Search

The spectrum of CD30+ cutaneous lymphoproliferative disorders is characterized by the histology of a high-grade lymphoma but frequent clinical regression of skin lesions in lymphomatoid papulosis (LyP) and occasional regression in CD30+ large cell lymphomas (LCLs). A recent study shows that apoptosis may be a significant mechanism of regression of LyP (Arch Dermatol 133:828-833, 1997). Therefore, we studied expression of proteins that induce apoptosis, including CD27, CD40, CD95, and nerve growth factor receptor (NGF-R), as well as anti-apoptotic protein bcl-2 in skin lesions from 25 patients within the spectrum of CD30+ cutaneous lymphoma. Our results show consistent expression of CD95 (APO-1/Fas), but rare or absent expression of CD27, CD40, and NGF-R on tumor cells from both regressing LyP lesions and nonregressing CD30+ lymphomas. Bcl-2 was expressed at low levels in LyP and at high levels in pleomorphic CD30+ lymphomas. These results indicate that, in addition to CD30, CD95 expression is preferentially expressed at high levels in all cutaneous CD30+ lymphomas and suggest that CD95 may play a role in the regression of CD30+ skin lesions. Expression of bcl-2 appears to protect tumor cells from apoptosis in CD30+ lymphoproliferative disorders.

We report a case of primary neuroendocrine carcinoma of the skin (PNECS) mimicking a lymphoepithelioma-like carcinoma of the skin (LELCS) with respect to both cytomorphology and the presence of a dense lymphoplasmacytic stroma. The tumor occurred in the left forearm of a 86-year-old woman, and its history was marked by aggressive behavior, with metastases to lymph nodes and to visceral sites within 1.5 years of diagnosis. The neoplastic epithelial cells had an immunophenotypic profile typical of PNECS, reacting for cytokeratin 20 and other low-molecular weight cytokeratins, neuron-specific enolase, neurofilament protein, synaptophysin, and chromogranin A. In addition, they were immunoreactive for epithelial membrane antigen, carcinoembryonic antigen, and S-100 protein, as observed in LELCS of supposed adnexal differentiation. The tumor-infiltrating lymphocytes were mostly of T-lineage, with a predominance of CD8+ cells. We believe the case is a morphologic variant of PNECS, retaining its aggressive behavior and high metastatic potential, and should not be confused with true LELCS, which has a more favorable outcome. Immunohistochemistry is paramount in establishing the diagnosis. Lymphoid infiltration, even if prominent, does not seem to be of favorable prognostic significance in such a context.

The t(2;5)(p23;q35) translocation associated with CD30-positive anaplastic large cell lymphoma results in the production of a NPM-ALK chimeric protein, consisting of the N-terminal portion of the NPM protein joined to the entire cytoplasmic domain of the neural receptor tyrosine kinase ALK. The ALK gene products were identified in paraffm sections by using a new anti-ALK (cytoplasmic portion) monoclonal antibody (ALKc) that tends to react more strongly than a previously described ALK1 antibody with the nuclei of ALK-expressing tumor cells after microwave heating in 1 mmol/L ethylenediaminetetraacetic acid buffer, pH 8.0. The ALKc monoclonal antibody reacted selectively with 60% of anaplastic large cell lymphoma cases (60 of 100), which occurred mainly in the first three decades of life and consistently displayed a T/null phenotype. This group of ALK-positive tumors showed a wide morphological spectrum including cases with features of anaplastic large cell lymphoma "common" type (75%), "lymphohistiocytic" (10%), "small cell" (8.3%), "giant cell" (3.3%), and "Hodgkin's like" (3.3%). CD30-positive large anaplastic cells expressing the ALK protein both in the cytoplasm and nucleus represented the dominant tumor population in the common, Hodgkin's-like and giant cell types, but they were present at a smaller percentage (often with a perivascular distribution) also in cases with lymphohistiocytic and small cell features. In this study, the ALKc antibody also allowed us to identify small neoplastic cells (usually CD30 negative) with nucleus-restricted ALK positivity that were, by definition, more evident in the small cell variant but were also found in cases with lymphohistiocytic, common, and "Hodgkin's-like" features. These findings, which have not been previously emphasized, strongly suggest that the neoplastic lesion (the NPM-ALK gene) must be present both in the large anaplastic and small tumor cells, and that ALK-positive lymphomas lie on a spectrum, their position being defined by the ratio of small to large neoplastic cells. Notably, about 15% of all ALK-positive lymphomas (usually of the common or giant cell variant) showed a cytoplasm-restricted ALK positivity, which suggests that the ALK gene may have fused with a partner(s) other than NPM. From a diagnostic point of view, detection of the ALK protein was useful in distinguishing anaplastic large cell lymphoma cases of lymphohistiocytic and small cell variants from reactive conditions and other peripheral T-cell lymphoma subtypes, as well as for detecting a small number of tumor cells in lymphohemopoietic tissues. In conclusion, ALK positivity appears to define a clinicopathological entity with a T/null phenotype ("ALK lymphomas"), but one that shows a wider spectrum of morphological patterns than has been appreciated in the past.

Castleman's disease is a rare B cell lymphoproliferative disorder related to excess interleukin-6 (IL-6)-like activity. Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8), which encodes a functional cytokine (vIL-6), has been found in some patients with Castleman's disease. Lymph nodes from 14 HIV-seronegative Castleman's disease patients were compared to hyperplastic lymph nodes from 25 HIV-seronegative patients as well as Kaposi's sarcoma lesions from 48 patients for KSHV infection and vIL-6, human IL-6, and Epstein-Barr virus EBER expression. While all Kaposi's sarcoma tissues examined were polymerase chain reaction-positive and all control lymph nodes were polymerase chain reaction-negative for KSHV, none had detectable vIL-6 expression. Six of 14 (43%) Castleman's tissues were positive for KSHV by polymerase chain reaction and all 6 had evidence of vIL-6 expression by immunohistochemistry. vIL-6-positive Castleman's disease patients generally had the multicentric plasma cell variant form of the disease and had a rapidly fatal clinical course frequently associated with autoimmune hemolytic anemia and gammopathy. In contrast, 7 (88%) of the 8 vIL-6-negative Castleman's disease patients had localized disease and have remained disease-free after therapy. KSHV vIL-6 expression appears to be limited to hematopoietic cells and is not present in Kaposi's sarcoma spindle cells. These data suggest that Castleman's disease is a syndrome of multiple etiologies involving aberrant IL-6 activity from either endogenous or viral sources.

We describe the clinicopathologic features of an unusual case of CD30+/CD50+ T-cell lymphoma in a child who presented with simultaneous primary extranodal cutaneous and bone localizations. The expression of CD56 (neural cell adhesion molecule, or NCAM) is rare in non-Hodgkin's lymphomas other than in a group of haematopoietic/lymphoid neoplasms of natural killer and natural killer-like T-cells, which usually involve extranodal sites and often pursue an aggressive clinical behavior. Coexpression of CD30 and CD56 in T-cell lymphomas is exceedingly rare, and its biological significance is unknown. Our patient responded well to an intensive chemotherapy regimen, and she is now in complete remission 4 years after discontinuation of chemotherapy. Expression of NCAM could be regarded as responsible, in part, for the extranodal localization of lymphoma cells; expression of CD56 also might contribute to the definition of a subset of CD30+ lymphomas with distinctive clinicopathologic features.

We evaluated the presenting clinical characteristics and outcome of 68 patients with nodular lymphocyte predominance Hodgkin's disease (NLP-HD), in order to delineate the pattern of evolution of the disease. The male to female ratio was 46/22 and median age 35 yrs (range, 14-86). Eight patients had a history of benign hyperplasia on lymph node biopsies performed 6 to 36 months before the diagnosis of NLP-HD. Early stage disease accounted for 75% of cases. One patient had a coexistent non-Hodgkin's lymphoma (NHL). Treatment was as follows: radiotherapy in 26, chemotherapy in 23, combined modality in 19. CR rate was 93% (63/68). 18 patients relapsed as HD and 5 developed NHL. The cumulative risk of NHL was 9% at 10 yrs. During remission, 4 patients had 5 episodes of follicular hyperplasia histologically documented. Overall survival rate was 71% at 10 yrs and and 63% at 15 yrs. Freedom from progression (FFP) declined from 67% at 5 yrs to 45% at 10 yrs, because of late relapses. Localized disease predicted for a better FFP (p = 0.01), but was not associated with a reduced risk of recurrence over time. NLP-HD is characterized by an indolent course with a constant pattern of relapse over time, also in patients with early stage disease at diagnosis. In addition to relapse as NLP-HD, patients may evolve into a NHL or develop benign lymph nodal hyperplasia. Careful long-term follow up is needed for these patients.

The present study aimed to investigate the relationship between acute rejection and human cytomegalovirus (HCMV) infection, as well as the coexpression of HLA-DR and immediate-early (IE) viral antigens, in 143 transbronchial biopsies and bronchoalveolar lavage fluids of 32 lung transplant recipients. We investigated the occurrence of morphologically overt viral infection with conventional histopathology, the expression of IE antigens with single labeling immunohistochemistry, the coexpression of IE antigens and HLA-DR molecules with double labeling techniques, and the presence of viral IE genes with polymerase chain reaction. Histopathologic study showed overt viral infections (12.6%) in 18 of the 143 biopsies; 8 were in a context of pneumonia and 10 were localizations without surrounding inflammatory cells; immunohistochemistry showed IE viral antigen expression in 31 (21.67%); PCR detected viral IE genes in 73/143 lavage fluids and biopsies (51%). The double labeling immunohistochemical technique showed that most IE antigen-expressing, noncytopathic cells were either HLA-DR negative in areas without infiltrates, or HLA-DR positive in those areas where inflammatory infiltrates were consistent, in the absence of viral cytopathy, with acute rejection. The results indicate that, in transplanted lung, the frequency of morphologically occult HCMV infection (as detected by immunohistochemically and/or PCR) is much higher than that of morphologically overt viral infection. The occurrence of inflammatory infiltrates (consistent with acute rejection) around morphologically occult infected cells and the possible lack of inflammation around both early- and late-infected cells suggest that in biopsies with occult infection the infiltrates should be attributed to allograft reaction. This conclusion would be in keeping with the coexpression of HLA-DR and HCMV IE in infiltrate-rich biopsies that are consistent with acute rejection, as well as with the absence of HLA-DR expression in IE antigen-positive cells in infiltrate-free-areas.

Sinus histiocytosis with massive lymphadenopathy (SHML), or Rosai-Dorfman disease, is rare histiocytic disorder of known origin which shares several cell markers with Langerhans' cell histiocytosis (LCH). Although Rosai-Dorfman cells exhibit an aberrant immunophenotype, the indolent clinical course of SHML suggests a reactive disorder rather than a neoplastic process. Until recently this was prevailing opinion concerning LCH also, but recent studies have detected clonal histiocytes in all forms of this latter condition, which is therefore considered a clonal neoplastic disorder with highly variable biological behaviour. To determine whether the histiocytic proliferation in SHML is polyclonal or clonal we used X-linked polymorphic loci to assess clonality in lesional tissues in two women. Polymorphic regions of the human androgen receptor (HUMARA) locus were amplified by polymerase chain reaction (PCR) analysis. The HUMARA locus was informative in both cases and, following digestion with methylation-sensitive enzymes, typical polyclonal X-inactivation patterns were observed. Since abnormal cells accounted for > 90% lesional tissue cells, we conclude that Rosai-Dorfman histiocytic proliferation was polyclonal in the women studied.

This report describes a case of a malignant vascular tumor of the spleen with the morphologic, immunologic, and ultrastructural features observed in splenic sinus-lining cells (littoral cells). Histological examination showed a well-differentiated neoplasm forming ectatic blood channels with intraluminal papillary fronds. Tumor cells displayed malignant nuclear features and hemophagocytosis. Solid neoplastic areas with mitotic figures were present. Ultrastructurally, the tumor cells showed the concomitant presence of lysosomes and Weibel-Palade bodies. Immunohistochemically, the tumor cells were positive for both endothelial (Factor VIII-AG, CD34) and histiocytic markers (cathepsin D, lysozyme, alpha-1-antichimotrypsin). Our results indicate that angiosarcoma may originate from all the vascular compartments of the spleen, including red-pulp sinuses, and may have morphologic and immunophenotypic similarities to littoral cell angioma, a recently described benign vascular tumor of the spleen.

Splenic marginal zone (MRZ) cell lymphoma is a recently described neoplasm arising in a unique compartment of splenic white pulp, producing massive splenomegaly and spreading to bone marrow and distant lymph nodes. We report three cases of splenic lymphoma that morphologically and immunohistochemically appear to originate from MRZ cells that presented as indolent neoplasms involving the spleen but with no or only moderate enlargement of the organ, presumably representing an early clinical stage of this disorder. Despite the evidence of involvement of the liver in one case, lymph nodes and bone marrow proved to be uninvolved. Histologically, the three spleens showed similar features, being characterized by the involvement of white pulp follicles and periarteriolar lymphoid sheaths by medium-sized lymphoid cells with slightly irregular nuclei and ample cytoplasm. Immunohistochemically, all the specimens expressed a series of B-lineage markers that, in contrast to specimens of monocytoid B cell lymphoma (MBCL) and hairy cell leukemia (HCL) studied for comparison, did not react with KiB3, LN1, and DBA.44 monoclonal antibodies.

The authors report a single case of primary soft tissue CD30+ non anaplastic non-Hodgkin's lymphoma. The clinical, histological and immunohistochemical features of this peculiar lymphoma type are discussed. Within extranodal lymphomas, a primary soft tissue involvement is rare and the literature lacks exhaustive data on the clinical behaviour of these malignancies. In our case, the prognosis appeared more closely related to the clinical stage of the disease than to histology.

The patient (TAL), a chronic asymptomatic HBV carrier with HBsAg-anti-HBsAg circulating immune complexes, was admitted to our hospital because of a nephrotic syndrome due to renal amyloidosis. There was no family history of hereditary amyloidosis. Recurrent arthralgias, asthenia, and weight loss were the prominent clinical features. Laboratory test results showing that severe chronic inflammatory activity had been present for 6 years. Interleukin-6 (IL-6) serum concentration was 10 times normal and C-reactive protein was 1.9 mg/ml. A complex immunological picture was also present (immune complex formation, exuberant B-cell reactivity, and decrease in the number of CD4 T cells). A localized form of Castleman's disease (CD) (plasma-cell type) was diagnosed by surgical excision of a giant axillary lymph node. AA amyloid was present in the blood vessels. Within 60 days after excision of the mass, the systemic symptoms subsided, laboratory signs of inflammatory activity disappeared and IL-6 serum concentration returned to normal, thus establishing a causal relationship between the localized Castleman's disease, elevated IL-6 concentration and the chronic inflammation responsible for AA amyloidosis. At 10 months of follow-up, the nephrotic syndrome has reversed, kidney function has slowly ameliorated, and the patient has gained 12 kg. Abdominal fat aspirates drawn to search for amyloid, positive before surgery, were subsequently negative. The latter finding, and the remission of the nephrotic syndrome, provided strong evidence for regression of the amyloid deposits. However, the HBsAg-anti-HBsAg immune complexes and depression of T-helper cell activity persist. This immunological derangement is therefore not a consequence of CD. Chronic stimulation of the immune system due to the patient's inability to eliminate HBV, in the contest of perturbed immunity, may have favored the genesis of the lymphadenopathy.

Nosological classification of sinus histiocytosis with massive lymphadenopathy (SHML; Rosai-Dorfman disease) is difficult, and the normal cellular counterpart of Rosai-Dorfman (RD) cells is uncharacterised. The peculiar S-100+ phenotype of RD cells suggests a relationship with the dendritic cell family. Recent investigations have revealed cathepsin E to be selectively concentrated in antigen-presenting cells, whereas cathepsin D was found to be expressed in cells of macrophage lineage. Cathepsin D and E distribution was investigated by immunohistochemistry in a series of SHML biopsies and in two types of dendritic cell proliferative lesions: dermatopathic lymphadenitis (DL) and Langerhans' cell histiocytosis (LCH). In SHML biopsies, RD cells and monocyte-related elements of the sinuses and pulp coexpressed cathepsin D and E. LCH cells also stained for both these aspartic proteinases. Conversely, in DL cathepsin E and D were localised to separate cells that resembled Langerhans' cells (LC) or macrophages, respectively, in morphology and distribution. Our data outline the peculiar immunophenotype of RD and LCH cells and suggest that caution should be exercised in the identification of their normal cellular counterpart. The common expression of cathepsin D and E and of S-100 protein suggests some phenotypic overlap between SHML and LCH cells, despite their striking morphological divergence.

The authors describe two cases of malignant non-Hodgkin's lymphoma in a mammary site observed at IRCCS Policlinico San Matteo (Pavia). Histologic, immunohistochemical and clinical features are illustrated. Correct diagnosis is essential so that appropriate multidisciplinary treatment may be applied.

A specific rabbit anti-human cathepsin E serum detected this aspartic proteinase in Langerhans cells of the skin, in interdigitating reticulum cells of lymph nodes and spleen and in histiocytosis X cells, but not in macrophages. Immunoblotting of tissue extracts confirmed the presence of cathepsin E in skin and lymph nodes. Electron immunocytochemistry with the protein A gold technique localized cathepsin E in the endoplasmic reticulum and in endosomal vesicles of both interdigitating and Langerhans cells, likely involving Birbeck bodies. A role of endosomal cathepsin E in antigen processing is suggested.

Histochemical and immunohistochemical studies performed in only a few cases of sinus histiocytosis with massive lymphoadenopathy (SHML) indicated that SHML cells belong to the macrophage--histiocyte system, though their exact origin is still uncertain. We analyzed the morphological, antigenic and enzymatic characteristics of the histiocyte-like cells in one paediatric case of SHML (also named Rosai-Dorfman disease). The SHML cells expressed the S-100 protein, lectins concanavalin A, peanut agglutinin and monocyte-macrophage related antigens CD 11c, CD 14, CD 33, CD 68 and LN 5. Reactivity with other anti-macrophage antibodies (MAC387, lysozyme, alpha-1 anti-chymotrypsin) was variable. The CD1a antigen was present only in scattered cells, whereas HLA-DR and the HLA-DR associated invariant chain were absent. Cytochemistry demonstrated an intense activity of acid phosphatase and non specific esterase of SHML cells. A large amount of medium sized mononuclear cells were located in the sinuses and intersinusoidal tissue. Our findings suggest that SHML cells have intermediate features between phagocytes and Langerhans cells/interdigitating reticulum cells. The heterogeneity of marker expression on SHML cells might be related to the local content of factors (e.g., cytokines), capable of modulating the phenotype of monocyted and derived cells.

Background: Inflammatory cytokines released by either the neoplastic or reactive cells in Hodgkin's disease (HD) might mediate its peculiar clinical and histopathological features. We investigated by Northern blotting the gene expressions of the pyrogenic and inflammation-associated cytokines IL-1 alpha, IL-1 beta, TNF-alpha, TNF-beta (lymphotoxin) and IL-6 in 14 HD lymph nodes and studied their relation to systemic symptoms (B symptoms)., Methods: Two ug of poly(A)+RNA from 14 HD lymph nodes (8 from symptomatic and 6 from asymptomatic patients, of different histological type and disease stage) were subjected to agarose electrophoresis, Northern blotted and hybridized to the various cytokine cDNA probes., Results: The inflammatory cytokines were expressed very heterogenously in HD, even in lymph nodes with the same histological type and with similar stromal inflammatory reactions. IL-1 beta was increased about 2 to 10 times in 5 of 8 lymph nodes from patients with B symptoms, whereas the other cytokines were heterogenously expressed in both symptomatic and asymptomatic patients. Statistical analysis on densitometric values demonstrated that the difference in IL-1 beta expression between symptomatic and asymptomatic patients was significant (p less than 0.02)., Conclusions: These results support the hypothesis of increased IL-1 levels in tumoral lymph nodes from symptomatic HD patients.

Composite lymphomas have rarely been reported in Hodgkin's disease (HD), except in the lymphocyte predominance sub-type, and immunohistochemical investigations have been performed in only few cases. We describe the histological and immunophenotypical findings in a case of composite nodular sclerosing HD and high-grade, large cell non-Hodgkin's lymphoma (NHL). In our case HD and NHL cells displayed striking morphological and immunophenotypical divergence, suggesting a lack of correlation between the two neoplasms.

We report the case of an 8-year-old child presenting with the pathological fracture of two vertebral bodies due to bone lytic lesions. Physical and instrumental examinations did not show any further evidence of disease. However, bone marrow aspirate showed an infiltrate of poorly differentiated cells. When the child was transferred to the Department of Pediatrics, lymphoblastic leukemia was suspected. Although the morphology of the bone marrow biopsy could have suggested a lymphoblastic lymphoma, further immunochemical and immunological studies together with the study of tissue surface antigens resulted in a diagnosis of embryonal rhabdomyosarcoma with an unusual presentation.

In this report we analyze the morphological and immunohistochemical findings observed in 5 cases of CD30/Ki-1 positive anaplastic large cell lymphoma, a recently recognized neoplastic entity. In comparison with the Ki-1 lymphomas so far described, these cases showed a fairly large number of Reed-Sternberg-like cells, often admixed with small lymphocytes and occasional eosinophils. Moreover, in all our cases immunohistochemical reactions detected the CD15/Leu-M1 antigen, together with markers of the T-lineage and of lymphoid activation. In previous studies the CD15/Leu-M1 antigen has been found in the majority of cases of Hodgkin's disease, but has been stated to be absent typically in Ki-1 lymphomas. Our results indicate that this antigen cannot be considered a reliable tool to distinguish between Ki-1 lymphomas and Hodgkin's disease. Furthermore, the morphological and immunohistochemical findings reported suggest that in some cases Ki-1 cell lymphoma and Hodgkin's disease may be closely related. They may represent different steps in the progression of the same lymphoproliferative disorder.

We describe an immunohistochemical technique adapted to tissues embedded in glycol-methacrylate (GMA). 1-micron-thick GMA sections from kidney, lymph node and bone marrow biopsies were trypsinized and then incubated with F(ab)2 antisera. GMA sections presented some distinct advantages with respect to compared paraffin and cryostatic sections: (1) reduction of background fluorescence, (2) higher resolution of morphologic details, (3) possibility of studying undecalcified bone marrow specimens and (4) possibility of coupling histochemistry with immunofluorescence on consecutive sections. Moreover, in a case of lymphoplasmacytoid lymphoma specific immunostaining for membrane IgM was obtained on GMA sections.

A case of well differentiated endometrial adenocarcinoma in a 70 year-old patient is reported, which evolved to undifferentiated small cell after being treated with chemotherapy for six months. The possible mechanisms of dedifferentiation are briefly discussed.

A case of large cell lymphoma presenting with hemophagocytic syndrome is reported. The clinicopathological findings suggested a diagnosis of malignant histiocytosis, but on the basis of immunohistological studies Ki-l lymphoma was diagnosed. Neoplastic cells expressed activation antigens such as HLA-DR, IL 2R, T10 and Ki-l, and showed high proliferative activity, but were devoid of T and B cell markers. The high percentage of reactive macrophages found in the bone marrow and lymph node probably reflected the release of lymphokines by the tumor population. The patient was treated with aggressive chemotherapy and is in complete remission at 8 months from diagnosis.

In this report we describe a case of granulocytic sarcoma (GS) developing in a patient after 66 months in complete remission of acute nonlymphoid leukemia. The granulocytic precursor cell proliferation arose simultaneously in two extramedullary sites (testis and small bowel), without evidence of bone marrow relapse. The intensive systemic chemotherapy with high-dose ARA-C allowed a clinical remission, lasting 8 months. GS eventually recurred as extramedullary multi-site disease (abdominal lymph nodes, central nervous system involvement), once again unassociated with blood and bone marrow relapse. Both, at onset and in relapse, special staining techniques on tissue sections (chloroacetate esterase) and immunohistochemical typing with monoclonal antibodies were necessary for a correct diagnosis. We discuss the relationship between systemic leukemia and the GS which showed a metastasizing tumor-like behavior.