Benign, atypical and malignant lymphoproliferative disorders in rheumatoid arthritis patients.

Lymphadenopathy, which may be associated with systemic symptoms, is frequently associated with rheumatoid arthritis (RA). Reactive non-neoplastic tissue comprises the majority of the lymph node lesions. However, several cohort studies have demonstrated that RA has an increased risk of non-Hodgkin's lymphomas (NHLs). Since the early 1990s, an atypical or malignant lymphoproliferative disorders (LPD) in patients immunosupressed with methtorexate (MTX) therapy for RA has been emphasized, namely MTX-associated LPDs. Epstein-Barr virus (EBV) has received attention in connection with the etiology of RA. The present review describes the clinicopathologic and immunohistochemical findings of reactive, atypical and malignant LPDs associated with RA along with the presence or absence of EBV in LPDs using the in situ hybridization (ISH) method. The majority of reactive lymph node lesions exhibit reactive follicular hyperplasia with interfollicular polyclonal plasmacytosis. Atypical LPDs rarely appears in RA patients. However, these cases occasionally pose difficult problems in the differential diagnosis from malignant lymphomas associated with RA or atypical and malignant LPDs showing RA-like clinicopathological findings. Clinicopathologically, three types of atypical LPDs have delineated, i.e. (i) resembling multicentric Castleman's disease (MCD); (ii) atypical paracortical hyperplasia with lymphoid follicles (APHLF) and; (iii) atypical lymphoplasmacytic immunoblastic proliferation. Malignant lymphoma associated with RA is characterized by; (i) predominance of elderly cases; (ii) usually female predominance, reflecting the sex ratio of RA; (iii) longstanding history of RA; (iv) relatively frequent advanced stage of disease; (v) majority of the patients had the B-cell phenotype; and (vi) an increased frequency of diffuse large B-cell lymphoma (DLBCL) in RA. It is unlikely that EBV is the causative agent of either reactive or atypical LPD. Among malignant lymphomas, EBV-associated lymphoma comprised only a small fraction of all NHLs in the general RA patient population.

Floral variant of follicular lymphoma containing marginal zone B-cell component. Report of two cases.

We here report two unusual cases of floral variant of follicular lymphoma containing marginal zone B-cells. Histologically, the neoplastic follicles consisted of three distinct layers. The inner layer was composed of neoplastic germinal centers exhibiting a floral design and the middle layer had unusually prominent mantle zones. The outer zone of neoplastic follicles was surrounded by a pale cuff of marginal zone B-cells. Immunohistological study demonstrated that both the germinal center and marginal zone component lay within the follicular dendritic cell network. The germinal center component was CD10+ and bcl-2+. However, a portion of the marginal zone component weakly expressed bcl-2 but not CD10. Nodal marginal zone B-cell lymphoma (NMZBL) occasionally possesses "floral" lymphoid follicles. Follicular lymphoma with marginal zone differentiation is a high-risk variant of follicular lymphoma. In diagnostic practice, the differential diagnosis between the floral variant of follicular lymphoma containing marginal zone B-cells and the "floral variant" of NMZBL is important.

Anaplastic large cell lymphoma: a distinct molecular pathologic entity: a reappraisal with special reference to p80(NPM/ALK) expression.

The p80(NPM/ALK) expression activated by the t(2;5) (p23;q35) translocation recently has been shown to play an important role in the pathogenesis of anaplastic large cell lymphoma (ALCL). However, the clinicopathologic significance of identification of p80 among ALCL cases has not been completely resolved. Difficulties also exist in the histologic and immunophenotypic identification of ALCL and Hodgkin's disease (HD) as separate processes, often complicating the clinicopathologic evaluation of and therapeutic approach to these entities. In order to clarify these issues, 67 specimens of ALCL and 63 specimens of HD (31 of the nodular-sclerosing type [NS-HD] and 32 of the mixed-cellularity type [MC-HD]) were immunostained using anti-p80 antibody and other relevant markers on paraffin sections. The clinicopathologic and immunophenotypic features were reviewed on the basis of p80 reactivity. The expression of p80 was detected in 43 of 67 cases of ALCL (64%), but none of HD. The p80+ ALCL cases constituted a very homogeneous group of tumors, characterized by the occurrence in a much younger group and relatively more favorable clinical course than the p80- ALCL, which were in keeping with the data previously reported. They showed virtually the identical immunophenotypic findings of p80+, CD30+, EMA+, CD15-, bcl-2-, and Epstein-Barr virus (EBV) with T- and null-cell phenotype, and showed the distinct morphologic features, including three cases of lymphohistiocytic/small-cell variant, as follows: the indented nuclei, often termed as reniform, embryolike, and horseshoelike; multiple, irregular, but indistinct nucleoli; and few reactive cells of eosinophils and epithelioid cells. Conversely, the 24 p80- ALCL cases, in which epithelial membrane antigen (EMA) and bcl-2 positivities were 33% and 55%, respectively, were heterogeneous and could be subdivided into five different categories, namely (a) 11 cases of HD-like ALCLs, (b) six cases of p80 common ALCL, (c) three cases of secondary ALCL, (d) two cases of primary cutaneous ALCL, and (e) two cases of primary classical ALCL that lacked p80 expression. This study clearly demonstrated that the immunohistochemical detection of p80 is of a crucial importance in delineating the biologically distinct entity of "primary classical ALCL" from various diseases that show morphologic and immunohistologic overlap, including HD and HD-like ALCL.

Hodgkin's disease expressing follicular dendritic cell marker CD21 without any other B-cell marker: a clinicopathologic study of nine cases.

Reed-Sternberg (RS) and Hodgkin's (H) cells are considered to be the neoplastic cells in Hodgkin's disease (HD). Although most data suggest their lymphoid origin, the nature of these cells still remains a subject of controversy. Recently, a number of RS cells have been found to express an antigen that is also present on follicular dendritic cells (FDCs), asserting FDCs as the possible progenitor cells of H-RS cells. This prompted us to investigate whether these CD21-positive cases had distinct clinicopathologic characteristics. In a series of 94 examined cases of HD, we identified 9 CD21-positive ones (4 of 37 cases of nodular sclerosis, 1 of 41 mixed cellularity, and 4 of 12 lymphocyte depletion HD) without any other B-cell marker on paraffin sections. The patients varied in age from 16 to 82 years (median, 50 years) and included six men and three women. They had superficial or mesenteric lymphadenopathy without hepatosplenomegaly. Peripheral blood leukocytosis was seen in three patients. The clinical course was indolent, and all patients but one achieved an initial complete response with HD-based treatment regimens, although three of them relapsed. Morphologically, two subgroups could be delineated. Six of the cases were characterized, besides by the classic RS cells, by a varying number of the cells with the distinctive walnutlike or cerebrumlike nuclei and cytologically with cytoplasmic processes. Their fine structural examination also revealed villous processes, but no desmosomes. The other three cases had multinucleated RS cells often with triangular nuclei, but not cytoplasmic processes. The percentage of CD21-positive tumor cells ranged from less than 10% to 60% among the H-RS cells. These RS cells were positive for CD30 (9 of 9), CD15 (7 of 9), CD68 (1 of 8), fascin (8 of 8), S-100 protein (1 of 7), and epithelial membrane antigen (2 of 8) on paraffin sections. Notably, of eight cases examined on frozen sections, two showed immunostaining for DRC1, CD35, R4/23, and Ki-M4p. Only CD35 was also detected in the other two cases. Genotypic investigation showed germline configuration of the T-cell receptor beta and gamma chain genes and the immunoglobulin heavy chain gene in all eight cases examined. In situ hybridization showed Epstein-Barr virus sequences in four cases, three of which were examined by the terminal region analysis and showed the Epstein-Barr virus to be monoclonal. We concluded that in a small proportion (9.6%) of HD, H-RS cells might be derived from FDCs and that they appear to represent a distinct pathologic variant based on morphologic and phenotypic traits within the framework of HD.

Nodal cytotoxic lymphoma spectrum: a clinicopathologic study of 66 patients.

The expression of cytotoxic granule-associated proteins has been reported in some T-cell or natural killer (NK)-cell lymphomas of mostly extranodal origin, but rarely of nodal origin except for anaplastic large cell lymphoma (ALCL) and Hodgkin's disease (HD). This study analyzed 66 nodal lymphomas expressing T-cell intracellular antigen-1 (TIA-1) and/or granzyme B to characterize the clinicopathologic spectrum of these neoplasms. Four main groups could be delineated. The first group consisted of p80/anaplastic lymphoma kinase (ALK)-positive ALCL (n = 35). The patients were 2 to 62 years of age (median age, 16 years), and the lymphomas pursued a relatively indolent clinical course. The tumors were phenotypically of either T- or null-cell type with constant expression of CD30, epithelial membrane antigen (EMA), and p80/ALK, but not CD15 or BCL2. None harbored Epstein-Barr virus (EBV). The second group consisted of peripheral T/NK-cell lymphoma, the nodal high-grade cytotoxic type (n = 13). The patients were 29 to 72 years in age (median age, 55 years), and the tumors pursued an aggressive clinical course. The tumors often showed pleomorphic, anaplastic, or centroblastoid morphology, and were featured by either EBV association or CD56 expression. The third group consisted of peripheral T-cell lymphoma, of the nodal low-grade cytotoxic type (n = 8). The patients, three men and five women, were 31 to 75 years old (median age, 61 years). Notably, six of them exhibited lymphoepithelioid (Lennert's) lymphoma. The fourth group consisted of cytotoxic Hodgkin's-like ALCL/HD (n = 10), included seven cases of Hodgkin's-like ALCL and three cases of HD, and was characterized by the presence of Reed-Sternberg cells and often the CD15+ phenotype. The patients were all men except for one woman, and they ranged in age from 24 to 84 years (median age, 62 years). The link among these four groups was reinforced by the presence of a highly characteristic large cell with horseshoelike or reniform nuclei-the frequent expression of CD30 and EMA-and the often lack of T-cell receptor-alphabeta. In this series, the expression of p80/ALK and CD56 was also associated with favorable and poor prognoses respectively (p<0.001, log-rank test).

Centroblastic and centroblastic-centrocytic lymphomas associated with prominent epithelioid granulomatous response without plasma cell differentiation: a clinicopathologic study of 12 cases.

To clarify the clinicopathologic features of B-cell lymphoma associated with prominent epithelioid granulomatous responses other than immunocytomas, 12 patients were studied. There were six men and six women. The lymphoma generally affected elderly patients (median age, 58.5 years) and was mostly nodal in origin. Seven of the 12 patients had a localized lesion (stage I or II), and five had an advanced lesion (stage III or IV). Histologically, four patients showed a follicular growth pattern and eight a diffuse growth pattern. Based on the updated Kiel classification, nine patients showed centroblastic lymphomas, and three showed centroblastic-centrocytic lymphomas. The epithelioid cells were accumulated in large, poorly demarcated masses. Trabecular fibrosis compartmentalized in the lymph nodes, producing a vague nodular pattern in low-power fields. Immunohistochemical studies of the tumor cells revealed positive membrane staining with L26 in all 12 patients and with LN-1 antibody in 9 of 10 patients. Expression of the bcl-2 protein was present in all seven patients tested. Genotypic investigation exhibited germline configuration of the immunoglobulin heavy chain gene, the T-cell receptor beta-chain gene and the bcl-2 gene in all three patients investigated. By in situ hybridization, Epstein-Barr virus genomes were detected in only a few tumor cells in three of the patients tested. This study indicated that most, if not all, of the B-cell lymphomas with prominent epithelioid granulomatous responses other than immunocytoma were of follicular center cell origin.

Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: a clinicopathological and immunohistochemical study of 10 cases.

An absence of germinal centers is one of the histological characteristics of angioimmunoblastic T-cell lymphoma (AITL). We report here 10 unusual cases of AITL with hyperplastic germinal centers. The clinical presentation of each patient was characterized by generalized lymphadenopathy, constitutional symptoms and polyclonal hypergammaglobulinemia. The initial biopsy findings of each patient were similar and were characterized by hyperplastic germinal centers with ill-defined borders and a proliferation of high endothelial venules (HEV). In the paracortical area there was a mixed infiltrate including irregularly shaped clusters or small nests of clear cells in all cases. Moreover, the clear cells invaded the lymphoid follicles, resulting in expansion of the germinal centers, except for one case. Immunohistochemistry revealed that the tumor cells, including clear cells, were CD4-expressing T cells. Some of the atypical lymphocytes were also Bcl-6-positive. A majority of the follicular dendritic cell networks showed a normal/reactive or an expanded/disrupted pattern in all cases. Moreover, three lesions possessed a few large irregularly shaped proliferations of follicular dendritic cells around the HEV Four cases progressed to AITL within a few years. The present 10 cases probably represent an early stage of AITL preceding follicular dendritic cell hyperplasia. Detection of clear cells, Bcl-6-positive atypical T lymphocytes, and foci of irregularly shaped proliferation of follicular dendritic cells appears to be critical for early diagnosis and treatment of AITL with hyperplastic follicles.

Autoimmune disease-associated lymphadenopathy with histological appearance of T-zone dysplasia with hyperplastic follicles. A clinicopathological analysis of nine cases.

Autoimmune disease-associated lymphadenopathy shows marked histopathological and clinical diversity. We describe the clinicopathological and immunohistochemical findings of nine cases of autoimmune disease-associated lymphadenopathy, which posed a serious differential diagnostic problem regarding T-zone dysplasia with hyperplastic follicles. There were two males and seven females aged 25 to 65 years (median 37 years). The patients had multicentric lymphadenopathy in association with clinical and laboratory findings suggestive of an "autoimmune disease". Four patients were diagnosed to have systemic lupus erythematosus (SLE), and the remaining five patients had antiphospholipid antibody syndrome and Sjogren's syndrome (SS), rheumatoid arthritis (RA), chronic thyroiditis, RA and SS, and SLE and SS, respectively. None of the nine patients developed malignant lymphomas during the follow-up periods from 44 to 225 months (median 103 months). The lesions were characterized by paracortical hyperplasia with prominent vascular proliferation and many lymphoid follicles with germinal centers. The paracortical area usually contained numerous small T-lymphocytes without cytological atypia, accompanied by a variable number of plasma cells, B-immunoblasts, and histiocytes. Polymerase chain reaction analysis demonstrated no clonal rearrangement of the T-cell receptor chain gene in four cases examined, although immunoglobulin heavy chain rearrangement was detected in only one case. These findings suggest that autoimmune disease-associated lymphadenopathy, especially SLE, shares the histological features with T-zone dysplasia with hyperplastic follicles. The nine cases presented here should be differentiated from T-zone lymphoma with follicles and angioimmunoblastic lymphoma with hyperplastic germinal centers. To avoid overdiagnosis and overtreatment, we emphasize the need to turn attention to these clinical and laboratory findings as well as to the morphological features.

Occurrence of monocytoid B-cells in reactive lymph node lesions.

Benign monocytoid B-cells are a peculiar subset of B-cells. They are closely related to marginal zone B-lymphocytes, show cytological diversity and may be recognized in a variety of reactive lymph node conditions. To analyze the incidence, cytological spectrum and phenotypic features of benign monocytoid B-cells, we investigated a series of 301 consecutively biopsied and unselected cases of reactive lymph node change from 1988 and 1995. A monocytoid B-cell reaction was identified in 46 (15%) cases and could be cytologically subclassified into two groups: 31 (67%) cases with common-type cells and 15 (33%) cases with large, transformed cells, according to the description by Plank et al. [19]. These reactions were regularly associated with follicular hyperplasia (95%) and were part of an epithelioid cell response in 24 cases (50%). Immunohistologically, both types of benign monocytoid B-cells were negative for bcl-2 protein expression, which was in contrast to the bcl-2 positive reaction in marginal zone B-lymphocytes and their neoplastic counterpart in monocytoid B-cell lymphoma. An association of Epstein-Barr virus (EBV) with monocytoid B-cells was investigated by in situ-hybridization. EBV genomes were detected in five (15%) of 31 cases tested. In each of these five cases, positive cells were represented in both high and low numbers. The morphologic features of the EBV-positive cells were not consistent with monocytoid B-cells, but rather with medium-sized to large lymphoid cells. It appeared that the occurrence of monocytoid B-cell reaction in reactive lymph node lesions was not related to EBV infection in the majority of cases.

Scaling lichenoid eruptions and Sjögren-like syndrome: manifestations of nonfatal postoperative transfusion-associated graft-versus-host disease?

We report a case of an 81-year-old woman in whom lichenoid eruptions and Sjögren-like sicca syndrome developed 45 days after cholecystectomy. During surgery, one unit (130 ml) of unirradiated packed red blood cells from a male donor was transfused. The lichenoid eruptions cleared up with exfoliation: however, sicca symptoms remained during the follow-up period of four years. Histological examinations of both skin and lip biopsy specimens were in agreement with those of graft-versus-host disease (GVHD). A Y-chromosomal body was identified in the lymphocytes in the skin lesion by staining with quinacrine dihydrochloride and in the lip lesion by a method with in situ hybridization. The findings suggest that this case demonstrated the manifestations of non-fatal transfusion-associated GVHD.

[A case of acute cervical spinal epidural hematoma caused by extradural arterio-venous malformation].

The authors report a rare case of acute cervical epidural hematoma caused by the hemorrhage from extradural arterio-venous malformation. The patient was a 74-year-old Japanese man with a past history of total gastrectomy after being diagnosed as having gastric cancer 12 years before. Six hours prior to admission, the patient had experienced a sudden episode of severe nuchal pain radiating to both scapular areas, followed by rapid development of left-side Brown-Sequard Syndrome below the C4 cord level, and urinary incontinence. Plain cervical X-ray films did not show any destructive lesion suggesting a metastatic tumor. T1 and T2 weighted images of MRI demonstrated a high intensity mass lesion, suggesting an acute epidural hematoma, extending from C3 to C6 and compressing severely the left side spinal cord posteriorly. Twelve hours after the onset of symptoms, emergency laminectomy from C3 to C6 was performed and a fresh epidural clot with small vascular tissue was totally removed. Histological examination of the small vascular tissue in the hematoma revealed arterio-venous malformation. The postoperative recovery of the patient was dramatic. He regained full muscle strength and there was complete disappearance of sensory deficits 2 weeks after the operation. Although acute spinal epidural hematoma caused by extradural arterio-venous malformation is a rare clinical entity, MRI is the most helpful diagnostic tool for this condition. It should be stressed that accurate neuroradiological diagnosis and prompt surgical decompression of the spinal cord are essential to obtain an excellent surgical outcome.

[A case of gastrointestinal stromal tumor of rectum, difficult to differentiate from leiomyosarcoma of prostate].

A 70 year-old male was seen at the hospital with the chief complaints of frequent miction and incomplete urinary retention. A hen's egg-sized firm mass was palpable in anterior wall of rectum by digital rectal examination. Intravenous urography showed severe bilateral hydronephroureter. Transrectal ultrasound, CT scan and MRI revealed a mass with 5 cm in diameter between prostate and rectum, and the margin of them were unclear. On needle biopsy of the tumor, leiomyosarcoma of the prostate was suspected. We performed radical cytectomy and created continent urinary reserver. Because the tumor and rectum could not be lysed, part of the rectum was resected. Histological examination showed gastrointestinal stromal tumor (GIST) of rectum. GIST of rectum is a rare entity, and in case of contact with the prostate, it is difficult to differentiate from leiomyosarcoma of prostate.

[The problems in the histopathological classification of non-Hodgkin's lymphomas--with special references to T-cell lymphomas].

The problems of histopathological classification and diagnosis of non-Hodgkin's lymphomas on discussed with special refences to 1) the low-grade T-cell lymphomas which usually exhibit fairly specific features for T-cell characteristics both morphological and clinical aspects, and 2) some of the higher-grade categories of T-cell tumors.

[A clinicopathologic study of primary gastric lymphoma of B-cell type among the Japanese with special reference to low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)].

The most common primary site of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is the gastrointestinal tract, particularly the stomach. The relationship of MALT lymphomas, however, with the more commonly occurring large B-cell gastric lymphoma has not been directly discussed except in the report of Chan et al. (1990), which lacked clinical information regarding the behavior of these tumors. To elucidate the relationship between high-grade large-cell lymphoma and MALT lymphoma, we studied in detail the histopathological and clinicopathologic features with the survival date of 77 Japanese cases of primary gastric lymphoma (PGL) of B-cell type. Based on degree of morphologically recognizable low- or high-grade components of the tumor, PGL was divided into four types: 18 cases of pure MALT lymphoma (type I); 13 cases of MALT lymphoma with small area of high-grade lymphoma (type II); 22 cases of high-grade lymphoma with small areas of MALT lymphoma (type III); and 24 cases pure high-grade lymphoma (type IV). Corresponding to the differences in the histologic pictures of each type, there were differences in the gross appearance, pathologic stage (including depth of invasion) and prognosis. These data suggests that both MALT and high-grade lymphomas of the stomach belong to the same cell lineage and constitute a pathological spectrum and that the histological grouping of PGL is clinico-pathologically useful.

[An immunohistopathological study on intrahepatic distribution of HBeAga/b in biopsied chronic type B hepatitis].

In order to evaluate the role of a expression of HBV-associated, we investigated histological and cytological distribution of HBeAga, HBeAgb, and HBcAg by immunoperoxidase procedure using monochronal antibodies. Materials submitted for this study were needle biopsied specimens obtained from 41 chronic carriers and serial paraffin sections were used for the immunohistological study. The localization of HBeAga/b antigens was limited in hepatocellular nuclei, and hepatocellular cytoplasm was HBeAg negative, HBeAg was detected in 11 cases (33%) of 33 cases with chronic active hepatitis (CAH) and in 5 cases (63%) of 8 cases with chronic inactive hepatitis (CIH). Among the HBeAg positive 16 cases, HBeAgb was demonstrated in 15 cases, however, HBeAga was revealed only each one case of CAH and CIH, respectively. Most of HBeAg positive cells were distributed in the peripheral zone of the hepatic lobules while the positive cells were found in central to midzonal zones of 3 cases CAH and one case of CIH. All in histopathologically HBeAga/b positive cases were also HBeAg positive serologically. On the other hand, in HBeAg sero-positive patients, histological positive rate of HBeAga/b was in 33% in CAH and 50% in CIH.