Tumors derived from histiocytic and dendritic cells encompass a large and heterogeneous group of neoplastic and reactive conditions, and their diagnosis is challenging both for pathologists and clinicians. Diagnosis is based on morphological and phenotypical findings, but hybrid features are not uncommon. Furthermore, recent studies uncovered the molecular mechanisms driving some of these tumors, improving diagnostic adequacy, and providing the basis for effective therapeutic breakthroughs.Sixty-seven cases were submitted to the accessory cell and histiocytic neoplasms session at the European Association of Haematopathology/Society for Hematopathology workshop 2016 held in Basel, Switzerland. The cases included histiocytic sarcomas (HS), Langerhans cell tumors (LCT), Erdheim-Chester disease, interdigitating dendritic cell sarcomas (IDCS), indeterminate dendritic cell tumors (IND-DCT), follicular dendritic cell sarcomas, and blastic plasmacytoid dendritic cell neoplasms. Rosai-Dorfman disease and, more rare, conditions such as ALK-positive histiocytosis were also submitted. These cases illustrated classical and unexpected features at morphological, phenotypical, and molecular levels, providing a valuable compendium for pathologists confronting with these tumors.The paper summarizes the most notable features of every single group of diseases, with comments about the most challenging issues, in the attempt to provide practical indications for their recognition.

The identification of metastatic cells in serous effusions has prognostic and therapeutic implications, thus leading to a continuous search for improvement of the existing diagnostic procedures, including immunocytochemistry. To evaluate the usefulness of an antibody recognizing the tight junction-associated protein Claudin 4 in detecting metastatic tumor cells and in the differential with reactive and neoplastic mesothelium, we stained 345 cases of benign and neoplastic serous effusions obtained from pleura, peritoneum, and pericardium. Two-hundred and twenty-eight of 230 cases (99.1%) of epithelial metastasis of different origin were strongly stained by anti-Claudin 4, whereas all cases of reactive mesothelitis (78) and malignant mesothelioma (37) were negative. With the exception of a single case of ovarian carcinoma hypercalcemic-type, all tumors originating from the anatomical sites that most frequently metastasize to the serosae, including lung (61), breast (23), female genital tract (67), gastrointestinal tract (27), and peritoneum (6), were found to be positive. Claudin 4 was also extremely useful in detecting single-tumor cells dispersed among heavy inflammatory reaction. Because of its high sensitivity (99.1%) and specificity (100%), Claudin 4 might be used as an ideal "single-shot" marker for the identification of metastatic epithelial cells in serous effusions.

Summary Follicular dendritic cells (FDC) are mesenchymal-derived dendritic cells located in B-follicles where they play a pivotal role in triggering and maintaining B-cell adaptive immune response. In 1986 Dr. Juan Rosai first reported a series of neoplasms showing features of FDC and defined it as Follicular Dendritic Cell Tumor, subsequently renamed as “sarcoma” (FDCS). In its seminal and subsequent articles Rosai and colleagues highlighted the heterogeneous microscopic appearance of FDCS and its immunohistochemical and ultrastructural features. FDCS mostly occurs in extranodal sites (79.4% of cases) and lymph nodes (15.1%); in about 7%-10% of cases it is associated with hyaline-vascular Castleman disease. Given its significant growth pattern and cytological variability, FDCS can be confused with various neoplasms and even inflammatory processes. The diagnosis requires the use of a broad spectrum of FDC markers (e.g. CD21, CD23, CD35, clusterin, CXCL13, podoplanin), particularly considering that tumor antigen-loss is frequent. The inflammatory-pseudotumor-like (IPT-like) variant of FDCS, in addition to its peculiar histopathological and clinical features, is characterized by positivity of tumor cells for Epstein-Barr virus, representing a diagnostic requisite. No distinctive genetic and molecular anomalies have been identified in FDCS. It often carries an aberrant clonal karyotype and chromosomal structural alterations, frequently involving onco-suppressor genes. Direct or next generation sequencing showed alterations on genes belonging to the NF-κB regulatory pathway and cell-cycle regulators. In contrast to hematopoietic-derived histiocytic and dendritic cells tumors, FDCS typically lacks mutations in genes related to the MAPK pathway. FDCS recurs locally in 28% and metastasizes in 27% of cases. Extent of the disease, surgical resectability and histopathological features are significantly associated with the outcome. IPT-like FDCS behaves as an indolent tumor, even if it often recurs locally over years. Complete surgical excision is the gold standard of treatment. Data on targeted therapies (e.g.: tyrosine kinase inhibitors) or immune checkpoint inhibitors are very limited and responses are variable. A better understanding of the molecular drivers of this tumor may lead to potential new therapeutic strategies.

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This article reports the clinical and the histological features in a 7-year-old girl affected by common variable immunodeficiency (CVID) who developed multiple Epstein-Barr virus-associated tumors, represented by bilateral adrenal smooth muscle tumors (EBV-SMT) and multifocal diffuse large B-cell lymphoma. The EBV-SMTs showed features compatible with a benign or at least a low-malignant potential neoplasm. A peculiar feature observed in both EBV-SMTs was the occurrence of numerous lymphocytes intermingled with the spindle cells, which consisted of CD3+ CD5+ T-cells, with a predominant cytotoxic CD8+ component. Interestingly, EBV status differed in the neoplasms, since the EBV-SMTs were negative for LMP1 and positive for EBER, whereas the B-cell lymphoma expressed both EBV markers. Furthermore, EBV-LMP1 deletion was positive only in the EBV-SMTs, thus indicating that these tumors were the consequence of 2 distinct, EBV-dependent transformations. Similarly, lymphocyte clonality assay also showed different clonal bands in different sites (skin and nasal cavity), suggesting the development of intratumoral mutations. Finally, the authors review all 127 previously reported EBV-SMT, with discussion of their clinical and pathological features.