Download Evening Session- Cytopathology USCAP Annual Meeting 2016 Dr

Evening Session‐ Cytopathology USCAP Annual Meeting 2016 Dr. Sara Monaco Case: Erdheim‐Chester Disease Discussion: Clinical features/background. Erdheim‐Chester Disease (ECD) is a non‐Langerhans cell histiocytosis that is also referred to as polyostotic sclerosing histiocytosis. Patients with this disease typically present between 40‐70 years of age with bone, retroperitoneal or central nervous system disease.[1‐3] Characteristic imaging findings include bilateral sclerotic bone lesions in the femur and tibia of the legs, and the infiltration of retroperitoneal structures with fibrosis. In fact, the retroperitoneal infiltration of perinephric fat can cause the “hairy kidney” appearance on CT imaging.[3] Although it was previously considered a non‐neoplastic inflammatory process, the discovery of the hotspot mutation causing a missense amino acid substitution (Valine replaced by glutamic acid at amino acid 600), referred to as the BRAF V600E mutation, in these lesions has confirmed that it is a clonal proliferation in over 50% cases.[4‐7] Further studies have also found other mutations in ECD, including an NRAS Q61R mutation.[8] Diagnosis of ECD involves incorporation of clinical findings, radiological imaging, and pathological findings. Pathologic features. On histology, these lesions show a xanthogranulomatous infiltrate with marked fibrosis, such that the bland‐appearing histiocytes can be difficult to identify and could potentially be missed as a negative or non‐diagnostic biopsy. The histiocytes include foamy or xanthomatous cells with numerous small vacuoles and Touton‐type giant cells. Touton‐type giant cells show peripherally arranged nuclei in histiocytic cells. The histiocytes do not show nuclear grooves or emperipolesis, which helps to distinguish them from Langerhans cell histiocytosis and Rosai‐Dorfman disease, respectively. In addition, on electron microscopy, these histiocytes do not have Birbeck granules. Given the extensive fibrosis in these lesions and the bland‐appearing nature of the xanthomatous cells, a diagnosis could easily be missed with FNA, unless there is meticulous review for these features in the appropriate clinical setting. On‐site evaluation could also be critical in terms of advocating for a core biopsy if the aspirates show features concerning for ECD without sufficient cellularity. As with most diseases, obtaining sufficiently cellular material for immunohistochemical stains and potential molecular studies is important, whether it be a cell block or core biopsy. With the use of immunostains, these histiocytes have been shown to be positive for CD68, CD163, factor XIIIa, fascin, and sometimes S100. However, the cells are typically negative for CD1a and Langerin (CD207). Of note, the morphological appearance and immunophenotype are essentially identical to juvenile xanthogranuloma, which occurs in the skin. A summary of the immunophenotypic findings in the major histiocytic proliferations is seen in Table 1. (Table 1) On molecular testing, about 57‐69% of these patients will have BRAF V600E mutations, which also occurs in Langerhans cell histiocytosis. In fact, ECD is the only non‐Langerhans cell histiocytosis that is known to be positive for the BRAF V600E mutation.[2‐4] Of note, there is also a BRAF V600E mutant specific antibody (VE1) that targets the mutant protein, and can be used to determine BRAF status. Most studies investigating this antibody have used strong cytoplasmic staining as a positive result.[10] Although it has been shown to be sensitive and specific, there can be heterogeneity in the staining pattern, and thus, the results should be confirmed with molecular testing.[3,9,10] The immunostain could be potentially useful in small biopsies or in biopsies of ECD with extensive fibrosis that have quantitatively few histiocytic cells, which may not be suitable for sequencing studies. Accurate detection of the BRAF mutation (by gene sequencing) or mutated protein (by IHC) is important given the targeted therapies (e.g. vemurafenib, dabrafenib) that are now available and have shown utility in this disease. Table 2 lists a variety of different tumors that have been shown to have a BRAF mutation. (Table 2) Differential diagnosis (Table 3). The differential diagnosis includes other histiocytic and dendritic lesions, such as other histiocytoses and foamy granulomatous inflammation due to atypical mycobacterial infection. Other lesions in the differential diagnosis include lipogenic neoplasms, renal cell carcinoma, or sampling of fibrous tissue and fat near the lesion of interest (e.g. non‐diagnostic biopsy). LCH is usually S100, CD1a, and langerin (CD207) positive, while negative for Factor XIIIa, and typically does not have extensive xanthomatous infiltrate. Morphologically, LCH tends to show more nuclear grooves and will have Birbeck granules on electron microscopy. However, composite disease with features of LCH and ECD has been reported, given the clinical overlap of the two diseases, especially when there is frequent multiorgan involvement, and the fact that both are positive for BRAF V600E mutations. A list of other tumors with BRAF mutations is seen in Table 2. While BRAF mutations are frequently discussed in the setting of common cancers like papillary thyroid carcinoma, melanoma, and colorectal carcinoma, the other diseases on the list are ones that are not as well known. Although Rosai‐Dorfman Disease (RDD) is frequently lumped into the differential diagnosis of LCH and ECD, there are many morphological differences (e.g., emperipolesis) despite some of the immunophenotypic overlap (e.g. S100 positive). Histologically, these lymph nodes show dilated sinuses infiltrated by large macrophages showing emperipolesis, increased plasma cells, and lymphocytes, in addition to pericapsular fibrosis. The disease course is variable, but most patients will have complete spontaneous remission, but rare aggressive cases have been described. Selected references. 1. Picarsic J, Jaffe R. Nosology and Pathology of Langerhans Cell Histiocytosis. Hematol Oncol Clin North Am. 2015;29(5):799‐823. 2. Volpicelli ER, Doyle L, Annes JP, Murray MF, Jacobsen E, Murphy GF, Saavedra AP. Erdheim‐
Chester disease presenting with cutaneous involvement: a case report and literature review. J Cutan Pathol. 2011 ;38(3):280‐5. 3. Diamond EL, Dagna L, Hyman DM, Cavalli G, Janku F, Estrada‐Veras J, Ferrarini M, Abdel‐Wahab O, Heaney ML, Scheel PJ, Feeley NK, Ferrero E, McClain KL, Vaglio A, Colby T, Arnaud L, Haroche J. Consensus guidelines for the diagnosis and clinical management of Erdheim‐Chester disease. Blood. 2014 Jul 24;124(4):483‐92. 4. Badalian‐Very G, Vergilio J‐A, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010;116:1919‐1923. 5. Sahm F, Capper D, Preusser M, et al. BRAF V600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. Blood 2012;120:e28‐e34. 6. Cangi MG, Biavasco R, Cavalli G, et al. BRAF V600E mutation is invariably present and associated to oncogene‐induced senescence in Erdheim‐Chester disease. Ann Rheum Dis 2014. 7. Harmon CM, Brown N.Langerhans Cell Histiocytosis: A Clinicopathologic Review and Molecular Pathogenetic Update. Arch Pathol Lab Med. 2015;139(10):1211‐4. 8. Diamond EL, Abdel‐Wahab O, Pentsova E, et al. Detection of an NRAS mutation in Erdheim‐
Chester disease. Blood 2013;122:1089‐1091. 9. Busam KJ, Hedvat C, Pulitzer M, vonDeimling A, Jungbluth AA. Immunohistochemical analysis of BRAF V600E expression of primary and metastatic melanoma and comparison with mutation status and melanocyte differentiation antigens of metastatic lesions. Am J Surg Pathol 2013;37:413‐420. 10. Pearlstein MV, Zedek DC, Ollila DW et al. Validation of the VE1 immunostain for the BRAF V600E mutation in melanoma. J Cutan Pathol 2014;41:724‐732. Table 1. Immunophenotype of Histiocytic/Dendritic cell tumors Tumor Rosai‐Dorfman disease Langerhans cell histiocytosis/sarcoma Erdheim Chester disease FDC sarcoma LCA + ± CD68 ± ± S100 + + CD21/35 ‐ ‐ CD1a ‐ + ± + ± ‐ ‐ ‐ ‐ 10% + ‐ ‐ ‐ IDC sarcoma ± ± + Table 2. Neoplasms that can be positive for BRAF V600E Metanephric adenoma of the kidney Papillary Craniopharyngioma Pleomorphic xanthoastrocytoma Ameloblastoma Langerhans cell histiocytosis Erdheim‐Chester disease Hairy cell leukemia‐ classic (not HCL‐variant) Papillary thyroid carcinoma Colonic adenocarcinoma Malignant melanoma Table 3. Differential Diagnosis of Histiocytic Lesions on Cytomorphologic Features Non‐neoplastic Cyst contents with foamy or hemosiderin‐laden macrophages Histiocytic or granulomatous inflammation (e.g., xanthogranulomatous pyelonephritis) Reactive myofibroblastic‐type proliferations (e.g., proliferative myositis, nodular fasciitis) Reactive or benign lesions with increased foamy histiocytes. (eg, pigmented villonodular synovitis/PVNS) Neoplastic Neurogenic tumors (eg, schwannoma, neurofibroma) Granular cell tumor Rhabdoid tumor Germ cell tumor (eg, seminoma) with associated lymphohistiocytic inflammation Malignant melanoma, especially spindle cell melanoma or pigmented types with melanophages Clear cell renal cell carcinoma Papillary renal cell carcinoma with increased foamy histiocytes Well‐differentiated adenocarcinoma with mucinous features and muciphages Other Langerin (CD207), VE1 FXIIIa, fascin, CD163, CD14, VE1 D2‐40, clusterin, EMA Sarcomas with histiocytic or adipocytic features (eg, follicular dendritic cell sarcoma or interdigitating dendritic cell sarcoma; liposarcoma)