ACCME/Disclosures. USCAP Specialty Evening Conference: Cytopathology New and recent Developments in Cytopathology: A case based approach
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1 USCAP Specialty Evening Conference: Cytopathology New and recent Developments in Cytopathology: A case based approach Sara E. Monaco, MD Associate Professor Program Director, UPMC Cytopathology Fellowship Director of FNA Biopsy Service & Clinic, Children s Hospital of Pittsburgh & UPMCShadyside Hospital University of Pittsburgh Medical Center (UPMC) Pittsburgh, PA ACCME/Disclosures The USCAP requires that anyone in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Sara Monaco declares she has no conflict(s) of interest to disclose. Why did Dina choose me? Even out the gender ratio 2 Female : 2 Male Even out the geographical representation 1 West Coast (CA) 1 Mid West (OH) 1 South (TX) 1 Northeast/East Coast (PA) Even out the political party representation 2 Red (TX, OH) : 2 Blue (CA, PA) All the other female cytopathologists from Democratic Northeastern states said NO Whatever the reason, I m honored to be here! Clinical History 40yearold woman with history of inflammatory skin lesions diagnosed 2 years prior, now found to have a 4.6 cm soft tissue mass near the right psoas muscle, and FDGavid sclerotic bone lesions. CTguided FNA and Core biopsy with touch preparation performed of the soft tissue mass.
2 FNA smear, DQ, high power FNA smear, DQ, high power FNA smear, DQ, medium & high power FNA smear, Pap, medium & high power Touch prep, DQ, high power Questions you are thinking.. Is this really all there is? Why is Dr. Monaco showing an unsatisfactory cytology case at USCAP? Did Dr. Monaco go onsite to determine if the FNA was adequate? If she was onsite, why didn t Dr. Monaco ask for a core biopsy?
3 Touch prep, DQ, high power Core Biopsy, H&E, high power Core Biopsy, H&E, high power What type of cells are these? Metastatic Renal Cell Carcinoma Adenocarcinoma Granulomas Benign Pleural Fluid Liposarcoma Granular cell tumor Resolving hematoma Fat necrosis
4 CD68 BRAF VE1 Histiocytic Disorders LCH NonLCH Dendritic cells Role: Ag presentation IHC: S100, CD1a Monocyte/Macrophages Role: Phagocytic cells IHC: CD68, FXIIIa Factor XIIIa CD1a, Langerin, S100, CK Langerhans cells in skin and bronchial epithelium Interdigitating and dendritic reticulum cells in LN and spleen Tissue macrophages Osteoclasts Microglia Kupffer cells Circulating monocytes More Clinical History 40yearold woman with history of single system, cutaneous Langerhans cell histiocytosis diagnosed two years prior to current case (No systemic dz). Then developed multiple papules on her extremity which were found to be BRAF V600E and with different IHC profile, suggestive of a nonlch. Upon imaging for further workup, patient was found to have: FDGavid (SUV= 7.8) calcified thyroid nodule 4.6cm soft tissue mass anteromedial to right psoas muscle at level L5S1 with moderate FDG uptake (SUV=3.8) Multiple mildly FDGavid sclerotic lesions in axial skeleton (L1, sacral ala) measuring 1.7cm in greatest dimension (SUV 2.5) Diffuse hyperdensity of bone marrow in bilateral femur, tibia, and fibula with increased FDG uptake (SUV ) Initial Presentation (LCH) Later Presentation (nonlch) Final Pathological Diagnosis Soft tissue infiltrate, Pelvic, CTguided Fine Needle Aspiration: Less than optimal scant cellularity. Atypical cells present. Atypical histiocytic proliferation. CD1a CD68 Soft tissue infiltrate, Pelvic, CTguided Core Biopsy with TP: Histiocytic proliferation/neoplasm, compatible with ErdheimChester Disease. Langerin BRAF VE1 Langerin BRAF VE1 Johnson WT et al, J Cutan Pathol, 2015
5 Thyroid Nodule in Patient with ECD FNA suspicious for PTC. BRAF V600E Thyroid Nodule in Patient with ECD Histology: PTC with involvement by Histiocytosis Final Impression & Followup Young woman with the following 3 entities (all BRAF V600E ): Cutaneous Langerhans cell histiocytosis Erdheim Chester Disease Papillary thyroid carcinoma Followup: Treated with methotrexate and Imuran (Azathioprine) with partial clinical resolution of skin lesions and bone lesions, but required stenting of ureter due to fibrosis ErdheimChester Disease (ECD) NonLangerhans cell histiocytosis Polyostotic sclerosing histiocytosis Onset: Middle adult age (approximately 50 years of age) Clinical symptoms: Bone pain (most frequent), Back pain, Renal pain/dysfunction, Exophthalmos with yellow bumps on eyelids, problems with coordinated movements, skin lesions Locations: bone, retroperitoneum ( hairy kidney ), & CNS Disease course: Ranges from single system disease (focal lesions, bone only) to multisystemic & fatal disease (multiple visceral organ involvement) Prognosis appears to be worse than other histiocytoses, so important to diagnose ECD: Clinical presentation Osteosclerotic bone lesions Bilateral, symmetrical involvement of long bones metaphysis & diaphysis sparing epiphyses >50% have extraskeletal component kidney, skin, brain, lung Volpicelli ER et al, J Cutan Pathol, 2011 ECD: Historical Aspects First 2 cases of ECD reported by Jakob Erdheim (Austrian pathologist) & William Chester (American pathologist) in 1930 Referred to the disease as a distinctive form of lipoid granulomatosis with bony disease Third case later reported by Dr. Ronald Jaffe (UPMC), who coined the term ECD Fig.: Professor Jakob Erdheim in the Vienna Municipal Hospital Morgue References: Romm S (1987) Jakob Erdheim: Eminent Pathologist of Vienna. American Journal of dermatopathology 9: Professor Jakob Erdheim an eminent Austrian pathologist Beside other complex syndromes, the craniopharyngioma, was originally named after him "Erdheim Tumor".
6 ECD: Cytological Findings Cytology: Lipidladen foamy histiocytes Toutontype giant cells Bland spindle cells/fibrosis No nuclear grooves No eosinophils No Birbeck granules on EM No cytological/nuclear atypia ECD: Histological Findings Histology: Xanthogranulomatous infiltrate Marked fibrosis CD68 Purgina B et al, Cytojournal 2011 ECD: xanthogranulomatous & fibrotic histology ECD: Immunohistochemical Findings Positive IHC: CD68, CD163, Factor XIIIa, fascin (/ S100) Xanthogranuloma phenotype CD163/CD68/CD14/fascin/FXIIIa Negative IHC: CD1a, Langerin, CK (usually S100) IHC of Histiocytic/Dendritic Tumors Tumor LCA CD68 S100 CD21/35 CD1a Other NOTE: Same IHC profile as JXG, but clinical presentation and age differ. RosaiDorfman disease ± Langerhans cell ± ± Langerin (CD207), BRAF VE1 histiocytosis/sarcoma Erdheim Chester Disease ± ± CD163, CD14, Fascin, FXIIIa, BRAF VE1 ECD: Molecular Findings Molecular: BRAF V600E mutations occur in 5769% patients with isolated LCH and in 5482% patients with isolated ECD BRAF Mutation occurs in LCH & ECD Similar molecular signature (activating mutations in MAPK pathway genes) May impact future classification (inflammatory myeloid neoplasms) Mixed Histiocytosis cases do exist: cases with overlap between LCH/ECD No BRAF mutation in other nonlch histiocytosis e.g. RosaiDorfman disease, cutaneous juvenile xanthogranuloma, histiocytic sarcomas, xanthoma disseminatum, interdigitating dendritic cell sarcoma, & necrobiotic xanthogranuloma FDC sarcoma 10% D240, clusterin, EMA IDC sarcoma ± ± Neoplasms that are positive for BRAF V600E Metanephric adenoma of the kidney Papillary craniopharyngioma Pleomorphic xanthoastrocytoma Ameloblastoma Langerhans cell histiocytosis Erdheim Chester Disease Hairy cell leukemiaclassic (Not in HCLvariant) Papillary thyroid carcinoma Colonic adenocarcinoma Malignant Melanoma BRAF Testing IHC (BRAF immunostain VE1) Monoclonal Ab (VE1) to detect mutant BRAF V600E protein expression Faster & cheaper High specificity & sensitivity Pitfall: Heterogeneity in BRAF expression Positive result: strong cytoplasmic staining PCR Sanger Sequencing Next generation sequencing (NGS) BRAF VE1 IHC (control) BRAF VE1 IHC (our case) Busam KJ et al, Am J Surg Pathol 2013
7 ECD: Treatment Cutaneous Treatment aimed at systemic dz Systemic Interferonalpha Systemic chemotherapy Glucocorticoids Radiotherapy Vemurafenib (BRAF inhibitor) Hyman DM et al, NEJM, 2015 ECD & LCH Overlap ( Mixed Histiocytosis ) Age comparison in Histiocytoses: 50s: ECD 40s: Mixed 30s: LCH Rare, but can occur Middle age onset (median age 43 yo) 48% concurrent, 52% present with LCH that develops to ECD Cutaneous lesions: more common in LCH LCH: 40%; plaques ECD: 25%; xanthelasma and reddish papules Bone lesions: bilateral sclerotic bone involvement in ECD (95%) and at least 1 other organ system involved, including retroperitoneal fibrosis Comparison of Systemic Histiocytic Disorders ECD, ECD LCH, RDD LCH RDD Immunoprofile CD68 & CD163 CD1a & Langerin S100 FXIIIa or weakly Histology Touton giant cells Xanthomatous infiltrate Fibrosis Emperipolesis Birbeck granules on EM BRAF V600E mutation Organs affected Long bones (femur, tibia), Perinephric or Retroperitoneal, Xanthelasma or yellow skin plaques Lung, craniofacial bones, scaly erythematous patches on skin Lymphadenopathy, firm papules of skin Diamond EL et al, Blood 2014 ECD: Differential Diagnosis Nondiagnostic/nonspecific findings Nonneoplastic xanthogranulomatous proliferation Fat necrosis Malakoplakia Hemophagocytic syndromes Other Histiocytoses LCH NonLangerhans cell histiocytosis Clear cell type neoplasms (e.g., Metastatic RCC) Sarcoma (e.g., Liposarcoma) Spindle cell proliferation (e.g., Fibromatosis) Langerhans cell histiocytosis
8 Rosai Dorfman Disease CD1a Dendritic Cell Sarcoma Granular Cell Tumor S100 PAS CD21 Images courtesy of Dr. Liron Pantanowitz Xanthogranulomatous Pyelonephritis Malakoplakia Images courtesy of Dr. Walid Khalbuss
9 Atypical Mycobacterial Infection AFB Desmoid type Fibromatosis Actin Beta catenin Take Home Messages Histiocytic lesions/neoplasms can be challenging Correct classification requires correlation with the clinical features Xanthogranulomatous lesions with fibrosis may be scant on FNA/TP or mistaken as normal on nondx findings on CNB The presence of the BRAF V600E mutation in any XGtype lesion should prompt a workup for ECD Utility of ancillary testing Molecular studies or IHC for BRAF mutations or mutated protein Exclude other types of histiocytoses and nonhistiocytic neoplasms (e.g. granular cell tumors & mimics) Diagnostic Challenges Small biopsies and cytology specimens from histiocytic & fibrotic lesions may be a challenge Acquisition Challenges Sampling issues due to focal or patchy disease Need to correlate pathology findings with radiology Interpretation Challenges Be careful not to dismiss findings as NonDx or Negative Need to have suspicion in order to initiate IHC panel Histiocytic markers can be challenging to interpret Cautionary Note Histiocytic markers can be tough to interpret Best to use a panel Metastatic Adenocarcinoma in Pleural Fluid CD68 MOC31 Cautionary Note Don t fight with the radiologist/clinician! There really may be something in the CNB if TP is scant.
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