim+ T-cell subset. Cases of CD20+ TCL in which the proportion of CD20+ cells changes over time may reflect aberrant expression of CD20, possibly as an activation marker, by neoplastic T cells. CD20+ TCL may cause diagnostic difficulty, particularly in cases that clinically and pathologically mimic BCL. Knowledge of the unusual phenomenon of CD20 expression in TCL, in conjunction with careful morphologic analysis, the use of a panel of antibodies, and molecular genetic studies, is important in avoiding a misdiagnosis of BCL.
The American Journal of Surgical Pathology, Jun 1, 2001
Cutaneous follicular lymphomas (FLs) and cutaneous B-cell lymphomas of extranodal marginal zone (... more Cutaneous follicular lymphomas (FLs) and cutaneous B-cell lymphomas of extranodal marginal zone (MZL)/mucosal-associated lymphoid tissue (MALT) type may have morphologic overlap, despite the fact that they are thought to be of distinct derivation (germinal center vs. postgerminal center). The problem is compounded by the reported absence of bcl-2 expression by many cutaneous FLs, leading to speculation that cutaneous FL may be unrelated to nodal FL. The authors analyzed the expression of the germinal center-associated antigens bcl-6 and CD10 and of bcl-2 in 18 cutaneous B-cell lymphomas (10 FLs and eight MZLs), in relationship to CD21+ follicular structures, to clarify the relationship of nodal to cutaneous FLs and to explore the value of these antigens in differential diagnosis. The authors studied 10 cutaneous FLs (seven primary and three secondary) and eight MZLs (six primary and two secondary). The FLs (found in six men and four women age 45-75 years) involved the trunk (n = 3) and scalp, face and neck (n = 7). The MZLs (found in five women and three men age 34-81 years) involved the trunk (n = 4), face and neck (n = 2), and arm (n = 2). Immunostaining for CD21, bcl-6, CD10, and bcl-2 allowed the delineation of compartments within the tumors and yielded distinct patterns of staining in FL and MZL. In both follicular and interfollicular/diffuse areas of FL the neoplastic cells were bcl-6+ (10 of 10), often CD10+ (seven of 10, four of seven primary), and bcl-2+ (nine of 10, six of seven primary). Only three of seven cases (one of five primary) had bcl-2 rearrangement detectable by polymerase chain reaction. In the MZLs, the neoplastic B-cells were bcl-6-, CD10-, and bcl-2+ (eight of eight). Three patterns of CD21+ follicles were identified in MZL: reactive germinal centers, uniformly bcl-6+, CD10+, and bcl-2- (five of eight MZLs); colonized follicles, both bcl-6-, bcl-2+, and L26+ cells, and bcl-6+ and bcl-2- cells (five of eight MZLs); and expanded/colonized follicular dendritic cell meshworks, bcl-6- and bcl-2+ B cells with rare residual bcl-6+ and bcl-2- cells (four of eight MZLs). The authors conclude that cutaneous FLs express bcl-6 uniformly, usually express CD10 and bcl-2, and have a follicular pattern similar to nodal FL and consistent with a germinal center origin. The immunophenotype of cutaneous FL is distinct from that of cutaneous MZL, which is negative for bcl-6 and CD10. Colonized follicles in MZL, identified by CD21+ follicular dendritic cell meshworks, contained numerous bcl-6- and bcl-2+ B cells, and were readily distinguished from neoplastic follicles in FL. Conversely, CD21- interfollicular and diffuse areas in FLs contained bcl-6+ and CD10+ cells, which were not seen in diffuse areas of MZLs. Thus, the combination of bcl-2, bcl-6, and CD21 staining is useful for the distinction of cutaneous MZL from cutaneous FL.
Extranodal lymphomas are a diverse group of low and high grade neoplasms of B-, T-, and NK-cell l... more Extranodal lymphomas are a diverse group of low and high grade neoplasms of B-, T-, and NK-cell lineage, each with characteristic sites of origin, morphology, immunophenotype, genetic features, patterns of spread, and prognosis. The diversity is sometimes seen even within a single histologic type of lymphoma. This phenomenon is especially striking in the category of diffuse large B-cell lymphoma (DLBCL). DLBCLs as classified in the WHO Classification are clinically and pathologically heterogeneous (Swerdlow et al. 2008; Stein et al. 2008). Since the publication of the most recent edition of the WHO Classification of tumours of haematopoietic and lymphoid tissues (Swerdlow et al. 2008), a number of advances in the understanding of these lymphomas have been made. This review provides an overview of extranodal DLBCLs and describes recent updates regarding these lymphomas.
Cutaneous marginal zone lymphoma (MZL) is a recently described low-grade B-cell lymphoma that usu... more Cutaneous marginal zone lymphoma (MZL) is a recently described low-grade B-cell lymphoma that usually follows an indolent course. This tumor shares many histologic and clinical features with cutaneous lymphoid hyperplasia (CLH), a benign reactive lymphoid proliferation. Sixteen biopsy specimens from 14 patients with CLH were studied, and compared with 16 cases of cutaneous MZL (9 primary cutaneous, 7 with secondary involvement of the skin) to determine whether there were features that would permit their distinction on routinely fixed, paraffin-embedded tissue sections. Both disorders showed a female preponderance (CLH: 9 F, 5 M; MZL: 11 F, 5 M). The median age was also similar (CLH: 54 years; cutaneous MZL: 55 years). CLH was most common on the arm (8) and the head and neck (7) but also involved the trunk (1); primary cutaneous MZL most often involved the limbs (3), trunk (3), and head and neck (3). Lymphoma did not develop in any of the 14 CLH patients (follow-up ranging from 9 to 246 months, mean 62 months). Six of 9 patients with primary cutaneous MZL and all 7 patients with secondary cutaneous MZL experienced relapses, most commonly isolated to skin or a subcutaneous site. On hematoxylin-eosin stained sections, a diffuse proliferation of marginal zone cells (p < 0.0001), zones of plasma cells (p = 0.01), the absence of epidermal change (p = 0.01), reactive germinal centers (p = 0.03), and a diffuse pattern of dermal or subcutaneous infiltration (p = 0.03) were more often seen in cutaneous MZL. A dense lymphocytic infiltrate, bottom-heavy or top-heavy growth pattern, eosinophils, and a grenz zone were seen equally often in both disorders. Dutcher bodies were observed only in cutaneous MZL. Immunoperoxidase stains on formalin-fixed paraffin-embedded tissue sections showed monotypic expression of immunoglobulin light chains by plasma cells in 11 of 16 MZL cases. By definition, no case with monotypic plasma cells was diagnosed as CLH. In CLH, T cells usually outnumbered B cells, and a B:T cell ratio > or = 3:1 was not observed in any case. By contrast, 40% of the MZL cases showed a B:T cell ratio > or = 3:1. No coexpression of CD20 and CD43 was seen in any case of either MZL or CLH. In summary, the clinical presentations of CLH and MZL are similar. In contrast to historical criteria for diagnosing cutaneous lymphoid infiltrates, the presence of reactive follicles favors a diagnosis of cutaneous B-cell lymphoma (CBCL). In addition, a bottom-heavy or top-heavy growth pattern is not a distinctive finding. Marginal zone cells and zones or sheets of plasma cells are strong morphologic indicators of marginal zone lymphoma. The diagnosis of CBCL can be supported in 40% of the cases by demonstrating a B:T cell ratio of > or = 3:1, and confirmed in 70% of the cases by demonstrating monotypic light chain expression of plasma cells on paraffin sections.
Neuroimaging Clinics of North America, Aug 1, 2003
Lymphomas are subdivided into HL and NHL and are more specifically classified into subtypes of HL... more Lymphomas are subdivided into HL and NHL and are more specifically classified into subtypes of HL or NHL according to the WHO classification. HLs involve the lymph nodes predominantly and only approximately 5% arise in extranodal sites, whereas 30% of NHLs present in extranodal sites. Imaging studies, including CT and MR imaging, cannot distinguish [figure: see text] HL from NHL, and cannot differentiate their various subtypes, necessitating a pathologic diagnosis. Clinical parameters, however, can be helpful in differentiating the two broad categories of lymphomas, and subtypes of lymphomas have predilections for different sites within the head and neck. HL is most commonly located in the lymph nodes of the neck and mediastinum. Marginal-zone lymphoma has an affinity for the ocular adnexa, salivary glands, larynx, and the thyroid gland. Diffuse large B-cell lymphoma is commonly encountered in the paranasal sinuses, mandible, maxilla, and Waldeyer ring. Burkitt lymphoma occurs more frequently in children and young adults and frequently affects the maxilla and mandible, with a greater distribution of involvement at a lower frequency. On imaging studies, the lymph nodes of HL and NHL are homogeneous and variable in size, with an average diameter from 2 to 10 cm. They may enhance slightly to moderately, display necrosis before and after treatment, and display calcification post-treatment. NHL in extranodal sites in the head and neck (nasopharynx, Waldeyer ring, oral cavity, and larynx) manifests frequently as a submucosal mass accompanied [figure: see text] by polypoid, bulky masses with a smooth mucosal surface. Clinically aggressive lymphomas, such as Burkitt lymphoma, diffuse large B-cell lymphoma, and NK-/T-cell lymphomas are characterized by destruction of the maxilla, mandible, and bones around the paranasal sinuses, which is indistinguishable from bony destruction in other malignant tumors, such as SCC. Contrast CT is indicated for evaluation of cervical lymph nodes; the chest, including the mediastinum; the pelvic cavity; paranasal sinuses; and orbits. CT is also useful for detection of bone destruction involving the base of the skull, paranasal sinuses, and the mandible or maxilla. MR imaging is preferred for the assessment of extension of lymphomas to different fascial spaces (parapharyngeal, masticator, infratemporal fossa, tongue, and nasopharynx) and for intracranial extension. Lymphomas are isodense to muscle on CT and circumscribed with distinct margins that occasionally display extranodal extension with less-well-defined margins and areas of necrosis within the tumor matrix. Lymphomas appear low in signal intensity on T1-weighted images and low to high in signal intensity on T2-weighted images, with variable, but usually low, enhancement following introduction of Gadolinium-DTPA (Gd-DTPA) contrast material.
In the 5th edition of the World Health Organization (WHO) Classification of Head and Neck Tumours... more In the 5th edition of the World Health Organization (WHO) Classification of Head and Neck Tumours, the discussion of hematolymphoid proliferations is substantially reorganized and expanded in comparison to the prior edition. The 5th edition includes, in addition to hematolymphoid neoplasms, reactive lymphoid proliferations. Much more information on hematolymphoid proliferations that commonly affect cervical lymph nodes, in addition to those affecting extranodal sites in the head and neck, is included. For the first time, there are dedicated sections on multiple entities, including recently described lymphoproliferative disorders such as EBV+ mucocutaneous ulcer and pediatric-type follicular lymphoma, and several types of histiocytic neoplasms. Tremendous advances have been made in understanding the genetic features that underlie the pathogenesis of hematolymphoid neoplasms, and these have been incorporated into the WHO Classification.
RIMARY central nervous system lymphoma is defined as an extranodal non-Hodgkin lymphoma located i... more RIMARY central nervous system lymphoma is defined as an extranodal non-Hodgkin lymphoma located in the craniospinal axis without evidence of a systemic primary tumor. It usually presents as an intracerebral mass but may occur initially in the orbit, leptomeninges, or spinal cord. Overall, at the time of diagnosis, the leptomeninges are involved in approximately 40% of cases and the eyes in approximately 20%. 30 The spinal cord is involved in 1% of cases, and systemic metastases are found in approximately 5%. Although the incidence of PCNSL has increased dramatically in recent years, it is still a rare tumor, much less common than nodal lymphoma. 37 Primary CNS lymphoma accounts for approximately 3 to 4% of primary brain tumors. These highly aggressive lesions leave patients with a median survival time of only a few months when left untreated or when treated with surgery alone. 25 Although the use of radiation and/or chemotherapy improves survival, some treatment regimens are associated with a high incidence of neurotoxicity, especially in patients older than 60 years of age. 2 In this article the pathological features of PCNSL are described, including the gross and microscopic appearance, as well as the role of stereotactic biopsy in diagnosis and management. Both the common (or "typical") and the uncommon forms of PCNSL will be discussed. The latter include low-grade and T-cell tumors, lymphomatosis cerebri, and dura-based lymphomas. Selected molecular studies addressing issues such as the derivation of PCNSL will be included. Epstein-Barr virus-related PCNSLs arising in the setting of immunodeficiency will be discussed separately because they differ in some respects from PCNSL seen in immunocompetent individuals. As a result, many recent studies are restricted to either immunocompetent or immunocompromised populations. Overview of Classification of PCNSLs Histologically, PCNSLs resemble systemic lymphomas, although a greater proportion of PCNSLs are highgrade and more than 95% are B-cell lymphomas. 30 The intraparenchymal cases, which represent the large majority of PCNSLs, are nearly always diffuse in architecture. Beyond these very general statements, any discussion of the classification of PCNSLs becomes complicated by a number of factors. At least three different classification systems (the Kiel, the Working Formulation, and the REAL) have been applied to PCNSL. Nevertheless, none of these classification systems, which were developed on the basis of studies of the nodal lymphomas, deals specifically with PCNSL. According to the Kiel classification, common subtypes include immunoblastic, centroblastic, lymphoblastic, and low-grade lymphomas. Many PCNSLs are unclassifiable by this system, however, and there is large variation from study to study in the relative frequencies of the various subtypes. 29 Application of the Working Formulation to
Immunohistochemistry is a powerful tool for the diagnosis and subclassification of hematolymphoid... more Immunohistochemistry is a powerful tool for the diagnosis and subclassification of hematolymphoid neoplasms. However, the expression of certain markers is not always as expected, and unusual patterns of staining can lead to misdiagnosis. CD20 and CD3 are our most commonly used markers for identification of B cells and T cells, respectively, and they almost always yield reliable, specific staining. This discussion focuses on diagnostic pitfalls related to the use of immunohistochemistry for CD20 and CD3 in hematopathology, and specifically on diagnostic challenges that arise when (1) CD20 is not expressed in B-cell lymphomas, when (2) CD20 is expressed in plasma cell neoplasms and T-cell lymphomas, and when (3) CD3 is expressed in B-cell lymphomas and Hodgkin lymphoma.
From the viewpoint of the pathologist, there are three major issues concerning Hodgkin's disease ... more From the viewpoint of the pathologist, there are three major issues concerning Hodgkin's disease (HD) that must be addressed. First is making the correct diagnosis; second is identifying any pathological features that may be of prognostic importance; and third is defining the identity of the neoplastic cell. Since Hodgkin's disease (HD) was first described, the origin of the Reed-Sternberg cell and the pathogenesis of HD have remained elusive. Recently developed techniques have allowed investigators to analyze the immunophenotype and genotype of Reed-Sternberg cells. The results of these studies include recognition that, in many cases, Reed-Sternberg cells are of lymphoid origin. Thus, although in most cases of HD the diagnosis is straightforward on routinely stained sections, the conceptual dividing line between HD and non-Hodgkin's lymphoma is not as sharp as it once seemed. Occasionally, there is difficulty in distinguishing between HD and non-Hodgkin's lymphoma. Nevertheless, fundamental differences in the clinical features, histology, immunophenotype, and genotype between non-Hodgkin's lymphoma and HD remain. The impact of histological features on prognosis are controversial, largely because of the excellent prognosis of most cases of HD.
A few uncommon but distinctive tumors may preferentially involve the paratestis. The 3 unusual tu... more A few uncommon but distinctive tumors may preferentially involve the paratestis. The 3 unusual tumors that represent the focus of this discussion are the ovarian-type epithelial tumors (OTET), the desmoplastic small round cell tumor (DSRCT), and the melanotic neuroectodermal tumor of infancy (MNTI). The OTETs are testicular homologues of their more common namesake counterparts that arise in the ovary. Most frequent of these are serous tumors of borderline malignancy, with fewer cases of serous carcinomas or other forms of mullerian differentiation. DSRCT is an increasingly recognized, aggressive, "small blue cell" neoplasm with distinctive clinical and pathologic features. These polyphenotypic tumors characteristically, but not invariably, arise in intimate association with the serosal membrane of the peritoneal cavity and harbor a signature translocation-t(11;22)(p13,q12). In the paratestis they often involve the surface of the epididymis. The MNTI is an enigmatic, histologically distinctive, low-grade neoplasm occasionally encountered in the epididymis. Recognition of its features is essential to avoid misdiagnosis as a more aggressive "small blue cell" neoplasm and consequent therapeutic mismanagement. Primary hematopoietic tumors of the paratesticular structures are rare. There appears to be a tendency for young men to have low-grade lymphomas with an indolent course and older patients to develop higher-grade tumors. Plasmacytoma and granulocytic sarcoma of the paratestis are even more rare and are often susceptible to misinterpretation. Finally, metastatic tumors and a variety of other very rare neoplasms are discussed.
Archives of Pathology & Laboratory Medicine, Sep 1, 2004
We report the case of a 73-year-old man who presented with a 2-to 3-month history of epigastric d... more We report the case of a 73-year-old man who presented with a 2-to 3-month history of epigastric discomfort and guaiac-positive stool. An upper gastrointestinal endoscopy revealed a diffuse erythematous nodular mucosa and submucosal thickening in the stomach. Diffuse mucosal nodularity was also found in the second portion of the duodenum. A complete workup with histologic, immunohistochemical, and molecular studies revealed 2 distinct, apparently unrelated lymphomas, namely, a gastric marginal zone B-cell lymphoma (mucosa-associated lymphoid tissue type) in a background of Helicobacter pylori gastritis and a grade 1/3 duodenal follicular lymphoma. The patient was then treated with an H pylori eradication regimen. No therapy was given for his duodenal follicular lymphoma because his symptoms were thought to be due to the gastric disease and because the duodenal lesion was small. A 6-month follow-up with upper gastrointestinal endoscopy revealed only focal biopsy scarring in the stomach and an apparently normal duodenum. The follow-up biopsies revealed significant regression of his mucosa-associated lymphoid tissue lymphoma, but persistence of his duodenal follicular lymphoma. The combination of these 2 lymphomas in the same patient and the different clinical responses to antibiotic treatment make this case unique.
The authors report a localized (primary) conjunctival marginal zone B-cell lymphoma (mucosa-assoc... more The authors report a localized (primary) conjunctival marginal zone B-cell lymphoma (mucosa-associated lymphoid tissue (MALT)-type), with amyloid deposition with relapse in the stomach, 14 months after the initial diagnosis. Ocular adnexal marginal zone B-cell MALT lymphoma is often localized at diagnosis; some relapse in typical MALT sites. There are few reports of localized conjunctival lymphoma with a relapse in the stomach. The authors suggest that all patients with localized ocular adnexal lymphoma be followed for an extended period.
Archives of Pathology & Laboratory Medicine, Apr 1, 2008
Lymphomas arising in extranodal sites are intriguing. The types of lymphomas encountered vary wid... more Lymphomas arising in extranodal sites are intriguing. The types of lymphomas encountered vary widely from one extranodal site to another. For many types of extranodal lymphomas, there are distinctive clinicopathologic features, sometimes including association with an underlying immunodeficiency syndrome, autoimmune disease, infection, or other immunologic disorder, or a predilection to affect patients of certain ethnic origins. Presented below is a review of lymphomas that are encountered most often in extranodal sites.
The American Journal of Surgical Pathology, Jul 1, 2007
Primary testicular lymphomas typically occur in patients over 60 years of age. Most are diffuse l... more Primary testicular lymphomas typically occur in patients over 60 years of age. Most are diffuse large B-cell lymphomas with frequent dissemination and a poor prognosis. Primary follicular lymphoma of the adult testis has not been well characterized. However, a small number of primary testicular follicular lymphomas have recently been described in children. These showed stage 1E disease, a lack of BCL2 gene rearrangement and Bcl-2 protein expression, and a good clinical outcome. Here, we describe 5 cases of primary follicular lymphoma of the testis and epididymis in adults. These presented as unilateral testicular masses 12 to 40 mm in diameter and were characterized histologically by small neoplastic follicles in a sclerotic background. The neoplastic cells expressed CD10 and Bcl-6, but not Bcl-2 and lacked t(14;18)(q32;q21)/ IGH-BCL2 and BCL6 gene rearrangements. Four of the five patients were 35 years old or younger, and 4 presented with stage 1EA disease. Although follow-up is 12 months or less in 2 of the 5 patients, to date each has followed an indolent clinical course. These features are different from those of most adult nodal follicular lymphomas but are very similar to those of the pediatric primary testicular follicular lymphomas. Together, the pediatric and adult cases represent a discrete clinicopathologic entity of t(14;18)(q32;q21)/IGH-BCL2-negative primary follicular lymphoma of the testis and epididymis, which typically present as clinically indolent localized disease in young males and should be distinguished from the diffuse large B-cell lymphoma more frequently seen in the testes of older adults.
IgG4 is the least common of all the IgG subclasses. In recent years an uncommon systemic disease ... more IgG4 is the least common of all the IgG subclasses. In recent years an uncommon systemic disease characterized by variable manifestations that may include the presence of tumour-like sclerosing lesions in a variety of extranodal sites, lymphadenopathy, presence of increased numbers of IgG4þ plasma cells in affected tissues, elevated serum IgG4 level, frequent presence of autoantibodies and often, a good response to steroid therapy or Rituximab has been described. The disorder has been called IgG4-related sclerosing disease, IgG4-related systemic disease and IgG4-related autoimmune disease; currently the preferred designation is IgG4-related disease (IgG4-RD). In addition to other changes that may be found in association with IgG4-RD, some investigators have suggested that IgG4-RD may serve as a substrate for the development of lymphoma. This review focuses on lymphadenopathy associated with IgG4-RD and also explores the significance of isolated lymphadenopathy with increased numbers of IgG4þ plasma cells. Emerging data on lymphomas arising in association with IgG4-RD and the possibility of an increased risk of lymphoma in patients with IgG4-RD are also discussed.
The American Journal of Surgical Pathology, Nov 1, 2008
Rare cases of CD20+ T-cell lymphoma (TCL) have been reported, but the clinicopathologic spectrum ... more Rare cases of CD20+ T-cell lymphoma (TCL) have been reported, but the clinicopathologic spectrum of this disorder is not known. We identified 9 cases of CD20+ TCL diagnosed at our institution and 26 additional cases through a search of the English language literature. Among current cases, there were 7 men (ages 71 to 81, median 75 y) and 2 women (ages 36 and 37 y). Five patients presented with predominantly nodal disease (localized in 3 and widespread in 2 cases) and 4 patients presented with purely extranodal disease involving the parotid glands, skin, or small intestine. CD20 was uniformly and strongly expressed in 5 cases and dimly expressed or present on a subset of neoplastic cells in 4 cases. The proportion of CD20+ T cells changed over time in 3 cases. Three cases fulfilled diagnostic criteria for clinicopathologically defined subtypes of TCL (2 mycosis fungoides; 1 enteropathy-type TCL), whereas 6 were peripheral TCL unspecified with variable cytomorphology, T-cell immunophenotype, and sites of involvement. In 8 of 9 cases, a clonal T-cell population was identified by molecular genetic analysis. Among 8 cases with clinical follow-up, 5 behaved aggressively with death from disease within 3 years of diagnosis in 4 cases (median survival: 11 mo, range: 1 to 35 mo), and recurrent disease at 10 months in 1 case; 1 patient died of an EBV+ B-cell lymphoma (BCL) 66 months after the original diagnosis; in the remaining 2 cases, patients were alive and undergoing treatment (follow-up: 4 and 18 mo). Historical cases showed similar clinicopathologic variability. CD20+ TCL is rare, and clinically and pathologically heterogeneous. When CD20 expression is present in TCL, it may be dimmer than that of normal B cells, suggesting neoplastic transformation of a normal CD20dim+ T-cell subset. Cases of CD20+ TCL in which the proportion of CD20+ cells changes over time may reflect aberrant expression of CD20, possibly as an activation marker, by neoplastic T cells. CD20+ TCL may cause diagnostic difficulty, particularly in cases that clinically and pathologically mimic BCL. Knowledge of the unusual phenomenon of CD20 expression in TCL, in conjunction with careful morphologic analysis, the use of a panel of antibodies, and molecular genetic studies, is important in avoiding a misdiagnosis of BCL.
The American Journal of Surgical Pathology, Jun 1, 2001
Cutaneous follicular lymphomas (FLs) and cutaneous B-cell lymphomas of extranodal marginal zone (... more Cutaneous follicular lymphomas (FLs) and cutaneous B-cell lymphomas of extranodal marginal zone (MZL)/mucosal-associated lymphoid tissue (MALT) type may have morphologic overlap, despite the fact that they are thought to be of distinct derivation (germinal center vs. postgerminal center). The problem is compounded by the reported absence of bcl-2 expression by many cutaneous FLs, leading to speculation that cutaneous FL may be unrelated to nodal FL. The authors analyzed the expression of the germinal center-associated antigens bcl-6 and CD10 and of bcl-2 in 18 cutaneous B-cell lymphomas (10 FLs and eight MZLs), in relationship to CD21+ follicular structures, to clarify the relationship of nodal to cutaneous FLs and to explore the value of these antigens in differential diagnosis. The authors studied 10 cutaneous FLs (seven primary and three secondary) and eight MZLs (six primary and two secondary). The FLs (found in six men and four women age 45-75 years) involved the trunk (n = 3) and scalp, face and neck (n = 7). The MZLs (found in five women and three men age 34-81 years) involved the trunk (n = 4), face and neck (n = 2), and arm (n = 2). Immunostaining for CD21, bcl-6, CD10, and bcl-2 allowed the delineation of compartments within the tumors and yielded distinct patterns of staining in FL and MZL. In both follicular and interfollicular/diffuse areas of FL the neoplastic cells were bcl-6+ (10 of 10), often CD10+ (seven of 10, four of seven primary), and bcl-2+ (nine of 10, six of seven primary). Only three of seven cases (one of five primary) had bcl-2 rearrangement detectable by polymerase chain reaction. In the MZLs, the neoplastic B-cells were bcl-6-, CD10-, and bcl-2+ (eight of eight). Three patterns of CD21+ follicles were identified in MZL: reactive germinal centers, uniformly bcl-6+, CD10+, and bcl-2- (five of eight MZLs); colonized follicles, both bcl-6-, bcl-2+, and L26+ cells, and bcl-6+ and bcl-2- cells (five of eight MZLs); and expanded/colonized follicular dendritic cell meshworks, bcl-6- and bcl-2+ B cells with rare residual bcl-6+ and bcl-2- cells (four of eight MZLs). The authors conclude that cutaneous FLs express bcl-6 uniformly, usually express CD10 and bcl-2, and have a follicular pattern similar to nodal FL and consistent with a germinal center origin. The immunophenotype of cutaneous FL is distinct from that of cutaneous MZL, which is negative for bcl-6 and CD10. Colonized follicles in MZL, identified by CD21+ follicular dendritic cell meshworks, contained numerous bcl-6- and bcl-2+ B cells, and were readily distinguished from neoplastic follicles in FL. Conversely, CD21- interfollicular and diffuse areas in FLs contained bcl-6+ and CD10+ cells, which were not seen in diffuse areas of MZLs. Thus, the combination of bcl-2, bcl-6, and CD21 staining is useful for the distinction of cutaneous MZL from cutaneous FL.
Extranodal lymphomas are a diverse group of low and high grade neoplasms of B-, T-, and NK-cell l... more Extranodal lymphomas are a diverse group of low and high grade neoplasms of B-, T-, and NK-cell lineage, each with characteristic sites of origin, morphology, immunophenotype, genetic features, patterns of spread, and prognosis. The diversity is sometimes seen even within a single histologic type of lymphoma. This phenomenon is especially striking in the category of diffuse large B-cell lymphoma (DLBCL). DLBCLs as classified in the WHO Classification are clinically and pathologically heterogeneous (Swerdlow et al. 2008; Stein et al. 2008). Since the publication of the most recent edition of the WHO Classification of tumours of haematopoietic and lymphoid tissues (Swerdlow et al. 2008), a number of advances in the understanding of these lymphomas have been made. This review provides an overview of extranodal DLBCLs and describes recent updates regarding these lymphomas.
Cutaneous marginal zone lymphoma (MZL) is a recently described low-grade B-cell lymphoma that usu... more Cutaneous marginal zone lymphoma (MZL) is a recently described low-grade B-cell lymphoma that usually follows an indolent course. This tumor shares many histologic and clinical features with cutaneous lymphoid hyperplasia (CLH), a benign reactive lymphoid proliferation. Sixteen biopsy specimens from 14 patients with CLH were studied, and compared with 16 cases of cutaneous MZL (9 primary cutaneous, 7 with secondary involvement of the skin) to determine whether there were features that would permit their distinction on routinely fixed, paraffin-embedded tissue sections. Both disorders showed a female preponderance (CLH: 9 F, 5 M; MZL: 11 F, 5 M). The median age was also similar (CLH: 54 years; cutaneous MZL: 55 years). CLH was most common on the arm (8) and the head and neck (7) but also involved the trunk (1); primary cutaneous MZL most often involved the limbs (3), trunk (3), and head and neck (3). Lymphoma did not develop in any of the 14 CLH patients (follow-up ranging from 9 to 246 months, mean 62 months). Six of 9 patients with primary cutaneous MZL and all 7 patients with secondary cutaneous MZL experienced relapses, most commonly isolated to skin or a subcutaneous site. On hematoxylin-eosin stained sections, a diffuse proliferation of marginal zone cells (p < 0.0001), zones of plasma cells (p = 0.01), the absence of epidermal change (p = 0.01), reactive germinal centers (p = 0.03), and a diffuse pattern of dermal or subcutaneous infiltration (p = 0.03) were more often seen in cutaneous MZL. A dense lymphocytic infiltrate, bottom-heavy or top-heavy growth pattern, eosinophils, and a grenz zone were seen equally often in both disorders. Dutcher bodies were observed only in cutaneous MZL. Immunoperoxidase stains on formalin-fixed paraffin-embedded tissue sections showed monotypic expression of immunoglobulin light chains by plasma cells in 11 of 16 MZL cases. By definition, no case with monotypic plasma cells was diagnosed as CLH. In CLH, T cells usually outnumbered B cells, and a B:T cell ratio > or = 3:1 was not observed in any case. By contrast, 40% of the MZL cases showed a B:T cell ratio > or = 3:1. No coexpression of CD20 and CD43 was seen in any case of either MZL or CLH. In summary, the clinical presentations of CLH and MZL are similar. In contrast to historical criteria for diagnosing cutaneous lymphoid infiltrates, the presence of reactive follicles favors a diagnosis of cutaneous B-cell lymphoma (CBCL). In addition, a bottom-heavy or top-heavy growth pattern is not a distinctive finding. Marginal zone cells and zones or sheets of plasma cells are strong morphologic indicators of marginal zone lymphoma. The diagnosis of CBCL can be supported in 40% of the cases by demonstrating a B:T cell ratio of > or = 3:1, and confirmed in 70% of the cases by demonstrating monotypic light chain expression of plasma cells on paraffin sections.
Neuroimaging Clinics of North America, Aug 1, 2003
Lymphomas are subdivided into HL and NHL and are more specifically classified into subtypes of HL... more Lymphomas are subdivided into HL and NHL and are more specifically classified into subtypes of HL or NHL according to the WHO classification. HLs involve the lymph nodes predominantly and only approximately 5% arise in extranodal sites, whereas 30% of NHLs present in extranodal sites. Imaging studies, including CT and MR imaging, cannot distinguish [figure: see text] HL from NHL, and cannot differentiate their various subtypes, necessitating a pathologic diagnosis. Clinical parameters, however, can be helpful in differentiating the two broad categories of lymphomas, and subtypes of lymphomas have predilections for different sites within the head and neck. HL is most commonly located in the lymph nodes of the neck and mediastinum. Marginal-zone lymphoma has an affinity for the ocular adnexa, salivary glands, larynx, and the thyroid gland. Diffuse large B-cell lymphoma is commonly encountered in the paranasal sinuses, mandible, maxilla, and Waldeyer ring. Burkitt lymphoma occurs more frequently in children and young adults and frequently affects the maxilla and mandible, with a greater distribution of involvement at a lower frequency. On imaging studies, the lymph nodes of HL and NHL are homogeneous and variable in size, with an average diameter from 2 to 10 cm. They may enhance slightly to moderately, display necrosis before and after treatment, and display calcification post-treatment. NHL in extranodal sites in the head and neck (nasopharynx, Waldeyer ring, oral cavity, and larynx) manifests frequently as a submucosal mass accompanied [figure: see text] by polypoid, bulky masses with a smooth mucosal surface. Clinically aggressive lymphomas, such as Burkitt lymphoma, diffuse large B-cell lymphoma, and NK-/T-cell lymphomas are characterized by destruction of the maxilla, mandible, and bones around the paranasal sinuses, which is indistinguishable from bony destruction in other malignant tumors, such as SCC. Contrast CT is indicated for evaluation of cervical lymph nodes; the chest, including the mediastinum; the pelvic cavity; paranasal sinuses; and orbits. CT is also useful for detection of bone destruction involving the base of the skull, paranasal sinuses, and the mandible or maxilla. MR imaging is preferred for the assessment of extension of lymphomas to different fascial spaces (parapharyngeal, masticator, infratemporal fossa, tongue, and nasopharynx) and for intracranial extension. Lymphomas are isodense to muscle on CT and circumscribed with distinct margins that occasionally display extranodal extension with less-well-defined margins and areas of necrosis within the tumor matrix. Lymphomas appear low in signal intensity on T1-weighted images and low to high in signal intensity on T2-weighted images, with variable, but usually low, enhancement following introduction of Gadolinium-DTPA (Gd-DTPA) contrast material.
In the 5th edition of the World Health Organization (WHO) Classification of Head and Neck Tumours... more In the 5th edition of the World Health Organization (WHO) Classification of Head and Neck Tumours, the discussion of hematolymphoid proliferations is substantially reorganized and expanded in comparison to the prior edition. The 5th edition includes, in addition to hematolymphoid neoplasms, reactive lymphoid proliferations. Much more information on hematolymphoid proliferations that commonly affect cervical lymph nodes, in addition to those affecting extranodal sites in the head and neck, is included. For the first time, there are dedicated sections on multiple entities, including recently described lymphoproliferative disorders such as EBV+ mucocutaneous ulcer and pediatric-type follicular lymphoma, and several types of histiocytic neoplasms. Tremendous advances have been made in understanding the genetic features that underlie the pathogenesis of hematolymphoid neoplasms, and these have been incorporated into the WHO Classification.
RIMARY central nervous system lymphoma is defined as an extranodal non-Hodgkin lymphoma located i... more RIMARY central nervous system lymphoma is defined as an extranodal non-Hodgkin lymphoma located in the craniospinal axis without evidence of a systemic primary tumor. It usually presents as an intracerebral mass but may occur initially in the orbit, leptomeninges, or spinal cord. Overall, at the time of diagnosis, the leptomeninges are involved in approximately 40% of cases and the eyes in approximately 20%. 30 The spinal cord is involved in 1% of cases, and systemic metastases are found in approximately 5%. Although the incidence of PCNSL has increased dramatically in recent years, it is still a rare tumor, much less common than nodal lymphoma. 37 Primary CNS lymphoma accounts for approximately 3 to 4% of primary brain tumors. These highly aggressive lesions leave patients with a median survival time of only a few months when left untreated or when treated with surgery alone. 25 Although the use of radiation and/or chemotherapy improves survival, some treatment regimens are associated with a high incidence of neurotoxicity, especially in patients older than 60 years of age. 2 In this article the pathological features of PCNSL are described, including the gross and microscopic appearance, as well as the role of stereotactic biopsy in diagnosis and management. Both the common (or "typical") and the uncommon forms of PCNSL will be discussed. The latter include low-grade and T-cell tumors, lymphomatosis cerebri, and dura-based lymphomas. Selected molecular studies addressing issues such as the derivation of PCNSL will be included. Epstein-Barr virus-related PCNSLs arising in the setting of immunodeficiency will be discussed separately because they differ in some respects from PCNSL seen in immunocompetent individuals. As a result, many recent studies are restricted to either immunocompetent or immunocompromised populations. Overview of Classification of PCNSLs Histologically, PCNSLs resemble systemic lymphomas, although a greater proportion of PCNSLs are highgrade and more than 95% are B-cell lymphomas. 30 The intraparenchymal cases, which represent the large majority of PCNSLs, are nearly always diffuse in architecture. Beyond these very general statements, any discussion of the classification of PCNSLs becomes complicated by a number of factors. At least three different classification systems (the Kiel, the Working Formulation, and the REAL) have been applied to PCNSL. Nevertheless, none of these classification systems, which were developed on the basis of studies of the nodal lymphomas, deals specifically with PCNSL. According to the Kiel classification, common subtypes include immunoblastic, centroblastic, lymphoblastic, and low-grade lymphomas. Many PCNSLs are unclassifiable by this system, however, and there is large variation from study to study in the relative frequencies of the various subtypes. 29 Application of the Working Formulation to
Immunohistochemistry is a powerful tool for the diagnosis and subclassification of hematolymphoid... more Immunohistochemistry is a powerful tool for the diagnosis and subclassification of hematolymphoid neoplasms. However, the expression of certain markers is not always as expected, and unusual patterns of staining can lead to misdiagnosis. CD20 and CD3 are our most commonly used markers for identification of B cells and T cells, respectively, and they almost always yield reliable, specific staining. This discussion focuses on diagnostic pitfalls related to the use of immunohistochemistry for CD20 and CD3 in hematopathology, and specifically on diagnostic challenges that arise when (1) CD20 is not expressed in B-cell lymphomas, when (2) CD20 is expressed in plasma cell neoplasms and T-cell lymphomas, and when (3) CD3 is expressed in B-cell lymphomas and Hodgkin lymphoma.
From the viewpoint of the pathologist, there are three major issues concerning Hodgkin's disease ... more From the viewpoint of the pathologist, there are three major issues concerning Hodgkin's disease (HD) that must be addressed. First is making the correct diagnosis; second is identifying any pathological features that may be of prognostic importance; and third is defining the identity of the neoplastic cell. Since Hodgkin's disease (HD) was first described, the origin of the Reed-Sternberg cell and the pathogenesis of HD have remained elusive. Recently developed techniques have allowed investigators to analyze the immunophenotype and genotype of Reed-Sternberg cells. The results of these studies include recognition that, in many cases, Reed-Sternberg cells are of lymphoid origin. Thus, although in most cases of HD the diagnosis is straightforward on routinely stained sections, the conceptual dividing line between HD and non-Hodgkin's lymphoma is not as sharp as it once seemed. Occasionally, there is difficulty in distinguishing between HD and non-Hodgkin's lymphoma. Nevertheless, fundamental differences in the clinical features, histology, immunophenotype, and genotype between non-Hodgkin's lymphoma and HD remain. The impact of histological features on prognosis are controversial, largely because of the excellent prognosis of most cases of HD.
A few uncommon but distinctive tumors may preferentially involve the paratestis. The 3 unusual tu... more A few uncommon but distinctive tumors may preferentially involve the paratestis. The 3 unusual tumors that represent the focus of this discussion are the ovarian-type epithelial tumors (OTET), the desmoplastic small round cell tumor (DSRCT), and the melanotic neuroectodermal tumor of infancy (MNTI). The OTETs are testicular homologues of their more common namesake counterparts that arise in the ovary. Most frequent of these are serous tumors of borderline malignancy, with fewer cases of serous carcinomas or other forms of mullerian differentiation. DSRCT is an increasingly recognized, aggressive, "small blue cell" neoplasm with distinctive clinical and pathologic features. These polyphenotypic tumors characteristically, but not invariably, arise in intimate association with the serosal membrane of the peritoneal cavity and harbor a signature translocation-t(11;22)(p13,q12). In the paratestis they often involve the surface of the epididymis. The MNTI is an enigmatic, histologically distinctive, low-grade neoplasm occasionally encountered in the epididymis. Recognition of its features is essential to avoid misdiagnosis as a more aggressive "small blue cell" neoplasm and consequent therapeutic mismanagement. Primary hematopoietic tumors of the paratesticular structures are rare. There appears to be a tendency for young men to have low-grade lymphomas with an indolent course and older patients to develop higher-grade tumors. Plasmacytoma and granulocytic sarcoma of the paratestis are even more rare and are often susceptible to misinterpretation. Finally, metastatic tumors and a variety of other very rare neoplasms are discussed.
Archives of Pathology & Laboratory Medicine, Sep 1, 2004
We report the case of a 73-year-old man who presented with a 2-to 3-month history of epigastric d... more We report the case of a 73-year-old man who presented with a 2-to 3-month history of epigastric discomfort and guaiac-positive stool. An upper gastrointestinal endoscopy revealed a diffuse erythematous nodular mucosa and submucosal thickening in the stomach. Diffuse mucosal nodularity was also found in the second portion of the duodenum. A complete workup with histologic, immunohistochemical, and molecular studies revealed 2 distinct, apparently unrelated lymphomas, namely, a gastric marginal zone B-cell lymphoma (mucosa-associated lymphoid tissue type) in a background of Helicobacter pylori gastritis and a grade 1/3 duodenal follicular lymphoma. The patient was then treated with an H pylori eradication regimen. No therapy was given for his duodenal follicular lymphoma because his symptoms were thought to be due to the gastric disease and because the duodenal lesion was small. A 6-month follow-up with upper gastrointestinal endoscopy revealed only focal biopsy scarring in the stomach and an apparently normal duodenum. The follow-up biopsies revealed significant regression of his mucosa-associated lymphoid tissue lymphoma, but persistence of his duodenal follicular lymphoma. The combination of these 2 lymphomas in the same patient and the different clinical responses to antibiotic treatment make this case unique.
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Papers by Judith Ferry