Small cell carcinoma of hypercalcemic type (SCCOHT) is a rare gynaecological neoplasm, originating mostly in the ovaries. Cervical origin of this very aggressive malignancy with unknown histogenesis is an extremely rare condition, without published management recommendations. Alterations in SMARCA4 gene are supposed to play the major role in SCCOHT oncogenesis and their identification is crucial for the diagnosis. Adequate genetic counselling of the patients and their families seems to be of great importance. Optimal management and treatment approaches are not known yet but may extremely influence the prognosis of young female patients that suffer from this very resistant disease. Nowadays, a translational research seems to be the key for the further diagnostic and treatment strategies of SCCOHT. The purpose of the case report is to provide practical information and useful recommendations on the diagnosis, management, and treatment of SMARCA4-deficient carcinoma of the uterine cervix resembling SCCOHT.

Department of Medical Genetics Faculty of Medicine and University Hospital Charles University Hradec Kralove Czechia

Department of Oncology and Radiotherapy Faculty of Medicine and University Hospital Charles University Hradec Kralove Czechia

Department of Radiation Medicine and Applied Sciences University of California San Diego La Jolla CA United States

Ludwig Institute for Cancer Research Lausanne University Hospital University of Lausanne Lausanne Switzerland

The Fingerland Department of Pathology Faculty of Medicine and University Hospital Charles University Hradec Kralove Czechia

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Patibandla JR, Fehniger JE, Levine DA, Jelinic P. Small Cell Cancers of the Female Genital Tract: Molecular and Clinical Aspects. Gynecol Oncol (2018) 149(2):420–7. 10.1016/j.ygyno.2018.02.004 PubMed DOI

Richard Dickersin G, Kline IW, Scully RE. Small Cell Carcinoma of the Ovary with Hypercalcemia: A Report of Eleven Cases. Cancer (1982) 49(1):188–97. 10.1002/1097-0142(19820101)49:1<188:aid-cncr2820490137>3.0.co;2-d PubMed DOI

Young RH, Oliva E, Scully RE. Small Cell Carcinoma of the Ovary, Hypercalcemic Type. Am J Surg Pathol (1994) 18(11):1102–16. 10.1097/00000478-199411000-00004 PubMed DOI

Lavrut P-M, Le Loarer F, Normand C, Grosos C, Dubois R, Buenerd A, et al. Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Report of a Bilateral Case in a Teenager Associated with SMARCA4 Germline Mutation. Pediatr Dev Pathol (2016) 19(1):56–60. 10.2350/15-04-1624-CR.1 PubMed DOI

Witkowski L, Donini N, Byler-Dann R, Knost JA, Albrecht S, Berchuck A, et al. The Hereditary Nature of Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Two New Familial Cases. Fam Cancer (2017) 16(3):395–9. 10.1007/s10689-016-9957-6 PubMed DOI PMC

Chen L, Dinh TA, Haque A. Small Cell Carcinoma of the Ovary with Hypercalcemia and Ectopic Parathyroid Hormone Production. Arch Pathol Labor Med (2005) 129(4):531–3. 10.5858/2005-129-531-sccoto PubMed DOI

Matias‐Guiu X, Prat J, Young RH, Capen CC, Rosol TJ, Delellis RA, et al. Human Parathyroid Hormone‐related Protein in Ovarian Small Cell Carcinoma. An Immunohistochemical Study. Cancer (1994) 73(7):1878–81. 10.1002/1097-0142(19940401)73:7<1878:AID-CNCR2820730717>3.0.CO;2-D PubMed DOI

Wynn D, Everett GD, Boothby RA. Small Cell Carcinoma of the Ovary with Hypercalcemia Causes Severe Pancreatitis and Altered Mental Status. Gynecol Oncol (2004) 95(3):716–8. 10.1016/j.ygyno.2004.08.038 PubMed DOI

Bourgain A, Acker O, Lambaudie E, Boukerrou M, Chevalier-Place A, Meignie P, et al. Small Cell Carcinoma of the Ovary of the Hypercalcemic Type Revealed by a Severe Acute Pancreatitis: about One Case. Gynecol Obstet Fertil (2005) 33(1–2):35–8. 10.1016/j.gyobfe.2004.11.004 PubMed DOI

Nasioudis D, Chapman-Davis E, Frey MK, Caputo TA, Witkin SS, Holcomb K. Small Cell Carcinoma of the Ovary: A Rare Tumor with a Poor Prognosis. Int J Gynecol Cancer (2018) 28(5):932–8. 10.1097/IGC.0000000000001243 PubMed DOI

Lu B, Shi H. An In-Depth Look at Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT): Clinical Implications from Recent Molecular Findings. J Cancer (2019) 10(1):223–37. 10.7150/jca.26978 PubMed DOI PMC

Tischkowitz M, Huang S, Banerjee S, Hague J, Hendricks WPD, Huntsman DG, et al. Small-Cell Carcinoma of the Ovary, Hypercalcemic Type-Genetics, New Treatment Targets, and Current Management Guidelines. Clin Cancer Res (2020) 26(15):3908–17. 10.1158/1078-0432.CCR-19-3797 PubMed DOI PMC

Foulkes WD, Clarke BA, Hasselblatt M, Majewski J, Albrecht S, McCluggage WG. No Small surprise - Small Cell Carcinoma of the Ovary, Hypercalcaemic Type, Is a Malignant Rhabdoid Tumour. J Pathol (2014) 233(3):209–14. 10.1002/path.4362 PubMed DOI

Fahiminiya S, Witkowski L, Nadaf J, Carrot-Zhang J, Goudie C, Hasselblatt M, et al. Molecular Analyses Reveal Close Similarities between Small Cell Carcinoma of the Ovary, Hypercalcemic Type and Atypical Teratoid/rhabdoid Tumor. Oncotarget (2016) 7(2):1732–40. 10.18632/oncotarget.6459 PubMed DOI PMC

Schrader KA, Hurlburt J, Kalloger SE, Hansford S, Young S, Huntsman DG, et al. Germline BRCA1 and BRCA2 Mutations in Ovarian Cancer. Obstet Gynecol (2012) 120(2):235–40. 10.1097/AOG.0b013e31825f3576 PubMed DOI

Ramos P, Karnezis AN, Craig DW, Sekulic A, Russell ML, Hendricks WPD, et al. Small Cell Carcinoma of the Ovary, Hypercalcemic Type, Displays Frequent Inactivating Germline and Somatic Mutations in SMARCA4. Nat Genet (2014) 46(5):427–9. 10.1038/ng.2928 PubMed DOI PMC

Witkowski L, Carrot-Zhang J, Albrecht S, Fahiminiya S, Hamel N, Tomiak E, et al. Germline and Somatic SMARCA4 Mutations Characterize Small Cell Carcinoma of the Ovary, Hypercalcemic Type. Nat Genet (2014) 46(5):438–43. 10.1038/ng.2931 PubMed DOI

Jelinic P, Mueller JJ, Olvera N, Dao F, Scott SN, Shah R, et al. Recurrent SMARCA4 Mutations in Small Cell Carcinoma of the Ovary. Nat Genet (2014) 46(5):424–6. 10.1038/ng.2922 PubMed DOI PMC

Jelinic P, Ricca J, Van Oudenhove E, Olvera N, Merghoub T, Levine DA, et al. Immune-active Microenvironment in Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Rationale for Immune Checkpoint Blockade. J Natl Cancer Instit (2018) 110(7):787–90. 10.1093/jnci/djx277 PubMed DOI PMC

Dong A, Lu Y, Lu B. Genomic/epigenomic Alterations in Ovarian Carcinoma: Translational Insight into Clinical Practice. J Cancer (2016) 7(11):1441–51. 10.7150/jca.15556 PubMed DOI PMC

Lin DI, Chudnovsky Y, Duggan B, Zajchowski D, Greenbowe J, Ross JS, et al. Comprehensive Genomic Profiling Reveals Inactivating SMARCA4 Mutations and Low Tumor Mutational burden in Small Cell Carcinoma of the Ovary, Hypercalcemic-type. Gynecol Oncol (2017) 147(3):626–33. 10.1016/j.ygyno.2017.09.031 PubMed DOI

Neigeborn L, Carlson M. Genes Affecting the Regulation of SUC2 Gene Expression by Glucose Repression in Saccharomyces cerevisiae . Genetics (1984) 108(4):845–58. 10.1093/genetics/108.4.845 PubMed DOI PMC

Pulice JL, Kadoch C. Composition and Function of Mammalian SWI/SNF Chromatin Remodeling Complexes in Human Disease. Cold Spring Harb Symp Quant Biol (2016) 81(1):53–60. 10.1101/sqb.2016.81.031021 PubMed DOI

Stern M, Jensen R, Herskowitz I. Five SWI Genes Are Required for Expression of the HO Gene in Yeast. J Mol Biol (1984) 178(4):853–68. 10.1016/0022-2836(84)90315-2 PubMed DOI

Clapier CR, Iwasa J, Cairns BR, Peterson CL. Mechanisms of Action and Regulation of ATP-dependent Chromatin-Remodelling Complexes. Nat Rev Mol Cel Biol (2017) 18(7):407–22. 10.1038/nrm.2017.26 PubMed DOI PMC

Shain AH, Pollack JR. The Spectrum of SWI/SNF Mutations, Ubiquitous in Human Cancers. PLoS ONE (2013) 8(1):e55119. 10.1371/journal.pone.0055119 PubMed DOI PMC

Callegaro-Filho D, Gershenson DM, Nick AM, Munsell MF, Ramirez PT, Eifel PJ, et al. Small Cell Carcinoma of the Ovary-Hypercalcemic Type (SCCOHT): A Review of 47 Cases. Gynecol Oncol (2016) 140(1):53–7. 10.1016/j.ygyno.2015.11.004 PubMed DOI PMC

Witkowski L, Goudie C, Ramos P, Boshari T, Brunet J-S, Karnezis AN, et al. The Influence of Clinical and Genetic Factors on Patient Outcome in Small Cell Carcinoma of the Ovary, Hypercalcemic Type. Gynecol Oncol (2016) 141(3):454–60. 10.1016/j.ygyno.2016.03.013 PubMed DOI PMC

Pautier P, Ribrag V, Duvillard P, Rey A, Elghissassi I, Sillet-Bach I, et al. Results of a Prospective Dose-Intensive Regimen in 27 Patients with Small Cell Carcinoma of the Ovary of the Hypercalcemic Type. Ann Oncol (2007) 18(12):1985–9. 10.1093/annonc/mdm376 PubMed DOI

Distelmaier F, Calaminus G, Harms D, Sträter R, Kordes U, Fleischhack G, et al. Ovarian Small Cell Carcinoma of the Hypercalcemic Type in Children and Adolescents. Cancer (2006) 107(9):2298–306. 10.1002/cncr.22213 PubMed DOI

Bakhru A, Liu JR, Lagstein A. A Case of Small Cell Carcinoma of the Ovary Hypercalcemic Variant in a Teenager. Gynecol Oncol Case Rep (2012) 2(4):139–42. 10.1016/j.gynor.2012.09.001 PubMed DOI PMC

Isonishi S, Nishii H, Saitou M, Yasuda M, Kiyokawa T, Fukunaga M, et al. Small Cell Carcinoma of the Ovary: Clinical and Biological Study. Int J Clin Oncol (2008) 13(2):161–5. 10.1007/s10147-007-0698-2 PubMed DOI

Harrison ML, Hoskins P, du Bois A, Quinn M, Rustin GJS, Ledermann JA, et al. Small Cell of the Ovary, Hypercalcemic Type-Analysis of Combined Experience and Recommendation for Management. A GCIG Study. Gynecol Oncol (2006) 100(2):233–8. 10.1016/j.ygyno.2005.10.024 PubMed DOI

Gamwell LF, Gambaro K, Merziotis M, Crane C, Arcand SL, Bourada V, et al. Small Cell Ovarian Carcinoma: Genomic Stability and Responsiveness to Therapeutics. Orphanet J Rare Dis (2013) 8(1):33. 10.1186/1750-1172-8-33 PubMed DOI PMC

Otte A, Rauprich F, Hillemanns P, Park-Simon T-W, von der Ohe J, Hass R. In Vitro and in Vivotherapeutic Approach for a Small Cell Carcinoma of the Ovary Hypercalcaemic Type Using a SCCOHT-1 Cellular Model. Orphanet J Rare Dis (2014) 9(1):126. 10.1186/s13023-014-0126-4 PubMed DOI PMC

Pressey JG, Kelly DR, Hawthorne HT. Successful Treatment of Preadolescents with Small Cell Carcinoma of the Ovary Hypercalcemic Type. J Ped Hematol Oncol (2013) 35(7):566–9. 10.1097/MPH.0b013e318282cca8 PubMed DOI

Qin Q, Ajewole VB, Sheu TG, Donohue R, Singh M. Successful Treatment of a Stage IIIC Small-Cell Carcinoma of the Ovary Hypercalcemic Subtype Using Multi-Modality Therapeutic Approach. ecancer (2018) 12. 10.3332/ecancer.2018.832 PubMed DOI PMC

Stephens B, Anthony SP, Han H, Kiefer J, Hostetter G, Barrett M, et al. Molecular Characterization of a Patient's Small Cell Carcinoma of the Ovary of the Hypercalcemic Type. J Cancer (2012) 3(1):58–66. 10.7150/jca.3872 PubMed DOI PMC

Henon C, Blay J-Y, Massard C, Mir O, Bahleda R, Dumont S, et al. Long Lasting Major Response to Pembrolizumab in a Thoracic Malignant Rhabdoid-like SMARCA4-Deficient Tumor. Ann Oncol (2019) 30(8):1401–3. 10.1093/annonc/mdz160 PubMed DOI

Shen J, Ju Z, Zhao W, Wang L, Peng Y, Ge Z, et al. ARID1A Deficiency Promotes Mutability and Potentiates Therapeutic Antitumor Immunity Unleashed by Immune Checkpoint Blockade. Nat Med (2018) 24(5):556–62. 10.1038/s41591-018-0012-z PubMed DOI PMC

Okamura R, Kato S, Lee S, Jimenez RE, Sicklick JK, Kurzrock R. ARID1Aalterations Function as a Biomarker for Longer Progression-free Survival after Anti-PD-1/pd-L1 Immunotherapy. J Immunother Cancer (2020) 8(1):e000438. 10.1136/jitc-2019-000438 PubMed DOI PMC

Auguste A, Blanc-Durand F, Deloger M, Le Formal A, Bareja R, Wilkes DC, et al. Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) beyond SMARCA4 Mutations: A Comprehensive Genomic Analysis. Cells (2020) 9(6):1496. 10.3390/cells9061496 PubMed DOI PMC

Kim KH, Kim W, Howard TP, Vazquez F, Tsherniak A, Wu JN, et al. SWI/SNF-mutant Cancers Depend on Catalytic and Non-catalytic Activity of EZH2. Nat Med (2015) 21(12):1491–6. 10.1038/nm.3968 PubMed DOI PMC

Kurmasheva RT, Sammons M, Favours E, Wu J, Kurmashev D, Cosmopoulos K, et al. Initial Testing (Stage 1) of Tazemetostat (EPZ-6438), a Novel EZH2 Inhibitor, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer (2017) 64(3):e26218. 10.1002/pbc.26218 PubMed DOI PMC

Chan-Penebre E, Armstrong K, Drew A, Grassian AR, Feldman I, Knutson SK, et al. Selective Killing of SMARCA2- and SMARCA4-Deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models. Mol Cancer Ther (2017) 16(5):850–60. 10.1158/1535-7163.MCT-16-0678 PubMed DOI

Wong JP, Todd JR, Finetti MA, McCarthy F, Broncel M, Vyse S, et al. Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors. Cel Rep (2016) 17(5):1265–75. 10.1016/j.celrep.2016.10.005 PubMed DOI PMC

Lang JD, Hendricks WPD, Orlando KA, Yin H, Kiefer J, Ramos P, et al. Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition. Clin Cancer Res (2018) 24(8):1932–43. 10.1158/1078-0432.CCR-17-1928 PubMed DOI PMC

Xue Y, Meehan B, Macdonald E, Venneti S, Wang XQD, Witkowski L, et al. CDK4/6 Inhibitors Target SMARCA4-Determined Cyclin D1 Deficiency in Hypercalcemic Small Cell Carcinoma of the Ovary. Nat Commun (2019) 10(1):558. 10.1038/s41467-018-06958-9 PubMed DOI PMC

Callegaro-Filho D, Burke TW, Eifel PJ, Ramirez PT, Euscher EE, Schmeler KM. Radiotherapy for Recurrent Small Cell Carcinoma of the Ovary: A Case Report and Review of the Literature. Gynecol Oncol Rep (2015) 11:23–5. 10.1016/j.gore.2014.12.003 PubMed DOI PMC

Kolin DL, Dong F, Baltay M, Lindeman N, MacConaill L, Nucci MR, et al. SMARCA4-deficient Undifferentiated Uterine Sarcoma (Malignant Rhabdoid Tumor of the Uterus): a Clinicopathologic Entity Distinct from Undifferentiated Carcinoma. Mod Pathol (2018) 31:1442–56. 10.1038/s41379-018-0049-z PubMed DOI

Lin DI, Allen JM, Hecht JL, Killian JK, Ngo NT, Edgerly C, et al. SMARCA4 Inactivation Defines a Subset of Undifferentiated Uterine Sarcomas with Rhabdoid and Small Cell Features and Germline Mutation Association. Mod Pathol (2019) 32:1675–87. 10.1038/s41379-019-0303-z PubMed DOI

Connor YD, Miao D, Lin DI, Hayne C, Howitt BE, Dalrymple JL, et al. Germline Mutations of SMARCA4 in Small Cell Carcinoma of the Ovary, Hypercalcemic Type and in SMARCA4-Deficient Undifferentiated Uterine Sarcoma: Clinical Features of a Single Family and Comparison of Large Cohorts. Gynecol Oncol (2020) 157:106–14. 10.1016/j.ygyno.2019.10.031 PubMed DOI PMC

Kolin DL, Quick CM, Dong F, Fletcher CDM, Stewart CJR, Soma A, et al. SMARCA4-deficient Uterine Sarcoma and Undifferentiated Endometrial Carcinoma Are Distinct Clinicopathologic Entities. Am J Surg Pathol (2020) 44:263–70. 10.1097/PAS.0000000000001375 PubMed DOI