CD5 expression in B-cell small lymphocytic malignancies. Correlations with clinical presentation and sites of disease.

The authors examined the relationship between CD5 antigen expression and a nodal or extranodal presentation for three subtypes of low-grade non-Hodgkin's lymphoma: small lymphocytic (23 cases), small lymphocytic with plasmacytoid differentiation (10 cases), and lymphocytic lymphoma of intermediate differentiation (IDL) (29 cases). Antigen expression was studied by the avidin-biotin complex immunoperoxidase technique in frozen sections and correlated with expression of other B- and T-cell markers. Lack of CD5 expression was significantly associated with extranodal presentation among the over-all study group (p less than 0.001), as well as for those with small lymphocytic lymphoma and IDL, but not for those presenting with small lymphocytic lymphomas with plasmacytoid differentiation (p less than 0.21). Eleven patients presented exclusively with extranodal disease involving lung and respiratory tract, skin and subcutaneous tissue, salivary gland, stomach, conjunctiva, and uterus. All such lesions were CD5 negative and had been classified as small lymphocytic (four cases), small lymphocytic-plasmacytoid (four cases), and IDL (three cases). Retrospective review of these 11 cases demonstrated common histologic features described as characteristic of lymphomas of mucosa-associated lymphoid tissue (MALT). Two additional patients presented with disseminated nodal disease and involvement of gastrointestinal tract and oropharynx; both were CD5 positive. These findings support the concept that at least two antigenically distinct B-cell subpopulations may be involved in pathogenesis of low-grade small lymphocytic malignancies.     

Precursor B-cell lymphoblastic lymphoma: a predominantly extranodal tumor with low propensity for leukemic involvement

Precursor B-cell lymphoblastic lymphoma (B-LBL) is uncommon and accounts for less than 10% of cases of lymphoblastic lymphoma. We collected 25 cases of B-LBL, occurring in children and adults, and report the clinical and histologic features. Patients with concurrent precursor B-cell acute lymphoblastic leukemia (B-ALL) or a history thereof were excluded. There was no evidence of bone marrow disease at the time of diagnosis in 23 patients; two patients had focal (<5%) involvement. Immunophenotypic analysis was performed in all cases using flow cytometry or immunohistochemical methods. The treatment and survival data available for a subset of patients with B-LBL were compared with those from a series of patients with B-ALL at our institution. The median age was 20 years (range, 5-68 yrs); 22 (88%) patients were younger than 35 years of age. There were 17 males and 8 females. The primary sites of disease were skin (nine cases), bones (five cases), soft tissue (four cases), lymph nodes, (three cases), breast (two cases), stomach and colon (one case), and mediastinum (one case). Clinical stage was stage I in 13 cases, stage II in seven cases, stage III in three cases, and stage IV in two cases. Histologically, each neoplasm was diffuse and composed of small to medium-sized lymphoid cells with blastic nuclear chromatin and a high mitotic rate. All cases were positive for B-cell antigens and terminal deoxynucleotidyl transferase. Thirteen (76.4%) of 17 cases analyzed were positive for CD10 and 13 (54.1%) of 24 cases assessed were positive for CD20. Of 14 patients with available survival data, all achieved complete clinical response after combination chemotherapy (13 patients) or surgical excision followed by local irradiation (one patient). Five (35.7%) patients subsequently relapsed, including the patient who had received only irradiation, and four of these patients died after a median survival time of 60 months. None of the patients had leukemia, although one patient developed extensive bone marrow involvement. Nine patients remained in complete remission and were alive at the last follow up (range, 6-144 months). Unlike precursor T-cell lymphoblastic lymphoma, which commonly involves lymph nodes and the mediastinum, B-LBL usually involves extranodal sites, most often the skin, and rarely presents as a mediastinal mass. With aggressive chemotherapy, patients with precursor B-LBL rarely develop leukemia and appear to have a better prognosis than do patients with B-ALL.     

Primary mediastinal lymphoma; a clinicopathologic case series

Treatment for primary mediastinal lymphoma generally involves chemotherapy and radiotherapy, and treatment regimens depend on histologic subtypes of lymphoma. The histologic subtype of lymphoma is mostly determined by computed tomography (CT)-guided core-needle biopsy or surgical procedures, including thoracotomy, thoracoscopy and mediastinoscopy. We describe the clinicopathologic features and diagnostic procedures of 8 cases of primary mediastinal lymphoma. The male-to-female ratio was 1:1, and median age at diagnosis was 27 years. The median size of the primary mediastinal tumor on CT was 8.5 cm. Five patients were diagnosed by CT-guided core-needle biopsy, 1 by open biopsy and 2 by surgery. Three patients were diagnosed with nodular sclerosis Hodgkin lymphoma, 3 with mediastinal diffuse large B-cell lymphoma, 1 with precursor T-lymphoblastic leukemia/lymphoma and 1 with thymic extranodal marginal zone B-cell lymphoma. According to their histological subtypes, 5 patients were treated with chemoradiotherapy, 2 patients with chemotherapy and 1 patient of thymic extranodal marginal zone B-cell lymphoma with surgery alone. All patients survived in the median follow-up of 34.5 months. Appropriate biopsy procedure should be performed in patients with suspected mediastinal lymphoma.     

Primary follicular lymphoma of the gastrointestinal tract: a clinical and pathologic study of 26 cases.

Although the gastrointestinal tract represents the most common site of extranodal lymphoma, primary follicular lymphoma of the gastrointestinal tract is an uncommon and poorly defined disease. We report the clinical and pathologic features of 26 patients with primary gastrointestinal follicular lymphoma. Ten of 26 patients (38.5%) were stage IIE, and 16 patients (61.5%) were stage IE. Of the 26 patients, 13 were female and 13 were male. The age range was 26-81 years (median 54.5 years). Abdominal pain was the most common presenting symptom, seen in 12 of 24 patients (50%). Nodularity of the mucosal surface was the most common endoscopic finding, seen in 10 of 14 patients (71.4%). The majority of cases (22 of 26, 84.6%) involved small bowel, four involved colorectum alone, and two involved the ileocecal valve. Within the small bowel the duodenum was the most commonly involved site (10 cases). Transmural involvement by follicular lymphoma was identified in 11 of the 16 patients who underwent surgical resection; five showed involvement of mucosa and submucosa only. The most common histologic grade was grade 1. Thirteen of 26 cases were grade 1, ten grade 2, and three grade 3. Twenty-one of 26 cases showed a predominantly follicular growth pattern, four mixed follicular and diffuse, and one predominantly diffuse. All cases were positive for CD20 and BCL2 and negative for CD3, CD5, CD23, CD43, and cyclin D1. Twenty-four of 26 were positive for CD10. Four of four cases showed cytogenetic or molecular genetic evidence of t(14;18). Initial treatment modalities included surgery plus chemotherapy (nine cases), surgery alone (seven cases), chemotherapy alone (four cases), observation alone (four cases), and chemotherapy and abdominal radiation (one case). One case presented with rectal polyps and was treated with polypectomy. A complete response was observed in 15 of 22 cases that received treatment, and of the 15 cases, five recurred 27-60 months after the initial diagnosis. Recurrence and progression were associated with histologic transformation to diffuse large cell lymphoma in one case. No significant correlation was identified between treatment response and various clinical and pathologic features. Overall, none of the 26 patients died of lymphoma. One patient died of a concomitant pancreatic carcinoma. Of the remaining 25 patients, 14 were disease free and 11 were alive with disease at a mean follow-up of 43 months. The estimated 5-year disease-free survival was 62%, and median disease-free survival was 69 months. The estimated 5-year relapse-free survival was 54%, and the median relapse-free survival was 63 months.     

CD10 expression in extranodal dissemination of angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is a systemic disease that often has evidence of extranodal involvement at presentation. In a recent study of lymph nodes in AITL, we showed that the neoplastic T cells in most cases can be identified by aberrant expression of CD10. The aim of this study was to investigate whether CD10 expression by the neoplastic T cells is maintained in extranodal sites. Ten cases of AITL with histologic and immunophenotypic evidence of extranodal dissemination were studied. Seven cases of peripheral T-cell lymphoma unspecified (PTLu), that included biopsies of involved extranodal sites, two cases of enteropathy type T-cell lymphoma (ETTL), and one case of extranodal NK/T lymphoma, nasal type were selected as controls. Diagnostic lymph node biopsies and biopsies of extranodal sites were reviewed. PCR for T-cell clonality and single layer immunostaining for CD3, CD20, CD10, and CD21 and double layer immunostaining for CD20/CD10 were performed. All 10 cases of AITL had characteristic histologic features and molecular evidence of the disease in lymph node biopsies. In these cases, aberrant CD10 expression was maintained in the lung, cecum, tonsil, nasopharynx, and one of six involved bone marrow trephines. In these extranodal biopsies, the distribution of CD10-positive tumor cells correlated with that of the follicular dendritic cell meshwork (FDC). The five bone marrow trephines that lacked aberrant CD10 expression were devoid of morphologic and immunohistochemical evidence of FDC. In these five cases, there was evidence of aberrant CD10 expression in other involved sites that had FDC. The neoplastic cells in PTLu, ETTL, and extranodal NK/T lymphoma, nasal type were CD10 negative. Our data show that aberrant CD10 expression is a useful phenotypic marker for diagnosis of AITL in most involved extranodal sites, except bone marrow, and suggest a possible role of FDC in the pathogenesis of AITL.     

Clinicopathologic reassessment of primary cutaneous B-cell lymphomas with immunophenotypic and molecular genetic characterization

Primary cutaneous B-cell lymphomas (PCBLs) may have particular clinicopathologic characteristics distinct from their lymph node-based counterparts. It has been suggested that PCBLs should have a separate classification system. The aim of this study was to determine whether the Revised European-American Lymphoid Neoplasms (REAL) classification is applicable to PCBL. Thirty-nine cases of PCBL from 36 patients, consisting of 20 men and 16 women (median age 66 yrs), were included in this study. Paraffin-section immunohistochemistry for CD3, CD5, CD10, CD20, CD43, Bcl-2, Bcl-6, and cyclin D1 was performed in all cases. Immunostaining for immunoglobulin light chains was also performed on cases histologically diagnosed as extranodal marginal zone lymphoma (MZL) and primary cutaneous B-cell lymphoma unclassifiable (PCBLu). Polymerase chain reaction (PCR) analysis of t(14;18) was performed in all cases. Immunoglobulin heavy chain gene rearrangement (VDJ) was tested by PCR on all follicle center lymphoma (FCL), MZL, and PCBLu cases. The 39 cases consisted of 15 (39%) FCLs, 13 (33%) diffuse large B-cell lymphomas (DLCL), 9 (23%) extranodal MZL, and 2 cases of PCBLu. Anatomically, 59% of PCBLs occurred in the head and neck, of which approximately 57% were FCL. Five of six cases presenting on the lower extremity were DLCL. Follow-up data was available from all 39 patients with a mean of 50.8 months. All but two patients are alive with or without disease at last contact. One patient with DLCL died of lung metastases and the other DLCL patient died of sepsis as a complication of therapy. In all 15 cases of FCL, CD10 and/or Bcl-6 expression supported the follicle center origin of the neoplastic cells. In contrast to previous reports, we found that 53% (8 of 15) of primary cutaneous FCL had either Bcl-2 protein expression or t(14;18). Our data indicate that many cases of primary cutaneous FCL have Bcl-2 alterations similar to their nodal counterpart. We found that 95% (37 of 39) of PCBLs could be classified according to the REAL classification, supporting its applicability in cutaneous lymphomas.     

Plasmablastic lymphoma in HIV-positive patients: an aggressive Epstein-Barr virus-associated extramedullary plasmacytic neoplasm

AIDS-associated aggressive B-cell lymphomas often have plasmacytoid features. Plasma cell neoplasms in HIV patients were commonly described to have atypical morphology and an aggressive clinical course in the literature. We reviewed 14 cases of neoplasms with marked plasmacytic differentiation in HIV-positive patients to determine their clinicopathologic features. Of these, 13 of 14 had homogeneous morphology and were generally CD45(+), CD20-, PAX-5-, and CD138(+). All were positive for Epstein-Barr virus-encoded RNA (EBER) but lacked EBV late membrane proteins (LMP). Human herpes virus 8 (HHV8) DNA was detected in 6 of 10 cases by nested PCR, but HHV8 latent nuclear antigen (LNA) was absent. The 13 patients ranged in age from 28 to 44 years (median, 41 years) (11 male patients; 2 female patients). All patients had extramedullary and 11 of 13 had extranodal tumor at the initial presentation; 2 had distant marrow involvement. The most commonly involved location was the oral cavity (6 of 13 cases), followed by bone and soft tissue (4 of 13), and the gastrointestinal tract (3 of 13). All 11 patients with follow-up died within 34 months (median, 7 months). The 14th patient who had a nodal disease with more undifferentiated morphology and expression of the HHV8 LNA protein was alive without disease at last follow-up (>72 months), probably representing a novel HHV8(+) lymphoma. We conclude that most plasmacytic tumors in HIV-positive individuals are extramedullary, clinically aggressive EBV(+) tumors identical to plasmablastic lymphoma that does not have the clinical features of plasma cell myeloma.     

Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities

Plasmablastic lymphoma was initially described as a variant of diffuse large B-cell lymphoma (DLBCL) involving the oral cavity of HIV+ patients and characterized by immunoblastic morphology and a plasma cell phenotype. However, other lymphomas may exhibit similar morphologic and immunophenotypic features. To determine the significance of plasmablastic differentiation in DLBCL and examine the heterogeneity of lymphomas with these characteristics, we examined 50 DLBCLs with low/absent CD20/CD79a and an immunophenotype indicative of terminal B-cell differentiation (MUM1/CD38/CD138/EMA-positive). We were able to define several distinct subgroups. Twenty-three tumors were classified as plasmablastic lymphoma of the oral mucosa type and showed a monomorphic population of immunoblasts with no or minimal plasmacytic differentiation. Most patients were HIV+ and EBV was positive in 74%. Eleven (48%) cases presented in the oral mucosa, but the remaining presented in other extranodal (39%) or nodal (13%) sites. Sixteen cases were classified as plasmablastic lymphoma with plasmacytic differentiation. These were composed predominantly of immunoblasts and plasmablasts, but in addition exhibited more differentiation to mature plasma cells. Only 33% were HIV+, EBV was detected in 62%, and 44% had nodal presentation. Nine cases, morphologically indistinguishable from the previous group, were secondary extramedullary plasmablastic tumors occurring in patients with prior or synchronous plasma cell neoplasms, classified as multiple myeloma in 7 of the 9. Two additional neoplasms were an HHV-8+ extracavitary variant of primary effusion lymphoma and an ALK+ DLBCL. HHV-8 was examined in 39 additional cases, and was negative in all. In conclusion, DLBCLs with plasmablastic differentiation are a heterogeneous group of neoplasms with different clinicopathological characteristics that may correspond to different entities.     

Lymphomas involving the breast: a study of 106 cases comparing localized and disseminated neoplasms

Lymphomas involving the breast account for approximately 2% of extranodal and <1% of all non-Hodgkin lymphomas. Our aim in this study was to classify breast lymphomas using the World Health Organization classification and then compare this classification with clinical, histologic, and radiologic findings as well as survival. The study group included 106 patients with breast lymphoma (105 women and 1 man). The neoplasms were divided into 2 groups based on extent of disease at initial diagnosis: localized disease (n=50) and disseminated disease (n=56). The follow-up period ranged from 4 to 252 months (median, 49 mo). Almost all (97%) patients presented with a palpable breast mass or masses. In the localized group, diffuse large B-cell lymphoma (DLBCL) was most frequent (n=32, 64%). In the disseminated group, follicular lymphoma was most frequent and exclusive to this group (P=0.0004). Mucosa-associated lymphoid tissue lymphomas occurred in both groups without a significant difference in frequency. A variety of other types of B-cell and T-cell non-Hodgkin lymphomas and classical Hodgkin lymphoma involved the breast at much lower frequency; most of these neoplasms involved the breast as part of disseminated disease. The clinical presentation correlated with radiologic findings: localized lymphomas presented as solitary masses, whereas disseminated lymphomas commonly presented as multifocal masses. There was a significant difference in the disease-free survival between patients with localized and disseminated DLBCL (P=0.003). In the disseminated group, patients with DLBCL had a worse disease-free survival compared with patients with mucosa-associated lymphoid tissue lymphoma or follicular lymphoma (P=0.01).     

Pathologic and clinical features of 77 Hodgkin's lymphoma patients treated in a lymphoma protocol (LNH87): a GELA study

Between 1987 and 1993, 77 of 2855 lymphomas included in the LNH87 protocol of the GELA as non-Hodgkin lymphoma (NHL) and reviewed by a panel of pathologists had a diagnosis changed to Hodgkin lymphoma (HL). Some of these lymphomas had been initially interpreted as anaplastic large-cell lymphoma Hodgkin-like (ALCL-HL subtype). The purpose of this study was to analyze the histologic pitfalls initially encountered, to define more clearly the diagnostic criteria of lymphomas placed in the gray zone around HL, and to follow the survival of these 77 patients affected with HL and initially treated with NHL regimens. The 77 cases of HL were reviewed by three hematopathologists and immunostained with a large panel of antibodies, including CD30, CD15, CD3, CD20, CD45, CD43, LMP-1, EMA, BNH-9, TiA1, and ALK1. Each case was classified according to the Lukes-Rye system and the British National Lymphoma Investigation (BNLI) grading. The initial clinical presentation of patients was analyzed, and the overall and event-free survival rates of the 77 patients were estimated. Among the 77 HLs, 46 were misinterpreted as NHL by primary individual pathologists (12 as ALCL, 8 as ALCL-HL, 12 as peripheral T-cell lymphoma (PTCL), 6 as B-cell lymphoma, and 8 as unclassifiable NHL). The other 31 cases had been first considered by the panel as consistent with ALCL-HL (n = 18) or with PTCL (n = 13) and were changed later in view of an immunophenotype concordant with HL. Fifty-five percent of the patients completed the full NHL treatment. The 5-year event-free and overall survival rates were 54% and 77%, respectively. The current results indicate that lymphomas initially called ALCL-HL should not be regarded as a variant of ALCL, but as HL. The clinical consequences of misdiagnoses seem to be a lower event-free survival rate compared with that of classical HL, probably because of more relapses of initially inappropriately treated HL.     

Progression to large B-cell lymphoma in splenic marginal zone lymphoma: a description of a series of 12 cases.

Splenic marginal zone lymphoma (SMZL) is considered to be an indolent extranodal B-cell lymphoma. Despite its low aggressivity, histologic progression has been described in sporadic reports, although the frequency, characteristics, and underlying molecular abnormalities of this phenomenon are largely unknown. We review here the clinical, morphologic, immunohistochemical, and molecular features of a series of 12 SMZL cases that showed progression to large B-cell lymphoma (LBCL). The most frequent location of secondary LBCL was in peripheral lymph node. This occurred between 12 and 85 months after diagnosis of SMZL. However, in two cases LBCL was diagnosed at the initial stage of the disease (one spleen tumoral nodule and one hilar lymph node). The histologic and immunophenotypic features of these cases were similar to those of transformed LBCL at other sites. In four cases the immunoglobulin heavy chain gene polymerase chain study revealed the same rearrangement pattern in both primary and secondary tumors, thereby confirming their identity and excluding the possibility of a second malignancy. As is the case with other low-grade lymphoproliferative disorders, SMZL may undergo high-grade transformation. These 12 cases represent 13% of our series of SMZL with adequate follow-up. The incidence of large cell transformation in SMZL seems to be lower than in follicular lymphoma (25-60%) and mantle cell lymphoma (11-39%), although it is similar to the frequency of transformation in B-chronic lymphocytic lymphoma/small lymphocytic lymphoma (1-10%). The mean proliferative index (MIB1 staining) in initial SMZL specimens of cases with LBCL transformation was 28.6%, higher than that of MIB1 staining in the overall SMZL series (21.8%), although not statistically significantly so. p53 or p16INK4a inactivation in this series was observed in only one case, in contrast with the situation observed in chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma. It seems that progression in SMZL is mainly independent of p53 or p16INK4a inactivation. The frequency of the 7q deletion in this series was 3 of 7 (42%). 7q loss may play an alternative role in the inactivation of the p53 and p16INK4a pathway, thereby favoring tumoral progression.     

Correlation of Prognostic Factors and Survival with Classical and Pleomorphic Variants of Invasive Lobular Carcinoma

Abstract: The pleomorphic variant of invasive lobular carcinoma has a worse prognosis than its classical counterpart. To determine if histologically separating invasive lobular carcinoma into either of these variants correlates with other prognostic indicators, we measured the mitotic figure index (number of mitotic figures/100 tumor cells), Ki67 labeling index (Ki67 positive cells/100 tumor cells), intratumoral microvessel density (microvessels/200X field), and the number of positive lymph nodes in 48 patients with invasive lobular carcinoma with a median follow-up of 63 months. There were 27 cases of classical lobular carcinoma (mean age, 58) and 21 cases of pleomorphic variant (mean age, 57). The mitotic figure index and Ki67 labeling index were significantly higher in the pleomorphic variant compared to the classical lobular carcinoma (p = 0.002, and 0.08 respectively). No significant differences in intratumoral microvessel density, number of positive lymph nodes, or age was found between the two histologic types. Relapse free survival was shorter in patients with pleomorphic variant (p = 0.05), but no difference in overall survival was detected (p = 0.47). Among all patients, lymph node status was the best predictor of relapse free (p = 0.001) and overall survival (p = 0.002), although there were no overall survival differences between patients with 0 to 3 positive lymph nodes. Relapse-free and overall survivals were better among patients who had lower indices of microvessel density (p = 0.07 and 0.08 respectively), Ki67 (p = 0.02 and 0.11), and mitotic figures (p = 0.10 and 0.07). By multivariate analysis no additional prognostic information was provided beyond that of the number of positive lymph nodes; except for overall survival, the mitotic figure index provided additional significant information. We conclude that the histologic diagnosis of pleomorphic invasive lobular carcinoma significantly correlates with shortened relapse-free survival, but among all invasive lobular carcinomas axillary nodal status and mitotic figure index provide more prognostic information than histologic subtyping into pleomorphic and classical variants.?     

Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients

A new group of subcutaneous, natural killer (NK), NK/T-cell, and other cytotoxic T-cell lymphomas of the skin has been recently described, and some have been included as distinct clinicopathologic entities in the classification of hematologic malignancies recently proposed by the World Health Organization. In the European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas, they would be classified either as CD30- large T-cell lymphoma, small/medium pleomorphic T-cell lymphoma, or subcutaneous T-cell lymphoma. Precise clinicopathologic and prognostic features of all of them have not yet been well characterized. We studied retrospectively 81 biopsies from 50 patients with subcutaneous, blastic natural killer (NK), NK/T-cell, or other non-mycosis fungoides cytotoxic T-cell lymphomas of the skin. Clinical, morphologic, phenotypical, and genetic features and data on Epstein-Barr virus association allowed us to classify our cases according to the following 7 categories: a) subcutaneous "panniculitis-like" T-cell lymphoma (SPTCL): 10 cases (estimated 5-year survival: 80%); b) blastic NK-cell lymphoma: 12 cases (estimated 5-year survival: 0%); c) nasal-type extranodal NK/T-cell lymphoma: 5 patients (estimated 5-year survival: 0%); d) epidermotropic CD8+ T-cell lymphoma: 5 cases (estimated 5-year survival: 0%); e) cutaneous gamma/delta T-cell lymphoma: 8 cases (estimated 5-year survival: 0%); f) cutaneous alpha/beta pleomorphic T-cell lymphoma: 8 cases (estimated 5-year survival: 0%); and g) cutaneous medium/large pleomorphic T-cell lymphoma, not otherwise specified: 2 cases. Our study shows that these cutaneous lymphomas can be classified according to precise diagnostic categories. With the exception of SPTCL, analysis of follow-up data from our patients showed that these groups of lymphomas are characterized by an aggressive course, regardless of the diagnostic category.     

Is lymphoplasmacytic lymphoma/immunocytoma a distinct entity? A clinicopathologic study of 20 cases

Lymphoplasmacytic lymphoma/immunocytoma (LLI) was defined initially as a small B-cell lymphoma with plasmacytoid or plasmacytic features. Because other types of small B-cell lymphoma, particularly marginal zone B-cell lymphoma may exhibit plasmacytic differentiation, the revised European-American lymphoma classification and World Health Organization has defined LLI more narrowly to exclude other small B-cell lymphomas. The goal of this study was to reevaluate LLI as a clinicopathologic entity. Twenty cases were selected from 43 previously diagnosed as "small lymphocytic lymphoma, plasmacytoid" or "immunocytoma" from 1985 to 1998. Cases fulfilling the criteria for B-cell small lymphocytic lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, or other types of B-cell lymphoma were excluded. The histopathology and immunoreactivity for CD20, CD79a, CD3, CD43, CD23, CD5, kappa, lambda, and immunoglobulins (Ig's) M, G, and A were reviewed, in addition to available clinical findings. There were 13 men and seven women, with a mean age of 69 years. Five patients had documented Waldenstr?m's macroglobulinemia (WM). Three architectural patterns were observed. Pattern A (seven of 20) showed open sinuses, small follicles, and hemosiderosis; pattern B (four of 20) showed hyperplastic follicles; and pattern C (nine of 20) showed diffuse effacement. Epithelioid histiocytes were prominent in patterns B and C but absent in A. Cytologically, six of 20 were polymorphous with 10% to 40% transformed cells; 14 of 20 were lymphoplasmacytic. Five cases showed minor foci of monocytoid B cells. One case showed a composite histology of LLI and small lymphocytic lymphoma. Amyloid was present in two cases. All cases were CD20 and/or CD79a immunoreactive, with two of 20 positive for CD43. Twelve cases were kappa monoclonal and eight cases were lambda monoclonal. Twelve of 17 cases that could be evaluated were positive for IgM and five were positive for IgG. All cases were negative for CD5 and CD23 with the exception of the one case with a composite histology. Eleven of 20 patients with available follow-up died of disease (median, 48 months), and eight of 20 are alive with disease at a follow-up of 6 months to 2 years. LLI does appear to represent a distinct clinicopathologic entity even though it shows morphologic heterogeneity and overlapping features with marginal zone B-cell lymphoma and small lymphocytic lymphoma. Recognition of LLI is important because the overall prognosis may be worse than for other types of small B-cell lymphomas.     

Lymphoma of the ocular adnexa: A study of 353 cases

We studied the cases of 353 patients with lymphoma involving the ocular adnexa diagnosed at the Massachusetts General Hospital between 1974 and 2005. The patients included 153 males and 200 females, aged 7 to 95 years, with a mean age of 64 years. In 277 cases, there was no known history of lymphoma. Seventy-six patients had a history of lymphoma, with the ocular adnexa being involved at relapse or with progression of the previously diagnosed lymphoma. The patients had marginal zone lymphoma (182 cases), follicular lymphoma (80 cases), mantle cell lymphoma (18 cases), small lymphocytic lymphoma/chronic lymphocytic leukemia (13 cases), lymphoplasmacytic lymphoma (4 cases), splenic marginal zone lymphoma (2 cases), low-grade B cell, not subclassified (19 cases), precursor B lymphoblastic lymphoma (3 cases), diffuse large B-cell lymphoma (26 cases), and 1 case each of high-grade B-cell lymphoma, not subclassified, peripheral T-cell lymphoma, unspecified type, extranodal NK/T-cell lymphoma, nasal type, and Hodgkin lymphoma, nodular sclerosis type. Almost all marginal zone lymphoma patients (168 of 182, 92%) had primary ocular adnexal lymphoma. Fourteen marginal zone lymphoma patients (8%) had a prior history of lymphoma, usually arising in another extranodal site. Twenty-five of 80 (31%) follicular lymphoma patients had a prior history of lymphoma, usually arising in lymph nodes. Patients with mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, and splenic marginal zone lymphoma almost always had a prior history of lymphoma or were known to have widespread disease at the time of diagnosis of ocular adnexal lymphoma. A subset of the diffuse large B-cell lymphomas were associated with large destructive masses involving adjacent structures such as paranasal sinuses, raising the possibility that they may have arisen from one of the adjacent structures and involved the ocular adnexa by direct extension. The relatively high proportion of low-grade lymphoma, not subclassified, highlights the difficulty that may arise in distinguishing different types of low-grade lymphoma, particularly when biopsies are small and artifactually distorted. Ocular adnexal lymphoma is primarily a disease of older adults, with a slight female preponderance. Most lymphomas are low-grade B-cell lymphomas, with marginal zone lymphoma being by far the most common type. Marginal zone lymphoma typically involves the ocular adnexa primarily, whereas other types of low-grade B-cell lymphoma often involve the ocular adnexa secondarily. High-grade B-cell lymphomas only occasionally involve the ocular adnexa, and T-cell lymphoma, NK-cell lymphoma, and Hodgkin lymphoma are only rarely encountered in this site.     

Primary lymphoma of the breast

Primary non-Hodgkin's lymphoma of the breast accounts for fewer than 3% of extranodal lymphomas. As compared to extranodal lymphomas in other sites they are characterised by more rapid progression and a worse prognosis. The aim of the study was to investigate 5 cases of primary lymphoma of the breast and review previous studies in a search for any preoperative characteristics that could assist in the management of lymphoma of the breast. All patients (n = 5) who were diagnosed with lymphomatous involvement of the breast between 1996 and 2004 were evaluated retrospectively. All patients staged IE (breast involvement only) or IIE (limited to the breast and ipsilateral armpit) were included. Most of the primary breast lymphomas were of intermediate grade. Patients received some combination of surgery, radiation, and chemotherapy. The mean follow-up was 48 months (range 24 to 72 months). All 5 patients survived at least 6 years from the time of diagnosis. Long-term survival in patients with primary non-Hodgkin's lymphoma of the breast is possible. The clinical outcome of patients with breast lymphoma depends on the histology and appears to parallel that of patients with lymphoma of similar histology involving other sites.     

Waldenstrom macroglobulinemia involving extramedullary sites: morphologic and immunophenotypic findings in 44 patients

Waldenstrom macroglobulinemia (WM) is a clinicopathologic syndrome in which a B-cell neoplasm involving the bone marrow, usually lymphoplasmacytic lymphoma (LPL), is associated with immunoglobulin M paraprotein in the serum. Extramedullary involvement occurs in a subset of patients and is infrequently examined histologically. The files of M.D. Anderson Cancer Center were searched for patients with WM who underwent biopsy of one or more extramedullary sites during the course of disease. Each biopsy specimen was classified using the criteria of the World Health Organization classification. The study group consisted of 44 patients (26 men and 18 women), with a total of 51 specimens obtained from lymph nodes (n = 36), soft tissue (n = 4), spleen (n = 3), skin (n = 2), lung (n = 2), tonsils (n = 1), colon (n = 1), liver (n = 1), and gallbladder (n = 1). Lymphoplasmacytic lymphoma was the most common histologic type, in 40 (78%) samples. This category was morphologically heterogeneous and was further subclassified as lymphoplasmacytic (n = 21), lymphoplasmacytoid (n = 18), and polymorphous (n = 1). Four of these LPL cases morphologically resembled marginal zone B-cell lymphoma. Four additional samples were involved by diffuse large B-cell lymphoma, probably transformed from LPL. Three more samples were involved by LPL with unusual features: two were CD5-positive and one was a composite tumor with classical Hodgkin's disease. Other categories of lymphoma in this group of patients with WM included small lymphocytic lymphoma/chronic lymphocytic leukemia (n = 2), mantle cell lymphoma (n = 1), and follicular lymphoma (n = 1). Waldenstrom macroglobulinemia is most commonly associated with LPL but can rarely occur with other types of B-cell lymphoma. Lymphoplasmacytic lymphoma in patients with WM is morphologically heterogeneous and can be indistinguishable from marginal zone B-cell lymphoma. CD5+ B-cell lymphomas with features otherwise typical of LPL are rare, and we think these tumors are part of the spectrum of LPL.     

T-cell/histiocyte-rich large B-cell lymphoma: a heterogeneous entity with derivation from germinal center B cells

T-cell/histiocyte-rich large B-cell non-Hodgkin's lymphoma (THRLBCL) is an unusual morphologic variant of diffuse large B-cell lymphoma. We reviewed 30 cases of THRLBCL to evaluate its heterogeneity based on morphologic, immunophenotypic, and genetic features. Cases were classified according to the appearance of the large neoplastic B cells into three morphologic variants: 1) lymphocytic and histiocytic (L&H-like) (resembling the L&H cells of nodular lymphocyte predominance Hodgkin's lymphoma (14 cases); 2) centroblast (or immunoblast)-like (10 cases), and 3) Reed-Sternberg cell-like (resembling the neoplastic cells of classic Hodgkin's lymphoma) (6 cases). We used a panel of immunohistochemical stains, including those with specificity for germinal center B cells: CD20, CD79a, CD30, CD15, epithelial membrane antigen, BCL-2, BCL-6, and CD10. The /JH polymerase chain reaction assay was further performed to investigate a relationship to follicular lymphoma. The results were correlated with Epstein-Barr virus status as determined by staining for latent membrane protein and EBER-1 in situ hybridization. All cases were of B-cell immunophenotype with strong surface CD20 reactivity in the neoplastic large lymphoid cells, although CD79a was more inconsistently and weakly expressed (10 of 17). Nuclear positivity for the BCL-6 protein was detected in the tumor cells in 26 of 29 (90%) cases. However, differences in expression of other antigens were encountered in the histologic subtypes. Epithelial membrane antigen positivity, a feature often seen in nodular lymphocyte predominance Hodgkin's lymphoma, was observed in 11 of 30 (37%) cases and was most commonly seen in cases with L&H cell morphology (8 of 14; 57%). CD30 expression was observed in 9 of 30 (30%) cases but was most frequent in cases with Reed-Sternberg-like morphology (3 of 6 [50%]). CD10 expression was infrequent overall (3 of 29; 10%), with 2 of 3 positive cases identified in the centroblastic group. The overall rarity of positivity for CD10, BCL-2 (3 of 22; 13%), and -2 JH rearrangement (1 of 28; 4%) indicates a lack of connection to follicular lymphoma for all subtypes. The three cases that were negative for BCL-6 protein were LMP-1 positive and EBER-1 positive by in situ hybridization, and 2 of 3 had neoplastic cells with Reed-Sternberg-like morphology. These results demonstrate that although a large proportion of THRLBCL represent tumors of germinal center B cell derivation, they exhibit a diversity of morphologic and immunophenotypic features. A subset of THRLBCL may be related to nodular lymphocyte predominance Hodgkin's lymphoma. A small percentage show features closely resembling classic Hodgkin's lymphoma and could be considered a variant of grey zone lymphoma.     

Non-B, non-T neoplasms with lymphoblast morphology: further clarification and classification

We studied the morphologic, immunohistochemical, and clinical characteristics of 158 cases of lymphoblastic lymphoma. Based on immunophenotyping and cell lineage, cases were classified into B-cell type (CD20,CD19 or CD79a+, n = 53), T-cell type (surface CD3+, n = 84), and non-B, non-T type (B cell marker- and surface CD3-, n = 21). The latter group was further divided based on immunohistochemistry into: 1) CD7+ stem cell lymphoma (CD7+SCL) [CD4-, CD7+, CD33+/-, CD56-], 2) blastic natural killer cell lymphoma (B-NKL) [CD4-, CD7+/-, CD33-, CD56+, CD123-], 3) myeloid/NK precursor cell leukemia (M/NKL) [CD4-, CD7+, CD33+, CD56+], and 4) CD4+CD56+ hematodermic malignancy (CD4+CD56+) type [CD4+, CD7+/-, CD33-, CD56+, CD123+]. The CD7+SCL and M/NKL types frequently exhibited bone marrow invasion and mediastinal masses. All CD4+CD56+ types were associated with skin lesions. B-NKL type is included into Blastic NK lymphoma in new World Health Organization classification with CD4+CD56+ type. But the cases of B-NKL were more reminiscent of CD7+SCL or M/NKL type than the CD4+CD56+ type, both clinically and histologically. We propose that blastic NK lymphoma, a disease entity in the new WHO classification, should be divided into two types based on phenotypes and clinical features. The non-B, non-T lymphomas exhibited poorer prognoses, similar to that of B-cell lymphomas, than T-cell type tumors (P = 0.009). Among the 21 tumors, the prognosis of the four subtypes did not differ significantly; however, cases receiving aggressive chemotherapy and stem cell transplantation had a more favorable prognosis than those receiving only traditional chemotherapy and radiation therapy (P = 0.0089).     

Pyothorax-associated lymphoma: a peculiar clinicopathologic entity derived from B cells at late stage of differentiation and with occasional aberrant dual B- and T-cell phenotype

We report 12 European cases of pyothorax-associated lymphomas occurring 30-67 years following artificial pneumothorax for pleuropulmonar tuberculosis. Eleven patients presented with a localized pleural tumor mass, whereas one patient also had liver involvement. Histologic examination showed a diffuse proliferation of large lymphoid cells with frequent plasmacytoid differentiation (n = 8), expressing CD20 (n = 10), CD79a (n = 11), and/or CD138 (n = 5) B-cell antigens. Aberrant expression of T-cell markers (CD2, CD3, CD4) was noted in five cases. The B-cell origin of lymphoma cells was confirmed by the demonstration of immunoglobulin light chain restriction or clonal B cell population in six cases. In 11 of 12 cases in situ hybridization disclosed Epstein-Barr virus genome in most tumor cells and immunohistochemistry a type III LMP-1+/ EBNA-2+ latency profile. HHV-8/ORF73 antigen was not detected in all tested cases (n = 11). All investigated cases (10 of 10) disclosed a uniform CD10-/BCL-6-/MUM1+/CD138+/- phenotype, consistent with a derivation from late germinal center (GC)/post-GC B cells. Clinical outcome was poor with a median survival time of 5 months. Only one patient was in complete remission after 34 months. This study further confirms that pyothorax-associated lymphoma represents a distinct clinicopathologic entity among diffuse large B-cell lymphoma, which is characterized by a peculiar clinical presentation, frequent plasmacytoid features, and a strong association with EBV. Moreover, we show that this lymphoma entity likely originates from B cells at a late stage of differentiation and occasionally shares an aberrant dual B/T phenotype.