We report a rare case of primary nodal, poorly differentiated endometrioid carcinoma associated with Lynch syndrome. A 29-year-old female patient was referred by her general gynecologist for further imaging with suspected right-sided ovarian endometrioid cyst. Ultrasound examination by an expert gynecological sonographer at tertiary center revealed unremarkable findings in the abdomen and pelvis apart from three iliac lymph nodes showing signs of malignant infiltration in the right obturator fossa and two lesions in the 4b segment of the liver. During the same appointment ultrasound guided tru-cut biopsy was performed to differentiate hematological malignancy from carcinomatous lymph node infiltration. Based on the histological findings of endometrioid carcinoma from lymph node biopsy, primary debulking surgery including hysterectomy and salpingo-oophorectomy was performed. Endometrioid carcinoma was confirmed only in the three lymph nodes suspected on the expert scan and primary nodal origin of endometroid carcinoma developed from ectopic Müllerian tissue was considered. As a part of the pathological examination immunohistochemistry analysis for mismatch repair protein (MMR) expression was done. The findings of deficient mismatch repair proteins (dMMR) led to additional genetic testing, which revealed deletion of the entire EPCAM gene up to exon 1-8 of the MSH2 gene. This was unexpected considering her insignificant family history of cancer. We discuss the diagnostic work-up for patients presenting with metastatic lymph node infiltration by cancer of unknown primary and possible reasons for malignant lymph node transformation associated with Lynch syndrome.

Department of Gynecology and Gynecologic Oncology Nairi Medical Center Yerevan Armenia

Department of Gynecology and Obstetrics Hospital de Braga Braga Portugal

Department of Gynecology and Obstetrics Ospedale Policlinico San Martino and University of Genoa Genova Italy

Department of Obstetrics and Gynecology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

Department of Obstetrics and Gynecology Burton Hospitals National Health System West Midlands United Kingdom

Department of Oncology 1st Faculty of Medicine Charles University Prague Czechia

Department of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

Department of Radiology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

See more in PubMed

Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet (London England) (2012) 379(9824):1428–35. doi: 10.1016/s0140-6736(11)61178-1 PubMed DOI

Justiz Vaillant AA, Stang CM. Lymphoproliferative disorders. StatPearls. Treasure Island (FL: StatPearls Publishing LLC; (2021). PubMed

Tchernev G, Chokoeva A, Popova LV. Primary solitary melanoma of the lymphatic nodes or a single metastasis of unknown melanoma: Do we need a new staging system? Open Access Maced J Med Sci (2017) 5(7):970–3. doi: 10.3889/oamjms.2017.222 PubMed DOI PMC

Cormier JN, Xing Y, Feng L, Huang X, Davidson L, Gershenwald JE, et al. . Metastatic melanoma to lymph nodes in patients with unknown primary sites. Cancer (2006) 106(9):2012–20. doi: 10.1002/cncr.21835 PubMed DOI

Sah S, Fulmali R, McCluggage WG. Low-grade serous carcinoma arising in inguinal nodal endosalpingiosis: Report of 2 cases and literature review. Int J Gynecol Pathol (2020) 39(3):273–8. doi: 10.1097/PGP.0000000000000613 PubMed DOI

Hillen HF. Unknown primary tumours. Postgraduate Med J (2000) 76(901):690–3. doi: 10.1136/pmj.76.901.690 PubMed DOI PMC

Zikan M, Fischerova D, Pinkavova I, Dundr P, Cibula D. Ultrasound-guided tru-cut biopsy of abdominal and pelvic tumors in gynecology. Ultrasound Obstet Gynecol. (2010) 36(6):767–72. doi: 10.1002/uog.8803 PubMed DOI

National Institute for Health and Care Excellence: Guidelines . Diagnosis and management of metastatic malignant disease of unknown primary origin. Cardiff (UK: National Collaborating Centre for Cancer (UK) Copyright © 2010, National Collaborating Centre for Cancer; (2010). PubMed

Fizazi K, Greco FA, Pavlidis N, Daugaard G, Oien K, Pentheroudakis G. Cancers of unknown primary site: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol (2015) 26(Suppl 5):v133–8. doi: 10.1093/annonc/mdv305 PubMed DOI

Fischerova D, Cibula D, Dundr P, Zikan M, Calda P, Freitag P, et al. . Ultrasound-guided tru-cut biopsy in the management of advanced abdomino-pelvic tumors. Int J Gynecol Cancer. (2008) 18(4):833–7. doi: 10.1111/j.1525-1438.2007.01015.x PubMed DOI

Epstein E, Van Calster B, Timmerman D, Nikman S. Subjective ultrasound assessment, the ADNEX model and ultrasound-guided tru-cut biopsy to differentiate disseminated primary ovarian cancer from metastatic non-ovarian cancer. Ultrasound Obstet Gynecol. (2016) 47(1):110–6. doi: 10.1002/uog.14892 PubMed DOI

Mascilini F, Quagliozzi L, Moro F, Moruzzi MC, De Blasis I, Paris V, et al. . Role of transvaginal ultrasound-guided biopsy in gynecology. Int J Gynecol Cancer. (2020) 30(1):128–32. doi: 10.1136/ijgc-2019-000734 PubMed DOI

Verschuere H, Froyman W, Van den Bosch T, Van Hoefs M, Kaijser J, Van Schoubroeck D, et al. . Safety and efficiency of performing transvaginal ultrasound-guided tru-cut biopsy for pelvic masses. Gynecol Oncol (2021) 161(3):845–51. doi: 10.1016/j.ygyno.2021.03.026 PubMed DOI

Arezzo F, Loizzi V, La Forgia D, Abdulwakil Kawosha A, Silvestris E, Cataldo V, et al. . The role of ultrasound guided sampling procedures in the diagnosis of pelvic masses: A narrative review of the literature. Diagnostics (2021) (Basel Switzerland: ) 11(12):2204. doi: 10.3390/diagnostics11122204 PubMed DOI PMC

Rades D, Kuhnel G, Wildfang I, Borner AR, Schmoll HJ, Knapp W. Localised disease in cancer of unknown primary (CUP): The value of positron emission tomography (PET) for individual therapeutic management. Ann Oncol (2001) 12(11):1605–9. doi: 10.1023/a:1013107732572 PubMed DOI

Timmerman D, Planchamp F, Bourne T, Landolfo C, du Bois A, Chiva L, et al. . ESGO/ISUOG/IOTA/ESGE consensus statements on the pre-operative diagnosis of ovarian tumours. Ultrasound Obstet Gynecol (2021) 58:148–68. doi: 10.1002/uog.23635 PubMed DOI

Carrabin N, Treilleux I, Meeus P, Tredan O, Ray-Coquard I. Primary ovarian borderline tumor in the inguinal lymph node. Int J Gynecol Pathol (2013) 32(2):167–70. doi: 10.1097/PGP.0b013e318257def6 PubMed DOI

Restaino S, Mauro J, Zermano S, Pellecchia G, Mariuzzi L, Orsaria M, et al. . CUP-syndrome: Inguinal high grade serous ovarian carcinoma lymph node metastases with unknown primary origin - a case report and literature review. Front Oncol (2022) 12:987169. doi: 10.3389/fonc.2022.987169 PubMed DOI PMC

Sessa C, Balmana J, Bober SL, Cardoso MJ, Colombo N, Curigliano G, et al. . Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice Guideline. Ann Oncol. (2023) 34(1):33–47. PubMed

Shu CA, Pike MC, Jotwani AR, Friebel TM, Soslow RA, Levine DA, et al. . Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations. JAMA Oncol (2016) 2(11):1434–40. doi: 10.1001/jamaoncol.2016.1820 PubMed DOI PMC

de Jonge MM, de Kroon CD, Jenner DJ, Oosting J, de Hullu JA, Mourits MJE, et al. . Endometrial cancer risk in women with germline BRCA1 or BRCA2 mutations: Multicenter cohort study. J Natl Cancer Inst (2021) 113(9):1203–11. doi: 10.1093/jnci/djab036 PubMed DOI PMC

Moreira L, Balaguer F, Lindor N, de la Chapelle A, Hampel H, Aaltonen LA, et al. . Identification of lynch syndrome among patients with colorectal cancer. Jama (2012) 308(15):1555–65. doi: 10.1001/jama.2012.13088 PubMed DOI PMC

Downes MR, Allo G, McCluggage WG, Sy K, Ferguson SE, Aronson M, et al. . Review of findings in prophylactic gynaecological specimens in lynch syndrome with literature review and recommendations for grossing. Histopathology (2014) 65(2):228–39. doi: 10.1111/his.12386 PubMed DOI

Helder-Woolderink JM, Blok EA, Vasen HF, Hollema H, Mourits MJ, De Bock GH. Ovarian cancer in lynch syndrome: A systematic review. Eur J Cancer. (2016) 55:65–73. doi: 10.1016/j.ejca.2015.12.005 PubMed DOI

Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, et al. . Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in lynch syndrome. Jama (2011) 305(22):2304–10. doi: 10.1001/jama.2011.743 PubMed DOI

Jones NC, Adashek JJ, Ayoub B. Carcinoma of unknown primary in a patient with lynch syndrome. Cureus (2021) 13(6):e15690. doi: 10.7759/cureus.15690 PubMed DOI PMC

Ghezzi F, Uccella S, Cromi A, Bogani G, Donadello N, Riva C. Primary peritoneal cancer in lynch syndrome: A clinical-pathologic report of a case and analysis of the literature. Int J Gynecol Pathol (2013) 32(2):163–6. doi: 10.1097/PGP.0b013e31825ac5c9 PubMed DOI

Koual M, Benoit L, Pacelli J, Lefrère Belda MA, Azaïs H, Bats AS. Discovery of an endometrioid cancer lymph node metastasis without primary tumor in a context of lynch syndrome. J Gynecol Obstet Hum Reprod (2021) 50(3):102060. doi: 10.1016/j.jogoh.2021.102060 PubMed DOI

Murali R, Davidson B, Fadare O, Carlson JA, Crum CP, Gilks CB, et al. . High-grade endometrial carcinomas: Morphologic and immunohistochemical features, diagnostic challenges and recommendations. Int J Gynecol Pathol (2019) 38 Suppl 1(Iss 1 Suppl 1):S40–s63. doi: 10.1097/pgp.0000000000000491 PubMed DOI PMC

Kobel M, Duggan MA. Napsin a: Another milestone in the subclassification of ovarian carcinoma. Am J Clin Pathol (2014) 142(6):735–7. doi: 10.1309/AJCPAVGZKA1A1HVC PubMed DOI

Richman S. Deficient mismatch repair: Read all about it (Review). Int J Oncol (2015) 47(4):1189–202. doi: 10.3892/ijo.2015.3119 PubMed DOI PMC

Stjepanovic N, Moreira L, Carneiro F, Balaguer F, Cervantes A, Balmaña J, et al. . Hereditary gastrointestinal cancers: ESMO clinical practice guidelines for diagnosis, treatment and follow-up†. Ann Oncol (2019) 30(10):1558–71. doi: 10.1093/annonc/mdz233 PubMed DOI

Gaddey HL, Riegel AM. Unexplained lymphadenopathy: Evaluation and differential diagnosis. Am Fam Physician. (2016) 94(11):896–903. PubMed

Fischerova D, Garganese G, Reina H, Fragomeni SM, Cibula D, Nanka O, et al. . Terms, definitions and measurements to describe sonographic features of lymph nodes: consensus opinion from the vulvar international tumor analysis (VITA) group. Ultrasound Obstet Gynecol. (2021) 57(6):861–79. doi: 10.1002/uog.23617 PubMed DOI