Subcutaneous 'lipoma-like' B-cell lymphoma associated with HCV infection: a new presentation of primary extranodal marginal zone B-cell lymphoma of MALT.

BACKGROUND: Hepatitis C virus (HCV) infection has been linked to lymphoproliferative disorders. Marginal zone B-cell lymphoma (MZL) represents one of the most frequent lymphoma subtypes associated with HCV infection. We describe an unusual subset of HCV-associated MZL characterized by subcutaneous presentation. MATERIALS AND METHODS: A series of 12 HCV-positive patients presenting with subcutaneous nodules that revealed lymphoma infiltration at biopsy. Molecular analysis of immunoglobulin heavy chain (IGH) gene rearrangement and FISH investigations for t(11;18)(q21;q21) and t(14;18)(q32;q21) were carried out in nine patients. RESULTS: The 12 patients (median age 69.5 years), all with positive HCV serology, presented with single or multiple subcutaneous nodules resembling lipomas. Histologically the lesions showed lymphoid infiltrates, consistent with extranodal MZL of mucosa-associated lymphoid tissue (MALT). Functional IGH gene rearrangements were identified in nine tested patients, with somatic mutations in 82%, indicating a histogenesis from germinal center-experienced B cells. The t(11;18) was found in two of nine cases. Staging did not show any other lymphoma localization. In two patients, a response was achieved with antiviral treatment. Extracutaneous spread to MALT sites occurred in a case. CONCLUSIONS: Our observations expand the spectrum of HCV-associated lymphomas to include a subset of extranodal MZL characterized by a novel primary 'lipoma-like' subcutaneous presentation and indolent clinical course.

Bone marrow histology in marginal zone B-cell lymphomas: correlation with clinical parameters and flow cytometry in 120 patients.

BACKGROUND: Among marginal zone lymphomas (MZLs), bone marrow (BM) involvement features are well established in the splenic marginal zone lymphoma (SMZL); few data are available for extranodal marginal zone lymphoma (EMZL) and nodal marginal zone lymphoma (NMZL). PATIENTS AND METHODS: Incidence and patterns of histologic BM involvement are studied in 120 MZL patients (48 SMZL, 59 EMZL, 13 NMZL) at onset and during follow-up; relationships between clinical features, BM histology and flow cytometry (FC) are analyzed. RESULTS: At diagnosis, BM involvement occurs in 90% SMZL, 22% EMZL and 54% NMZL (P<0.0001); at reevaluation, incidence raises to 96% in SMZL and 34% in EMZL. Concordance between histology and FC is found in 87% of cases; most discordant cases have positive histology but negative FC. SMZL and EMZL show a nodular BM infiltration; the interstitial pattern is frequent in NMZL (P<0.0001); sinusoidal localization is typical of SMZL, frequent in NMZL and occasional in EMZL (P=0.0001). Stage, leukemic disease, B symptoms, more than one extranodal involved site, splenomegaly, elevated beta2-microglobulin, serum monoclonal component, International Prognostic Index (IPI) and age-adjusted IPI are directly related to BM infiltration. CONCLUSIONS: The different prevalence of BM involvement in MZL subtypes reflects their heterogeneous dissemination modalities; histology seems more sensible than FC to detect BM infiltration; development of BM involvement during follow-up is typical of EMZL.

[Molecular biology, basic research and diagnosis of Hirschsprung's disease]. / Molekularbiologie, Grundlagenforschung und Diagnose des Morbus Hirschsprung.

The proto-oncogene RET is the major gene responsible for Hirschsprung's disease (HSCR), with RET mutations also implied in different pathologies. A variety of mutations of the RET proto-oncogene have been detected in HSCR patients. Special attention should be paid to rare patients who carry mutations of one of the critical cysteine residues of these exons, known to predispose to MEN2A. In these cases, HSCR can be associated with the development of neuroendocrine tumors such as medullary thyroid carcinoma (MTC) or MEN2A, for which a prophylactic thyroidectomy is advisable in the presence of a tumor causing RET mutation. In combined MEN2A/HSCR families, RET gene testing, tumor screening and prophylactic thyroidectomy are indicated as in MEN2A. The multigenic origin of HSCR and the absence of a "standard" RET mutation associated with HSCR currently make a routine molecular diagnosis impossible.

[The Haemolymphopathology Italian Group (H.I.G.): an essential resource for the new technical and organization problems troubling modern haemolymphopathology diagnostics]. / II Gruppo Italiano di Emolinfopatologia (G.I.E.): una esigenza per le nuove e complesse problematiche tecnico-organizzative della moderna diagnostica emolinfopatologica.

Recently, many progresses have been recorded in the molecular and histogenetic characterization of the haematopoietic and lymphoid tumours, resulting in important classifying changes. As a consequence, the exact definition of lymphoma subtype requires an integration between traditional morphologic "expertise" and several bio-functional data obtained from advanced and complex ancillary techniques (immunohistochemistry, molecular biology and cytogenetics). At the same time, the data provided by gene expression profiling studies are going to deeply modify the therapies in haematological cancers. These studies are expected to allow the achievement of single-patient-tailored genic therapy; for this reason it is necessary to get biological samples of good quality. Indeed, while these progresses contribute to highlight the pathologist's diagnostic role, they should make us reflect on the state of the art of the Italian haemolymphopathology diagnostics and on its ability to cope up with the new challanges. The aim of this article is to outline a realistic picture of the present condition, and to explain the reasons for setting up, inside SIAPEC-IAP, the Haemolymphopathology Italian Group (H.I.G.). The purpose of H.I.G. will be twofold: first of all, scheduling of a series of projects so as to the haemolymphopathological diagnostic standardization; secondly, building a national network among all the pathologists involved in this exciting and complex field of the anatomic pathology.

Lymph node reticulum cell neoplasm with progression into cytokeratin-positive interstitial reticulum cell (CIRC) sarcoma: a case study.

AIMS: To detail on sequential biopsies the morphological and immunohistochemical features of a case of primary lymph nodal fibroblastic reticulum cell (FBRC) tumour which progressed into a clinically aggressive cytokeratin-positive interstitial reticulum cell (CIRC) sarcoma. METHODS AND RESULTS: A 70-year-old female underwent surgical excision of an enlarged submandibular lymph node. The nodal architecture was effaced by a neoplastic proliferation of medium to large cells, round to oval to spindle in shape, growing in a storiform pattern. The tumour stained for vimentin, CD68, factor XIIIa, alpha1-antitrypsin, fascin and actin. Dendritic and endothelial cell markers were negative. A diagnosis of FBRC tumour was made by combining pathological and clinical data. The patient received no therapy but 5 months later the tumour relapsed, exhibiting a deceptively pleomorphic cytology, phenotypic changes (strong cytokeratin positivity), intense p53 expression and aggressive clinical course with fatal outcome. In-situ hybridization for Epstein-Barr virus was negative. CONCLUSIONS: We speculate that the morphological changes and p53 expression of the relapsing neoplasm might reflect tumour cell dedifferentiation, in keeping with the aggressive clinical course. The intense p53 expression suggests that this oncoprotein might also play a role in reticulum cell tumorigenesis.

[Stomach lymphomas: minimum diagnostic requirements for gastrointestinal histopathological diagnosis]. / Linfomi gastrici: requisiti diagnostici minimi in diagnostica istopatologica gastrointestinale.

Gastric lymphomas have been the subject of intensive studies in the last years and important progress has been made regarding their etiopathogenesis and therapy. Diagnosis of gastric lymphoma is usually made on bioptic material taken at endoscopy. Histopathologic diagnosis is frequently difficult. This paper summarizes the main diagnostic criteria of this setting. It analyses the morphological, immunohistochemical and molecular features to be considered for the differential diagnosis between: reactive process vs low grade B-cell gastric MALT lymphoma, B-cell MALT lymphoma vs other low grade lymphomas involving the stomach and low grade vs high grade gastric lymphoma. The histopathological aspects of gastric biopsies after antibiotic treatment for Helicobacter pylori eradication and the role of molecular analysis in the follow-up of these patients are also considered.

ALK positive lymphohistiocytic variant of anaplastic large cell lymphoma in an adult.

BACKGROUND AND OBJECTIVES: The lymphohistiocytic (LH) variant of anaplastic large cell lymphoma (ALCL) has, for a long time, been considered typical of children and adolescents. The aim of this study is a detailed characterization of a case of this peculiar ALCL subtype affecting an adult patient. DESIGN AND METHODS: A 36-year old male presented with diffuse adenopathy and systemic symptoms (high fever, anorexia, asthenia); a diagnosis of CD30+/ALK+ ALCL, LH variant, was morphologically suspected and corroborated by immunohistochemistry that was crucial for the definitive diagnosis and subtyping. RESULTS: The neoplastic population consisted of cells highly variable in size and shape but more often isolated and largely obscured by a predominant reactive cellular infiltrate of histiocytes and plasma cells. The lymphoma cells exhibited a null non-B non-T antigenic profile, but reacted strongly for the Ber-H2/CD30, EMA, ALKc anti-TIA-1 monoclonal antibodies. The patient underwent chemotherapy plus bone marrow transplantation and, one year after diagnosis, he is well and in complete remission. INTERPRETATION AND CONCLUSIONS: Our findings provide additional evidence that: a) ALK+ lymphoma represents a single disease with a broad spectrum of morphology; b) clinicians and pathologists should be aware of the possible occurrence of LH variant of ALK+ ALCL also in adults in whom a favorable response to therapy may be expected despite systemic disease and an aggressive clinical presentation.

Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium.

The autosomal dominant, giant-platelet disorders, May-Hegglin anomaly (MHA; MIM 155100), Fechtner syndrome (FTNS; MIM 153640) and Sebastian syndrome (SBS), share the triad of thrombocytopenia, large platelets and characteristic leukocyte inclusions ('Döhle-like' bodies). MHA and SBS can be differentiated by subtle ultrastructural leukocyte inclusion features, whereas FTNS is distinguished by the additional Alport-like clinical features of sensorineural deafness, cataracts and nephritis. The similarities between these platelet disorders and our recent refinement of the MHA (ref. 6) and FTNS (ref. 7) disease loci to an overlapping region of 480 kb on chromosome 22 suggested that all three disorders are allelic. Among the identified candidate genes is the gene encoding nonmuscle myosin heavy chain 9 (MYH9; refs 8-10), which is expressed in platelets and upregulated during granulocyte differentiation. We identified six MYH9 mutations (one nonsense and five missense) in seven unrelated probands from MHA, SBS and FTNS families. On the basis of molecular modelling, the two mutations affecting the myosin head were predicted to impose electrostatic and conformational changes, whereas the truncating mutation deleted the unique carboxy-terminal tailpiece. The remaining missense mutations, all affecting highly conserved coiled-coil domain positions, imparted destabilizing electrostatic and polar changes. Thus, our results suggest that mutations in MYH9 result in three megakaryocyte/platelet/leukocyte syndromes and are important in the pathogenesis of sensorineural deafness, cataracts and nephritis.

Nijmegen breakage syndrome-associated T-cell-rich B-cell lymphoma: case report.

In 1981 Weemaes et al. first described the Nijmegen breakage syndrome (NBS), a rare autosomal recessive disorder characterized by stunted growth, microcephaly, immunodeficiency, spontaneous chromosome instability, and a peculiar predisposition to cancer development. Most NBS-related malignancies are lymphomas, but their pathologic features have rarely been specified. We report here the case of a northern Italian 8-year-old child who, 2 years after the diagnosis of NBS, developed a diffuse large B-cell lymphoma (T cell-rich B-cell lymphoma variant). The histological and immunobiological features of the lymphoma population are analyzed and discussed in detail.

Mediastinal B-cell lymphoma: a study of its histomorphologic spectrum based on 109 cases.

Mediastinal B-cell lymphoma (MBL) is a distinct variant of aggressive non-Hodgkin's lymphoma with characteristic clinical and biological features but less well-defined histomorphology. We reevaluated 124 biopsy specimens from 109 MBL patients of an Italian/French/German retrospective clinical study. MBL was primarily diagnosed on clinical and histological grounds in conjunction with the detection of CD20 expression by immunohistology. Cytologically, MBL features limited intralesional but considerable interindividual cytological diversity, ranging from medium-sized to very large, atypical cells. Sclerosis and necrosis are restricted to extrathymic and extranodal sites of involvement, predominantly the lung, as is angioinvasion, which predominantly affects larger vessels. The medium-sized and the large cell variants resemble marginal zone lymphoma variants, whereas the very large cell variant of MBL has not so far been found to have any extramediastinal counterpart. We conclude that MBL displays a broad morphological spectrum covering more than is implied by the term "diffuse large cell lymphoma." Because statistical analysis of cytological and histological criteria failed to correlate with prognosis in this comprehensive group of patients, we think it inadvisable further to subclassify MBL.

Cutaneous CD30+ lymphoproliferative disorders: expression of bcl-2 and proteins of the tumor necrosis factor receptor superfamily.

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.

ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum.

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.

Thrombocytopenia, giant platelets, and leukocyte inclusion bodies (May-Hegglin anomaly): clinical and laboratory findings.

PURPOSE: May-Hegglin anomaly is a rare hereditary condition characterized by the triad of thrombocytopenia, giant platelets, and inclusion bodies in leukocytes. Clinical features and the pathogenesis of bleeding in this disease are poorly defined. PATIENTS AND METHODS: From 1988 to 1996 we studied 15 new May-Hegglin anomaly patients from 7 unrelated Italian families. In addition to clinical examination and routine laboratory testing, we measured bleeding time, platelet aggregation and release reaction, and platelet staining for tubulin, and performed ultrastructural study of polymorphonuclear leukocytes. RESULTS: Although the mean age of our patients was 33 years, May-Hegglin anomaly had not been previously recognized in any of them. Bleeding diatheses ranged from severe to absent, and platelet count from 26 to 178 x 10(9)/L. No correlation was found between bleeding tendency and platelet count. Previous therapy with corticosteroids, high-dose immunoglobulins, and splenectomy had no effect on platelet count or bleeding diathesis. Desmopressin infusion greatly shortened the bleeding time in the most severely affected patient. The in vitro function of platelets was normal except for the absence of shape change in all subjects and defective response to epinephrine in 8 of 15 patients. Platelet tubulin was distributed unevenly instead of being organized in a circumferential band at the cell periphery. CONCLUSION: The diagnosis of May-Hegglin is easily missed, and its frequency is probably underestimated. A qualitative defect of platelets may be responsible for mild bleeding diathesis even in the absence of thrombocytopenia, while severe bleeding results from both qualitative and quantitative platelet defects. May-Hegglin anomaly should be suspected whenever a patient has a low platelet count or a bleeding diathesis of unknown origin.

Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman's disease.

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.

CD56/neural cell adhesion molecule expression in primary extranodal Ki-1/CD30+ lymphoma. Report of a pediatric case with simultaneous cutaneous and bone localizations.

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.

Nodular lymphocyte predominance Hodgkin's disease: long-term observation reveals a continuous pattern of recurrence.

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.

Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma: a multicenter study of 106 patients.

PURPOSE: To define clinicopathologic features, response to treatment, and prognostic factors of primary mediastinal B-cell lymphoma (MBL), a CD20+ tumor recognized as a distinct entity among non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: One hundred six patients presented with disease confined to thorax (86%), bulky mediastinum (73%), superior vena cava syndrome (47%), and contiguous infiltration (57%). Ninety-nine received doxorubicin-containing chemotherapy (CHT). RESULTS: Thirty-five of 99 patients were primarily CHT-resistant, and 64 responded: 23 achieved complete response (CR) and 41 achieved response with residual mediastinal abnormality. Seventy-seven percent of responders received mediastinal radiotherapy (RT). Of 64 responders, 18 (28%) relapsed: none of 23 CR patients and 18 of 41 (44%) with residual mediastinal abnormality. Relapse-free survival rate of responders was 71% at 3 years. Actuarial 3-year survival rate was 52% for all patients and 82% for responders. Predictive factors of poor outcome were identified by logistic regression; Cox survival analysis was performed on death and relapse. Pericardial effusion (P < .001) and Eastern Cooperative Oncology Group (ECOG) performance status > or = 2 (P = .009) predicted nonresponse (NR) and affected survival. Less than partial midway response to CHT predicted NR to subsequent therapies. Bulky disease was related to persistent mediastinal abnormality and risk of relapse (P = .025). CONCLUSION: MBL is an aggressive NHL with unique clinicopathologic aspects, often refractory to current CHT designed for high-grade NHL. Poor performance status and pericardial effusion predict NR and poor survival. Inadequate response after the first courses of front-line CHT predicts failure of subsequent treatment. Responders with bulky mediastinum or residual mediastinal abnormality after CHT are at risk of relapse. These factors should help to select high-risk patients for intensive treatments.

Primary mediastinal B-cell lymphoma: update of its clinicopathologic features.

The peculiar clinical, histomorphological and biological characteristics of PMBCL are reviewed. Special emphasis is given to the frequent aggressive clinical behaviour of this lymphoma in which conventional prognostic factors seem inadequate to identify high risk cases. The need for new clinical and/or biological prognostic markers is stressed.