The complex clinical challenges of secondary ovarian tumors and cancer of unknown primary: diagnostic and therapeutic considerations

Favorable Carcinoma of Unknown Primary (CUP) types, representing approximately 20% of cases, are diagnosed through detailed histological, immunohistochemical, and imaging analyses that resemble known primary cancers. These include single-site or oligometastatic CUP, breast-like CUP, ovary-like CUP, head and neck-like CUP, prostate-like CUP, colon-like CUP and renal-like CUP. Patients benefit from site-specific treatments aligned with presumed primary sites, often leading to better prognoses. However, the remaining 80% of CUP cases are unfavorable, showing poor outcomes despite platinum-based chemotherapy, molecular targeted therapies and immunotherapy. Diagnosis of Secondary Tumors of Unknown Primary Origin (STOs) involves distinguishing primary tumor sites through molecular profiling and imaging. Cytoreductive surgery may offer survival benefits, particularly in ovarian metastases from colorectal cancer, although its role in gastric-origin STOs is less clear. Adjuvant chemotherapy, including platinum-based regimens, is considered beneficial but lacks robust evidence from randomized trials. Managing CUP and STOs requires a tailored approach based on tumor characteristics, site-specific treatments, cytoreductive surgery, and systemic therapies. Continued research and flexible treatment protocols are essential for optimizing outcomes in this complex and heterogeneous group of cancers.

Cancer of unknown primary; Gene expression profiling; Cytoreductive surgery; Adjuvant chemotherapy; Krukenberg tumor; Metastasis

[1] Kubeček O, Laco J, Špaček J, Petera J, Kopecký J, Kubečková A, et al. The pathogenesis, diagnosis, and management of metastatic tumors to the ovary: a comprehensive review. Clinical & Experimental Metastasis. 2017; 34: 295–307.

[2] Kovalev V, Tariq A. A review of Krukenberg tumors from a gastrointestinal primary site. World Journal of Colorectal Surgery. 2023; 12: 31–35.

[3] Laprovitera N, Riefolo M, Ambrosini E, Klec C, Pichler M, Ferracin M. Cancer of unknown primary: challenges and progress in clinical management. Cancers. 2021; 13: 451.

[4] Moore RG, Chung M, Granai CO, Gajewski W, Steinhoff MM. Incidence of metastasis to the ovaries from nongenital tract primary tumors. Gynecologic Oncology. 2004; 93: 87–91.

[5] Ayhan A, Guvenal T, Salman MC, Ozyuncu O, Sakinci M, Basaran M. The role of cytoreductive surgery in nongenital cancers metastatic to the ovaries. Gynecologic Oncology. 2005; 98: 235–241.

[6] Alvarado-Cabrero I, Rodriguez-Gomez A, Castelan-Pedraza J, Valencia-Cedillo R. Metastatic ovarian tumors: a clinicopathologic study of 150 cases. Analytical and Quantitative Cytopathology and Histopathology. 2013; 35: 241–248.

[7] Bruls J, Simons M, Overbeek LI, Bulten J, Massuger LF, Nagtegaal ID. A national population-based study provides insight in the origin of malignancies metastatic to the ovary. Virchows Archiv. 2015; 467: 79–86.

[8] Skirnisdottir I, Garmo H, Holmberg L. Non-genital tract metastases to the ovaries presented as ovarian tumors in Sweden 1990–2003: occurrence, origin and survival compared to ovarian cancer. Gynecologic Oncology. 2007; 105: 166–171.

[9] Zhang JJ, Cao DY, Yang JX, Shen K. Ovarian metastasis from nongynecologic primary sites: a retrospective analysis of 177 cases and 13-year experience. Journal of Ovarian Research. 2020; 13: 128.

[10] Ganesh K, Shah RH. Clinical and genetic determinants of ovarian metastases from colorectal cancer. Cancer. 2017; 123: 1134–1143.

[11] Vajdic CM, Perez-Concha O, Dobbins T, Ward RL, Schaffer AL, van Leeuwen MT, et al. Demographic, social and lifestyle risk factors for cancer registry-notified cancer of unknown primary site. Cancer Epidemiology. 2019; 60: 156–161.

[12] Shah B, Tang W, Karn S. An up-to-date understanding of the “Krukenberg Tumor” mechanism. Advances in Reproductive Sciences. 2016; 4: 31–36.

[13] Tan DS, Agarwal R, Kaye SB. Mechanisms of transcoelomic metastasis in ovarian cancer. The Lancet Oncology. 2006; 7: 925–934.

[14] Yamanishi Y, Koshiyama M, Ohnaka M, Ueda M, Ukita S, Hishikawa K, et al. Pathways of metastases from primary organs to the ovaries. Obstetrics and Gynecology International. 2011; 2011: 612817.

[15] Kall SL, Koblinski JE. Genes that mediate metastasis organotropism. In Jandial R (ed.) Metastatic cancer: clinical and biological perspectives (pp. 2000–2013). 1st edn. Landes Bioscience: Austin. 2013.

[16] Lu Y, Govindan R, Wang L, Liu PY, Goodgame B, Wen W, et al. MicroRNA profiling and prediction of recurrence/relapse-free survival in stage I lung cancer. Carcinogenesis. 2012; 33: 1046–1054.

[17] Crobach S, Ruano D, van Eijk R, Schrumpf M, Fleuren G, van Wezel T, et al. Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: identification of driver and passenger mutations. The Journal of Pathology: Clinical Research. 2016; 2: 166–174.

[18] van den Berg CB, Dasgupta S, Ewing-Graham PC, Bart J, Bulten J, Gaarenstroom KN, et al. Does serous tubal intraepithelial carcinoma (STIC) metastasize? The clonal relationship between STIC and subsequent high-grade serous carcinoma in BRCA1/2 mutation carriers several years after risk-reducing salpingo-oophorectomy. Gynecologic Oncology. 2024; 187: 113–119.

[19] Yang H, He F, Xu W, Cao Z. Clinical features of cancer with unknown primary site (clinical features, treatment, prognosis of cancer with unknown primary site). BMC Cancer. 2022; 22: 1372.

[20] Bruchim I, Ben-Harim Z, Piura E, Tepper R, Fishman A. Preoperative clinical and radiological features of metastatic ovarian tumors. Archives of Gynecology and Obstetrics. 2013; 288: 615–619.

[21] McCluggage WG. The value of immunohistochemistry as a diagnostic aid in ovarian neoplasia: a review. AJSP: Reviews & Reports. 2006; 11: 31–37.

[22] Guidi L, Valenza C, Battaiotto E, Trapani D, Ghioni MC, Crimini E, et al. Unfavorable carcinoma of unknown primary with a gastrointestinal profile: a retrospective study. ESMO Open. 2024; 9: 103662.

[23] Qaseem A, Usman N, Jayaraj JS, Janapala RN, Kashif T. Cancer of unknown primary: a review on clinical guidelines in the development and targeted management of patients with the unknown primary site. Cureus. 2019; 11: e5552.

[24] Tian F, Liu D, Wei N, Fu Q, Sun L, Liu W, et al. Prediction of tumor origin in cancers of unknown primary origin with cytology-based deep learning. Nature Medicine. 2024; 30: 1309–1319.

[25] National Comprehensive Cancer Network. Occult primary (cancer of unknown primary [CUP]) (version 2.2016). 2016. Available at: https://www.nccn.org/professionals/physician_gls/pdf/occult.pdf (Accessed: 01 August 2016).

[26] Willmott F, Allouni KA, Rockall A. Radiological manifestations of metastasis to the ovary. Journal of Clinical Pathology. 2012; 65: 585–590.

[27] Park HL, Yoo Ie R, O JH, Han EJ, Kim SH. F-18 FDG PET/CT findings of metastatic ovarian tumors from gastrointestinal tract origin. Journal of Cancer Research and Clinical Oncology. 2015; 141: 1871–1878.

[28] Rosen EL, Eubank WB, Mankoff DA. FDG PET, PET/CT, and breast cancer imaging. RadioGraphics. 2007; 27: S215–S229.

[29] Kwee TC, Basu S, Alavi A. PET and PET/CT for unknown primary tumors. Methods in Molecular Biology. 2011; 727: 317–333.

[30] Moller AK, Loft A, Berthelsen AK, Pedersen KD, Graff J, Christensen CB, et al. A prospective comparison of 18F-FDG PET/CT and CT as diagnostic tools to identify the primary tumor site in patients with extracervical carcinoma of unknown primary site. Oncologist. 2012; 17: 1146–1154.

[31] Yemelyanova AV, Vang R, Judson K, Wu LS, Ronnett BM. Distinction of primary and metastatic mucinous tumors involving the ovary: analysis of size and laterality data by primary site with reevaluation of an algorithm for tumor classification. The American Journal of Surgical Pathology. 2008; 32: 128–138.

[32] Höhn AK, Brambs CE, Hiller GGR, May D, Schmoeckel E, Horn LC. 2020 WHO Classification of female genital tumors. Geburtshilfe und Frauenheilkunde. 2021; 81: 1145–1153.

[33] Meagher NS, Wang L, Rambau PF, Intermaggio MP, Huntsman DG, Wilkens LR, et al. A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases. Modern Pathology. 2019; 32: 1834–1846.

[34] Dundr P, Singh N, Nožičková B, Němejcová K, Bártů M, Stružinská I. Primary mucinous ovarian tumors vs. ovarian metastases from gastrointestinal tract, pancreas and biliary tree: a review of current problematics. Diagnostic Pathology. 2021; 16: 20.

[35] Okamoto T, Matsumura N, Mandai M, Oura T, Yamanishi Y, Horiuchi A, et al. Distinguishing primary from secondary mucinous ovarian tumors: an algorithm using the novel marker DPEP1. Modern Pathology. 2011; 24: 267–276.

[36] Cai SQ, Wu MR, Ma XL, Lu JJ, Qiang JW, Guan YY, et al. Mucin-producing tumors of the ovary—preoperative differentiation between metastatic ovarian mucinous carcinoma and primary mucinous malignant tumors. Journal of Ovarian Research. 2024; 17: 59.

[37] Beauchamp K, Moran B, O’Brien T, Brennan D, Crown J, Sheahan K, et al. Carcinoma of unknown primary (CUP): an update for histopathologists. Cancer and Metastasis Reviews. 2023; 42: 1189–1200.

[38] Negri G, Egarter-Vigl E, Kasal A, Romano F, Haitel A, Mian C. p16INK4a is a useful marker for the diagnosis of adenocarcinoma of the cervix uteri and its precursors: an immunohistochemical study with immunocytochemical correlations. The American Journal of Surgical Pathology. 2003; 27: 187–193.

[39] Zubovits J, Buzney E, Yu L, Duncan LM. HMB-45, S-100, NK1/C3, and MART-1 in metastatic melanoma. Human Pathology. 2004; 35: 217–223.

[40] Hoshino A, Kim HS, Bojmar L, Gyan KE, Cioffi M, Hernandez J, et al. Extracellular vesicle and particle biomarkers define multiple human cancers. Cell. 2020; 182: 1044–1061.e18.

[41] Krämer A, Bochtler T, Pauli C, Baciarello G, Delorme S, Hemminki K, et al; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Cancer of unknown primary: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology. 2023; 34: 228–246.

[42] Jiang R, Tang J, Cheng X, Zang RY. Surgical treatment for patients with different origins of Krukenberg tumors: outcomes and prognostic factors. European Journal of Surgical Oncology. 2009; 35: 92–97.

[43] Rayson D, Bouttell E, Whiston F, Stitt L. Outcome after ovarian/adnexal metastectomy in metastatic colorectal carcinoma. Journal of Surgical Oncology. 2000; 75: 186–192.

[44] McCormick CC, Giuntoli RL 2nd, Gardner GJ, Schulick RD, Judson K, Ronnett BM, et al. The role of cytoreductive surgery for colon cancer metastatic to the ovary. Gynecologic Oncology. 2007; 105: 791–795.

[45] Lu LC, Shao YY, Hsu CH, Hsu C, Cheng WF, Lin YL, et al. Metastasectomy of Krukenberg tumors may be associated with survival benefits in patients with metastatic gastric cancer. Anticancer Research. 2012; 32: 3397–3401.

[46] Rosa F, Marrelli D, Morgagni P, Cipollari C, Vittimberga G, Framarini M, et al. Krukenberg tumors of gastric origin: the rationale of surgical resection and perioperative treatments in a multicenter western experience. World Journal of Surgery. 2016; 40: 921–928.

[47] Kato S, Alsafar A, Walavalkar V, Hainsworth J, Kurzrock R. Cancer of unknown primary in the molecular era. Trends in Cancer. 2021; 7: 465–477.

[48] Massard C, Loriot Y, Fizazi K. Carcinomas of an unknown primary origin––diagnosis and treatment. Nature Reviews Clinical Oncology. 2011; 8: 701–710.

[49] Oien KA. Pathologic evaluation of unknown primary cancer. Seminars in Oncology. 2009; 36: 8–37.

[50] Zaun G, Borchert S, Metzenmacher M, Lueong S, Wiesweg M, Zaun Y, et al. Comprehensive biomarker diagnostics of unfavorable cancer of unknown primary to identify patients eligible for precision medical therapies. European Journal of Cancer. 2024; 200: 113540.

[51] Kerr SE, Schnabel CA, Sullivan PS, Zhang Y, Singh V, Carey B, et al. Multisite validation study to determine performance characteristics of a 92-gene molecular cancer classifier. Clinical Cancer Research. 2012; 18: 3952–3960.

[52] Meiri E, Mueller WC, Rosenwald S, Zepeniuk M, Klinke E, Edmonston TB, et al. A second-generation microRNA-based assay for diagnosing tumor tissue origin. Oncologist. 2012; 17: 801–812.

[53] Hainsworth JD, Rubin MS, Spigel DR, Boccia RV, Raby S, Quinn R, et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. Journal of Clinical Oncology. 2013; 31: 217–223.

[54] Erroi F, Scarpa M, Angriman I, Cecchetto A, Pasetto L, Mollica E, et al. Ovarian metastasis from colorectal cancer: prognostic value of radical oophorectomy. Journal of Surgical Oncology. 2007; 96: 113–117.

[55] Brandi G, De Lorenzo S, Nannini M, Curti S, Ottone M, Dall’Olio FG, et al. Adjuvant chemotherapy for resected colorectal cancer metastases: literature review and meta-analysis. World Journal of Gastroenterology. 2016; 22: 519–533.

[56] Langer B, Bleiberg H, Labianca R, Shepherd L, Nitti D, Marsoni S, et al. Fluorouracil (FU) plus I-leucovorin (I-LV) versus observation after potentially curative resection of liver or lung metastases from colorectal cancer (CRC): results of the ENG (EORTC/NCIC/CTG/GIVIO) randomized trial. Proceedings of the American Society of Clinical Oncology. 2002; 21: 149a.

[57] Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. Journal of Clinical Oncology. 2006; 24: 4976–4982.

[58] PDQ Adult Treatment Editorial Board. Cancer of unknown primary (CUP) treatment (PDQ®): health professional version. 2002. Available at: https://www.ncbi.nlm.nih.gov/books/NBK65811/ (Accessed: 28 May 2024).

[59] Rassy E, Pavlidis N. Progress in refining the clinical management of cancer of unknown primary in the molecular era. Nature Reviews Clinical Oncology. 2020; 17: 541–554.

[60] Olivier T, Fernandez E, Labidi-Galy I, Dietrich PY, Rodriguez-Bravo V, Baciarello G, et al. Redefining cancer of unknown primary: is precision medicine really shifting the paradigm? Cancer Treatment Reviews. 2021; 97: 102204.