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Lymphoproliferative neoplasms of uncertain biological significance are increasingly encountered due to widespread usage of immunophenotypic and molecular techniques. Considering that clearer biological criteria and patient management have been established for B-cell lymphoproliferative diseases of undetermined significance occurring in the peripheral blood, many issues are still obscure for early lesions detected in lymphoid tissues. Regardless that some categories of lymphoproliferative neoplasms of uncertain biological significance have been recognized by the 4th edition of the WHO, other anecdotal early lymphoproliferative lesions still remain fully undefined. Some early lesions frequently originate from the germinal center, including atypical germinal centers BCL2-negative, an early pattern of large B-cell lymphoma with IRF4 rearrangement, and “in situ” high-grade B lymphomas. Moreover, other early lymphoproliferative lesions arise outside the germinal center and include those developing within the setting of monocytoid B-cell hyperplasia, but they also can be directly or indirectly associated with chronic inflammations. This review aims to summarize the concepts discussed during the IV Workshop organized by the Italian Group of Hematopathology, focus on the state-of-the-art on B-cell lymphoproliferative neoplasms of uncertain biological significance, and offer operative insights to pathologists and clinicians in routine diagnostics.

We analyzed the clinicopathological, immunohistochemical and cytogenetic features of 106 extranodal (EN) diffuse large B-cell lymphomas (DLBCLs) from stomach (34 cases), intestine (10), cervico-cephalic region (11), central nervous system (13), testes (21), skin (8), and miscellaneous sites (9). Hans’ algorithm and the immunohistochemical double expressor score (DES) for MYC and BCL2 were applied to all cases. A subset of fifty-eight cases were analyzed with fluorescent in situ hybridization (FISH) with specific break apart probes for BCL6, MYC, BCL2, CCND1, BCL10 and MALT1 genes. Clinical records were available for all patients. The immunohistochemical study showed that, in our series of EN-DLBCLs, the Hans’ subgroup and the DES differed significantly according to the site of origin. At FISH analysis, BCL6 and BCL2 were the most commonly rearranged genes in non-GC and in GC cases, respectively. Gastrointestinal lymphomas displayed the highest rate of gene rearrangements, often with MYC involvement. One testicular DLBCL showed BCL2/MYC double hit. At survival analysis, cerebral and testicular origin was associated with poor prognosis. In addition, Hans’ subgroup and other immunohistochemical markers influenced patients’ outcome. In conclusion, our data suggest that immunophenotypic, genetic and survival characteristics of EN-DLBCL are related to the specific primary site of the disease.

Lymphoproliferative disorders (LPDs) rarely involve the endocrine system, either as dissemination of a systemic condition, or as primary diseases. Due to their rarity, LPDs of endocrine organs can represent a diagnostic challenge for both pathologists and clinicians. Nevertheless, a comprehensive review of LPDs arising in endocrine organs reveals several specific clinico-pathological features that can be helpful in the correct management of the cases, from both a diagnostic and a therapeutic point of view. We designed this review with the aim of systematically addressing the morphological, immunohistochemical and genetic characteristic of LPDs of the different endocrine organs. Both lymphomas and mass forming immune cell-based inflammatory diseases, such as IgG4-related lesions, are included in the discussion. In addition, for each primary site, we propose a step-wise diagnostic approach and provide the reader with practical tools to address differential diagnostic and prognostic issues that can be useful to manage such unexpected lesions in daily practice. Finally, endocrine function in lymphoma is discussed.

Primary marginal zone B-cell MALT-type lymphomas of the uterine corpus are exceedingly rare entities, with only 6 cases reported in the literature to date. We present the additional case of a 70-yr-old white woman who underwent a laparoscopic total hysterectomy with bilateral salpingo-oophorectomy for an asymptomatic ovarian cyst. At microscopic examination, endometrial samples showed a dense, nodular lymphocytic infiltrate, suggestive of a lymphoproliferative disorder. Morphology, immunohistochemistry, and molecular analysis supported the diagnosis of MALT-type lymphoma of the endometrium. Benign reactive conditions, such as endometritis and other small B-cell lymphomas were ruled out. Moreover, we investigated the pathogenesis of our case, focusing on Chlamydia trachomatis infection, chromosomal translocations affecting the NF-kB pathway, and discussing the role of autoimmunity in the development of MALT-type lymphomas.

Composite follicular lymphoma (FL) and mantle cell lymphoma (MCL) is rare and not fully characterized from a genetic and clinicopathological point of view. We report a composite lymphoma (CL) in which a G1-2 FL was associated with an in situ mantle cell neoplasia (ISMCN) and a mantle zone growth pattern (MZGP) MCL, followed-up for six years after the first diagnosis, until the exitus of the patient. We performed a comprehensive immunohistochemical study and a detailed cytogenetic analysis, including conventional karyotyping, SKY FISH, FISH on metaphases and interphasic separated nuclei, and FISH on histological sections. The study was completed by the review of the 13 published composite FL and MCL. Our results show that this entity generally behaves like an indolent lymphoma, with the outcome of patients driven by the progression of the FL component. The MCL component generally does not evolve in an aggressive disease. Indeed, half of the cases present exclusively ISMCN. In our case, mantle cell neoplasia at diagnosis was represented by ISMCN and MZGP MCL and it was characterized by a simple karyotype, with t(11;14) as the sole cytogenetic abnormality. This cytogenetic aspect well correlates with the indolent behavior of the mantle cell component. Conversely, the complex karyotype of the FL component was associated with disseminated disease that influenced patient's outcome. Finally, we suggest that not only ISMCN, but also isolated MZGP MCL, may be considered as lesions with low potential of transformation in an aggressive MCL.

Both EBV+ and MSI gastric cancers (GCs) have high lymphoid infiltration which is rare in MSS/EBV− cancers. PD-L1/PD-1 interaction leads to a down-regulated immune response and it is one of the most promising targets for gastric cancer immunotherapy. PD-L1/PD-1 and CD8 expression were immunohistochemically investigated in a series of 169 FFPE GCs, including 33 EBV+, 59 MSI and 77 MSS/EBV− cases. PD-L1 membrane immunoreactivity in more than 5% of tumor cells was present in 31/169 GCs and was associated with high levels of CD8 intraepithelial lymphocytes (TILs; p < 0.001). PD-L1+ cases were mainly poorly differentiated (71%), intestinal type (85%) and high lymphoid response (HLR; 90%) tumors. PD-L1 expression was only present in EBV⁺ (46%), MSI (24%) and rare MSS/EBV− (3%) GCs with high CD8+ TILs (p < 0.001). Despite being associated with a better prognosis both in the whole series (p < 0.05) and in the MSI subset, PD-L1 is not an independent prognostic factor. PD-L1 gene amplification was detected in 3/17 cases, including 2/7 EBV+ and 1/8 MSI GC. PD-1⁺ TILs were significantly higher in EBV⁺ than MSI and MSS/EBV− cases. PD-L1/PD-1 pathway is selectively activated in HLR GCs and could be considered an emerging therapeutic target, particularly for EBV and MSI GCs.

Objective To investigate different treatment strategies for primary early-stage (pT1-T2) sinonasal adenocarcinomas. Methods Retrospective case-control study. From 2000 to 2011, 61 cases were radically resected using an endoscopic endonasal approach. Surgery as a single treatment modality was adopted for 33 patients (study group) while it was followed by postoperative radiotherapy (poRT) in 28 patients (control group). Results Median follow-up was 61 and 67 months for the study and control group respectively. Patients were stratified according to the pT classification and no statistically significant differences were found in terms of Overall (OS) and Recurrence-free (RFS) survival. When analyzing the high-grade tumors (47 cases), statistically significant differences were observed between the control and study groups both in terms of OS (90.5% ± 6.5% versus 57.6% ± 15.4%, P = 0.03) and RFS (92.3% ± 7.39% versus 80.2% ± 8.88%, P = 0.05). Using multivariate analysis, OS was independently determined by poRT (Hazard Ratio = 0.16; P = 0.03) thus confirming its protective role for high-grade adenocarcinomas. Conclusion Our preliminary results suggest that endoscopic endonasal surgery could be used as a single treatment modality for primary early-stage low-grade sinonasal adenocarcinoma, resected with negative margins. Surgery followed by poRT offers the best treatment strategy not only for advanced-stage lesions but also for high-grade adenocarcinomas, regardless of the stage of disease at presentation. J. Surg. Oncol. 2015; 112:561–567. © 2015 Wiley Periodicals, Inc.

Primary testicular (PT) lymphoma accounts for about 1–2% of all non-Hodgkin lymphomas. Albeit rare, this is the most common testicular malignancy occurring in men aged 60 or over. The dominant hist...

ACTH-producing pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms, accounting for a minority of all PanNETs. Nevertheless, they are one of the leading non-pulmonary causes of the so-called ectopic ACTH-dependent Cushing’s syndrome (ECS). The first ECS-associated PanNET was described in 1950 by Del Castillo and coworkers. Since then, less than 150 cases have been reported in the English literature.

Histopathologic diagnosis: Merkel cell carcinoma (MCC) with infiltration of small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL). Microscopically, the punch biopsy showed an intact epidermis overlying a dense, diffuse proliferation of uniform, medium-sized cells infiltrating the whole thickness of the dermis and extended into the subcutaneous fat tissue. Neoplastic cells had scant cytoplasm and round nuclei with distinct membranes, finely dispersed chromatin, and inconspicuous nucleoli (Fig. 1a). The mean number of mitotic figures per high power fields was 67. A second population of neoplastic cells was observed in the superficial dermis, along the cutaneous adnexa, and around the hypodermal neoplastic infiltration. This population was composed of small cells with round nuclei, condensed chromatin, and a small amount of cytoplasm. Mitotic figures were absent in this component (Fig. 1b). On the basis of the clinical history of the patient, immunohistochemical stains for CD20, CD5, and CD23 were performed and a strong positivity was observed in the small cell component, consistent with CLL. In contrast, all the mediumsized cells were negative for CD20, CD5, and CD23 as well as for other lymphoid markers (CD3, CD10, Bcl6, and IRF4/MUM1). Considering the cutaneous site and the cell morpho logy, immunos ta ins for cy tokera t in 20 , synaptophysin, and chromogranin A were performed. All markers were strongly positive in the medium-sized cells whereas they were lacking in the lymphoid component. TTF-1 expression was not observed in either component. A MCC was diagnosed and the Merkel cell polyomavirus, detected with the antibody anti-MCPyV, was found to be present in the MCC cells. However, it was absent in the lymphocytic infiltrate (Fig. 2). The Ki67 proliferative index was low (about 5 %) in the lymphoid component, whereas it was about 90 % in the non-lymphoid neoplastic cells (Fig. 3).

Metastases to the pituitary occur more frequently in patients with widespread cancer and mainly involve the posterior lobe. A few cases of metastatic carcinoma to a pituitary adenoma have been described so far. Here, the authors present an additional case of a clear cell renal cell carcinoma (CCRCC) metastatic to a FSH/LH/α-subunit pituitary adenoma and systematically review the literature. Immunohistochemistry and electron microscopy were performed to characterize both neoplastic components at the morphological level. Moreover, it was hypothesized that expression of VEGF and of the corresponding receptor VEGFR1 could be implicated in the development of the carcinomatous metastasis within the adenoma.