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Northshore University Health SystemIRAP 2019-2020 OutlineCase #1PRESENTER: Kiran Manjee, MDATTENDINGS: Ajit Paintal, MDCASE History: The patient is a 66 year-old female with past medical history of invasive rectal adenocarcinoma, treated with colectomy and chemotherapy 2 years ago. Complete response was noted. Surveillance imaging and PET scan showed 2.2 cm hypodense lesion in the interpolar region of the left kidney and several enlarged left periaortic nodes. Patient underwent radical nephrectomy.Final Diagnosis:Renal cell carcinoma, unclassified type (uRCC)Differential Diagnosis:Urothelial carcinomaHigh grade renal cortical tumorsClear cell (conventional) renal cell carcinomaPapillary renal cell carcinomaAnaplastic lymphoma kinase rearrangement-associated RCCSuccinate dehydrogenase-deficient RCCXp11 translocation RCCFumarate hydratase-deficient RCCRenal medullary carcinomaCollecting duct carcinomaIntroduction:It is a diagnostic category for tumors that do not readily fit into any recognized subtypes of RCC, including:Tumors with combination of features of > 1 recognized subtype.Unrecognized epithelial cell subtypes.Low or high-grade unclassified oncocytic neoplasms.Renal cell tumors with pure sarcomatoid histology.Molecular Subsets:Molecular analysis of uRCC cases have shown distinct molecular subsets characterized by:NF2-lossHyperactive mTORC1 signalingFumarate hydratase deficiencyChromatin/DNA damage regulator mutationsALK translocationTargetable Pathway:Molecular analysis of uRCC cases have also shown some potential targetable pathways including MTOR, CHEK2 and PRRM1.Prognosis:These molecular subsets are also associated with differential clinical outcomes: mTORC subsets associated with a better clinical outcome.FH cohort associated with the worst clinical outcome.NF2-loss associated cases shows poor outcome.References:Chen, Y. B.?et al.?Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets.?Nat. Commun.2016;7:13131.Sirohi D, Smith SC, Agarwal N, Maughan BL. Unclassified renal cell carcinoma: diagnostic difficulties and treatment modalities.?Res Rep Urol. 2018;10:205–217.Perrino CM, Grignon DJ, Williamson SR, Idrees MT, Eble JN, Cheng L. Morphological spectrum of renal cell carcinoma, unclassified: an analysis of 136 cases. Histopathology. 2018;72(2):305–319Trpkov K, Hes O. New and emerging renal entities: a perspective post-WHO 2016 classification. Histopathology. 2019:74;31–59.Kryvenko ON, Jorda M, Argani P, Epstein JI. Diagnostic approach to eosinophilic renal neoplasms.?Arch Pathol Lab Med.?2014;138(11):1531–1541.Case #2PRESENTER: Haytham Hasan, M.D.ATTENDINGS: James Padgett, M.D.CASE HISTORY: A 34 year old female with a history of common variable immune deficiency (CVID) and recurrent pneumonias was referred to our institution for evaluation of multiple bilateral lung nodules seen on chest CT. She currently denies shortness of breath, cough, fever, or chills. She then underwent surgical lung wedge biopsies of the left upper lobe and left lower lobe.DIAGNOSIS: Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD)DIFFERENTIAL DIAGNOSIS: Infections (e.g. mycobacteria and fungi), Lymphocytic Interstitial Pneumonia (LIP), Sarcoidosis, and Hypersensitivity Pneumonitis (HP).DISCUSSION:When a CVID patient presents with granulomatous lung disease, infectious organisms such as mycobacteria and fungi should be ruled out first with special stains (e.g. Grocott's methenamine silver stain and AFB). Then other non-infectious etiologies can be considered, such as LIP, Sarcoidosis, HP, and GLILD.Lymphocytic Interstitial Pneumonia (LIP):Most cases present without granulomas. Prominent inflammation with lymphoid aggregates is usually anizing pneumonia may or may not be present (minor feature).Fibrosis is usually absent.Sarcoidosis:Granulomas are present in a lymphatic distribution, and are well formed with sparse to absent lymphocytic cuffing.Interstitial inflammation and organizing pneumonia are usually absent.Fibrosis is occasionally present. Hypersensitivity Pneumonitis (HP):Will often show poorly formed granulomas accompanied by lymphocytic infiltrate.The inflammatory pattern is bronchiolocentric or anizing pneumonia is usually present.In chronic cases, fibrosis is usually present.GLILD:Granulomas are present in the vast majority of cases, with a variable lymphocytic infiltrate.Inflammatory pattern: variable density, peribronchial and anizing pneumonia is usually present.Fibrosis is usually present.References:Rao N, Mackinnon AC, Routes JM. Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD): A Spectrum of Pulmonary Histopathological Lesions in Common Variable Immunodeficiency (CVID) - Histological and Immunohistochemical Analysis of 16 cases. Hum Pathol. 2015 September ; 46(9): 1306–1314. doi:10.1016/j.humpath.2015.05.011.Hurst JR, Verma N, Lowe D, et al. British Lung Foundation/United Kingdom Primary Immunodeficiency Network Consensus Statement on the Definition, Diagnosis, and Management of Granulomatous Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders. J ALLERGY CLIN IMMUNOL PRACT. 2017:938-945.Park JH, Levinson AI. Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID). Clinical Immunology (2010) 134, 97–103.Bates CA, Ellison MC, Lynch DA, et al. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol 2004;114:415-21.Case #3:PRESENTER: Amandeep Kaur, MDATTENDING: Ajit Paintal, MDCASE HISTORY: A 72-year-old female presented for surveillance scanning for renal cell carcinoma (diagnosed in 2017) for which she underwent nephrectomy. She also reported scant vaginal bleeding and bloating. On CT scan, a 9 cm area of soft tissue infiltration is identified in the right renal bed. Fine needle aspiration is performed from the same area. DIAGNOSIS: Malignant mesothelioma with BAP1- Tumor predisposition syndromeDIFFERENTIAL DIAGNOSIS:Metastatic renal cell carcinomaMetastatic adenocarcinomaMalignant mesotheliomaDISCUSSION: BAP1- Tumor predisposition syndrome (BAP1-TPDS) is an autosomal dominant, highly penetrant hereditary cancer syndrome. It predisposes to many tumors including melanoma, mesothelioma, renal cell carcinoma and atypical melanocytic tumors. BAP1-TPDS?should be suspected?in an individual who has either two or more confirmed?BAP1-TPDS tumors or one?BAP1-TPDS tumor and a first- or second degree relative?with a confirmed?BAP1-TPDS tumor. These patients present with cancer diagnosis earlier than general population and have worse prognosis except peritoneal mesotheliomas which have better prognosis. Some tumors like uveal melanomas and renal cell carcinomas present with higher stage, larger tumor size and high risk of metastases. PARP inhibitors and check point inhibitors may be of therapeutic use in these tumors but will need to be addressed in future trials. BAP1 and malignant mesothelioma:Second most frequent cancer (22%) identified in?BAP1-TPDS. Associated with female predominance, epithelioid differentiation, peritoneal location and better prognosis.BAP1 can be used as diagnostic marker for malignant mesothelioma.BAP1 and RCC:10% of patients are reported with BAP1-TPDS.Clear cell renal cell carcinomas with loss of BAP1 exhibit rhabdoid/ sarcomatoid cytological features, necrosis, higher T stage, higher nuclear grade, large tumor size, and presence of metastasis at diagnosis.BAP1 loss increases renal cancer cell sensitivity to radiation and PARP inhibitors.BAP1 and malignant melanoma:Uveal melanoma is the most frequent cancer (31%) identified in?BAP1-TPDS.Ciliary body is the most common site of involvement. They have a high risk of metastasis.Cutaneous melanoma is the third most common cancer identified in?BAP1-TPDSBAP1 loss is associated with desmoplastic morphology and worse disease-free survival.KEYPOINTS:BAP1 is a tumor suppressor gene that encodes a deubiquitinating enzyme.Germline BAP1 mutations result in a novel cancer syndrome with increased risks of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma and other malignancies.BAP1 IHC is a useful test in many settings, including screening for germline BAP1 mutations, diagnosis of malignant mesothelioma and prognostic stratification of various cancer types.References:Di Nunno V, Frega G, Santoni M, Gatto L, Fiorentino M, Montironi R, Battelli N, Brandi G, Massari F. BAP1 in solid tumors. Future Oncol. 2019 Jun;15(18):2151-2162. doi: 10.2217/fon-2018-0915. Epub 2019 Jun 4. PubMed PMID: 31159579.Ladanyi M, Sanchez Vega F, Zauderer M. Loss of BAP1 as a candidate predictive biomarker for immunotherapy of mesothelioma. Genome Med. 2019 Mar 26;11(1):18. doi: 10.1186/s13073-019-0631-0. PubMed PMID: 30914057; PubMed Central PMCID: PMC6436227.Yoshimura M, Kinoshita Y, Hamasaki M, Matsumoto S, Hida T, Oda Y, Iwasaki A, Nabeshima K. Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia. Lung Cancer. 2019 Apr;130:187-193. doi: 10.1016/j.lungcan.2019.02.004. Epub 2019 Feb 27. PubMed PMID: 30885343.Hung YP, Dong F, Dubuc AM, Dal Cin P, Bueno R, Chirieac LR. Molecular characterization of localized pleural mesothelioma. Mod Pathol. 2019 Aug 1. doi: 10.1038/s41379-019-0330-9. [Epub ahead of print] PubMed PMID: 31371807.Rai K, Pilarski R, Cebulla CM, Abdel-Rahman MH. Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin Genet. 2016 Mar;89(3):285-94.Masoomian et al Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. J Curr ophthalmol. 2018 Jun; 30(2): 102–109.Wang A, Papneja A, Hyrcza M, Al-Habeeb A, Ghazarian D. Gene of the month: BAP1. J Clin Pathol. 2016 Sep;69(9):750-3. Murali R, Wiesner T, Scolyer RA. Tumours associated with BAP1 mutations. Pathology. 2013 Feb;45(2):116-26.Hakimi AA et al; ccRCC Cancer Genome Atlas (KIRC TCGA) Research Network investigators. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin Cancer Res. 2013 Jun 15;19(12):3259-67. Bihr S et al. Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma. Neoplasia. 2019 Feb;21(2):247-256.Shrestha R, Nabavi N, Lin YY, Mo F, Anderson S, Volik S, Adomat HH, Lin D, Xue H, Dong X, Shukin R, Bell RH, McConeghy B, Haegert A, Brahmbhatt S, Li E, Oo HZ, Hurtado-Coll A, Fazli L, Zhou J, McConnell Y, McCart A, Lowy A, Morin GB, Chen T, Daugaard M, Sahinalp SC, Hach F, Le Bihan S, Gleave ME, Wang Y, Churg A, Collins CC. BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma. Genome Med. 2019 Feb 18;11(1):8.Case #4Presenter: Cory Gray, DOAttending: Jerome Taxy, MD, Ajit Paintal, MDCase History: A 59 year old male with a past medical history of Stage I large cell immunoblastic lymphoma status post excision with chemotherapy and radiation treatment. He presented with a lump on the right side of his neck, which lead to an excisional biopsy with subsequent removal of a submandibular salivary gland.Diagnosis:Myoepithelial CarcinomaDiscussion:Myoepithelial carcinoma demographics:Affects a wide age range, with mean in 6th decade.Genders equally affected.Approximately 1/3 mortality rate.Most commonly occurs in parotid gland.Histology:Architecture:Multinodular or nodular lobulated and pattern.Can be poorly encapsulated and invasive or encapsulated without invasion.Cells: Exclusively myoepithelial; epithelioid, spindled, plasmacytoid or clear cells.Arranged in nests or cords with fibrous septa between nodules.No ductal structures.Abundant mitotic activity.Round to oval nuclei with irregular contours.Nuclei open and vesicular with prominent nucleoli.Background: Mucoid or myxoid differential: Morphologic diagnosis.Cellular/Myoepithelial-rich pleomorphic adenoma:Benign mixed tumor that can be epithelial or myoepithelial predominant.By definition has duct structures mixed with myoepithelial cells.Chondromyxoid stroma.No infiltrative borders, mitotic activity, necrosis.Epithelial-Myoepithelial carcinoma:Displays classic features of biphasic tubular histology.Myoepithelioma:Well-defined capsule with bland cytology.Lacks mitotic figures.No invasion into surrounding parenchyma.Myoepithelial carcinoma can be a challenging diagnosis:Rare and understudied with poorly defined diagnostic criteria.Reported to account for <2% of salivary gland malignancies; incidence is higher.Under-recognized given broad histologic spectrum and morphologic overlap.Can arise de novo or in association with existing pleomorphic adenoma.Can appear histologically and cytologically bland.Can show minimal or no capsular invasion, especially in cases of MECA ex-PA.Prognosis: MECA is aggressive, even when intracapsular or minimally invasive MECA ex-PA.37% risk of local recurrence; 22% chance of distant metastasis.Statistically significant correlation with decreased survival:Presence of MECA ex-PA.Necrosis.Vascular invasion.Criteria for diagnosis: Important to distinguish from benign mimics.Existing:Destructive invasion, atypia, mitoses.Central areas of hyalinized stroma.Positive staining for 1 cytokeratin and 1 myoepithelial marker.Proposed:Homogenous monotonous growth of myoepithelial cells.Expansive lobular or nodular lobulated growth.Zonal distribution of myoepithelial cells.Molecular:PLAG1 and HMGA2 gene rearrangements common in PA and CA ex-PA.TGFBR3-PLAG1 gene fusion is specific marker for MECA (not found in PA)References:Xu B, Mneimneh W, Torrence DE, Higgins K, Klimstra D, Ghossein R, Katabi N. Misinterpreted Myoepithelial Carcinoma of Salivary Gland: A Challenging and Potentially Significant Pitfall. Am J Surg Pathol. 2019 May;43(5):601-609. doi:10.1097/PAS.0000000000001218. PubMed PMID: 30789358.Kong M, Drill EN, Morris L, West L, Klimstra D, Gonen M, Ghossein R, Katabi N. Prognostic factors in myoepithelial carcinoma of salivary glands: a clinicopathologic study of 48 cases. Am J Surg Pathol. 2015 Jul;39(7):931-8. Doi: 10.1097/PAS.0000000000000452. PubMed PMID: 25970687; PubMed Central PMCID: PMC4939272. Skalova A, Sima R, Kaspirkova-Nemcova J, Simpson RH, Elmberger G, Leivo I, Di Palma S, Jirasek T, Gnepp DR, Weinreb I, Perez-Ordo?ez B, Mukensnabl P, Rychly B, Hrabal P, Michal M. Cribriform adenocarcinoma of minor salivary gland origin principally affecting the tongue: characterization of new entity. Am J Surg Pathol. 2011 Aug;35(8):1168-76. doi: 10.1097/PAS.0b013e31821e1f54. PubMed PMID: 21716087.Case #5PRESENTER: Pouya Jamshidi, MDATTENDING: John Groth, MDCASE HISTORY: A 68 year-old female with no significant medical history noted a mass in her posterior medial left calf. Ultrasound showed a heterogenous mass and biopsy revealed a pleomorphic sarcoma arising in the subcutaneous tissue. She underwent neoadjuvant radiation therapy which was complicated by skin erosion and drainage. Given the continued discomfort, she underwent surgical resection. DIAGNOSIS: BRAF amplified, MGEA5-rearranged high-grade myxoid sarcoma. DISCUSSION:Poorly-defined heterogenous-appearing subcutaneous lesion Potential for high-grade transformation Location is the most important prognostic factor (complete vs. partial resection). Histology:Areas of spindle cell proliferation, with necrosis, hyalinization, myxoid proliferation, diffuse foci of hemosiderin deposition in periadipocytic area. There are scattered bizarre-looking cells with prominent macronucleoli (virocyte-like) and multi-nucleated giant cells. Top differential: Myxofibrosarcoma (MFS)Frist described by Ozzello et al. in 1963Usually in superficial soft tissues of extremities in older adultsMultinodular growth pattern and abundant myxoid matrixCurvilinear vascular network variably prominentNo hyalinized zonesInflammatory cells comprise minor componentPleomorphic hyalinizing angiectatic tumor (PHAT):First reported by Smith et al. in 2004Most common in ankle/foot regionPleomorphic atypical stromal cells, conspicuous ectatic hyalinized vessels, and abundant hemosiderinCan show areas of sarcomatous progressionCD34(+)t(1;10)(p22;q24) (TGFBR3; MGEA5)Hemosiderotic fibrolipomatous tumor (HFLT):First described by Marshall-Taylor and Fanburg-Smith in 2000Classically involves ankle and feetMildly atypical spindle cells and prominent hemosiderin deposition, irregular septal and perilobular growth around mature adipose tissueNeutrophils and eosinophils are not typical featuresStrongly CD34(+)t(1;10)(p22;q24) (TGFBR3; MGEA5?)Myxoinflammatory fibroblastic sarcoma (MIFS)First reported in 1998 by three independent groups (Montgomery et al., Michal et al., and Meis-Kindbolm et al.)Commonly involves hand, wrist, knee and dorsal lower legMixture of myxoid, hyalinized, and inflammatory zonesLarge ganglion-like cells, virocyte-like macronucleoliMultinucleated giant cellst(1;10)(p22;q24) (TGFBR3; MGEA5?)Undifferentiated pleomorphic sarcomaStoriform, fascicular, or pattern- less arrangement Highly atypical spindled or polyglonal cells with marked nuclear pleomorphismOften abundant mitosis or necrosisDiagnosis of exclusionKEY POINTSDifferential diagnosis of a high-grade myxoid sarcoma should include MIFS/HFLT/PHAT, MFS and undifferentiated pleomorphic sarcomaGenetics:MIFS: BRAF or MGEA5HFLT, hybrid MIFS-HFLT, PHAT: TGFBR3-MGEA5 MFS: Unknown with rare BRAFSome cases defy current WHO classifications:Opportunity for accurate classificationPrognostic assessment Targeted therapyReferences:Michal M., Kazakov DV, Hadravsky? L, Kinkor Z., Kuroda N., Michal M. High-grade myxoinflammatory fibroblastic sarcoma: a report of 23 cases. Annals of Diagnostic Pathology 19 (2015) 157-163. Laskin WB., Fetsch JF., Miettinen M. Myxoinflammatory fibroblastic sarcoma, a clinicopathologic analysis of 104 cases, with emphasis on predictors of outcome. Am J Surg Pathol 2014;38:1-12. Liu H., Sukov WR., Ro JY. The t(1;10)(p22;q24) TGFBR3/MGEA5 translocation in pleomorphic hyalinizing angiectatic tumor, myxoinflammatory fibroblastic sarcoma, and hemosiderotic fibrolipomatous tumor. Arch Pathol Lab Med. 2019;143:212–221Kao Y., Ranucci V., Zhang L., Sung Y., Athanasian EA., Swanson D., Dickson BC., Antonescu CR. Recurrent BRAF gene rearrangements in myxoinflammatory fibroblastic sarcomas, but not hemosiderotic fibrolipomatous tumors. Am J Surg Pathol 2017;41:1456–1465Hallor KH., Sciot R., Staaf J., Heidenblad M., Rydholm A., ,et al. Two genetic pathways, t(1;10) and amplification of 3p11–12, in myxoinflammatory fibroblastic sarcoma, haemosiderotic fibrolipomatous tumour, and morphologically similar lesions. J Pathol 2009; 217: 716–727Lucas DR. Myxoinflammatory fibroblastic sarcoma, review and update. Arch Pathol Lab Med. 2017;141:1503–1507 ................
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