Cancer of Unknown Primary: Opportunities and Challenges

Abstract

Cancer of unknown primary (CUP) is defined as histologically proven metastatic tumors whose primary site cannot be identified during pretreatment evaluation. Among all malignancies, 3%–5% remained as CUP even after the extensive radiological and pathological workup. Immunohistochemistry and molecular gene expression tumor profiling are being utilized to predict the tissue of origin. Unfortunately, the survival of these patients remains poor (6–9 months) except in 20% of patients who belong to a favorable subset (12–36 months). There is a need to understand the basic biology and to identify the molecular pathways which can be targeted with small molecules. This article reviews our current approach as well as treatment evolution occurred in the past three decades.

Keywords

Cancer of unknown primary - empirical chemotherapy - immunohistochemistry - molecular tumor profiling

Publication History

Article published online:
23 June 2021

• References

• 1 Greco FA, Hainsworth JD. Cancer of unknown primary site. In: DeVita VTJR, Hellman S, Rosenberg SA. editors Cancer : Principles and Practice of Oncology. Philadelphia: Philadelphia: Lippincott Williams & Wilkins; 2008. 8. 2363-87
• 2 Pavlidis N, Briasoulis E, Hainsworth J, Greco FA. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer 2003; 39: 1990-2005
• 3 Horning SJ, Carrier EK, Rouse RV, Warnke RA, Michie SA. Lymphomas presenting as histologically unclassified neoplasms: Characteristics and response to treatment. J Clin Oncol 1989; 7: 1281-7
• 4 Oien KA, Dennis JL. Diagnostic work-up of carcinoma of unknown primary: From immunohistochemistry to molecular profiling. Ann Oncol 2012; 23 Suppl 10: x271-7
• 5 Kerr SE, Schnabel CA, Sullivan PS, Zhang Y, Huang VJ, Erlander MG. et al. A 92-gene cancer classifier predicts the site of origin for neuroendocrine tumors. Mod Pathol 2014; 27: 44-54
• 6 Oien KA. Pathologic evaluation of unknown primary cancer. Semin Oncol 2009; 36: 8-37
• 7 Varadhachary GR. Carcinoma of unknown primary origin. Gastrointest Cancer Res 2007; 1: 229-35
• 8 Anderson GG, Weiss LM. Determining tissue of origin for metastatic cancers: Meta-analysis and literature review of immunohistochemistry performance. Appl Immunohistochem Mol Morphol 2010; 18: 3-8
• 9 Erlander MG, Ma XJ, Kesty NC, Bao L, Salunga R, Schnabel CA. et al. Performance and clinical evaluation of the 92-gene real-time PCR assay for tumor classification. J Mol Diagn 2011; 13: 493-503
• 10 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: 801-12
• 11 Monzon FA, Lyons-Weiler M, Buturovic LJ, Rigl CT, Henner WD, Sciulli C. et al. Multicenter validation of a 1,550-gene expression profile for identification of tumor tissue of origin. J Clin Oncol 2009; 27: 2503-8
• 12 Pentheroudakis G, Golfinopoulos V, Pavlidis N. Switching benchmarks in cancer of unknown primary: From autopsy to microarray. Eur J Cancer 2007; 43: 2026-36
• 13 Bloom G, Yang IV, Boulware D, Kwong KY, Coppola D, Eschrich S. et al. Multi-platform, multi-site, microarray-based human tumor classification. Am J Pathol 2004; 164: 9-16
• 14 Tothill RW, Tothill A, Rischin D, Bousioutas A, Haviv I, van Laar RK. et al. An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin. Cancer Res 2005; 65: 4031-40
• 15 Brachtel EF, Operaña TN, Sullivan PS, Kerr SE, Cherkis KA, Schroeder BE. et al Molecular classification of cancer with the 92-gene assay in cytology and limited tissue samples. Oncotarget 2016; 7: 27220-31
• 16 Greco FA, Spigel DR, Yardley DA, Erlander MG, Ma XJ, Hainsworth JD. et al. Molecular profiling in unknown primary cancer: Accuracy of tissue of origin prediction. Oncologist 2010; 15: 500-6
• 17 Handorf CR, Kulkarni A, Grenert JP, Weiss LM, Rogers WM, Kim OS. et al. A multicenter study directly comparing the diagnostic accuracy of gene expression profiling and immunohistochemistry for primary site identification in metastatic tumors. Am J Surg Pathol 2013; 37: 1067-75
• 18 Joshi U, van der Hoeven JJ, Comans EF, Herder GJ, Teule GJ, Hoekstra OS. et al In search of an unknown primary tumour presenting with extracervical metastases: The diagnostic performance of FDG-PET. Br J Radiol 2004; 77: 1000-6
• 19 Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer 2004; 101: 2641-9
• 20 Rudmik L, Lau HY, Matthews TW, Bosch JD, Kloiber R, Molnar CP. et al. Clinical utility of PET/CT in the evaluation of head and neck squamous cell carcinoma with an unknown primary: A prospective clinical trial. Head Neck 2011; 33: 935-40
• 21 Moller AK, Loft A, Berthelsen AK, Damgaard PedersenK, Graff J, Christensen CB. et al 18F-FDG PET/CT as a diagnostic tool in patients with extracervical carcinoma of unknown primary site: A literature review. Oncologist 2011; 16: 445-51
• 22 Greco FA, Vaughn WK, Hainsworth JD. Advanced poorly differentiated carcinoma of unknown primary site: Recognition of a treatable syndrome. Ann Intern Med 1986; 104: 547-53
• 23 Motzer RJ, Rodriguez E, Reuter VE, Bosl GJ, Mazumdar M, Chaganti RS. et al. Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site. J Clin Oncol 1995; 13: 274-82
• 24 Rowley JD. Recurring chromosome abnormalities in leukemia and lymphoma. Semin Hematol 1990; 27: 122-36
• 25 Schorge JO, Muto MG, Welch WR, Bandera CA, Rubin SC, Bell DA. et al. Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations. J Natl Cancer Inst 1998; 90: 841-5
• 26 Tobacman JK, Greene MH, Tucker MA, Costa J, Kase R, Fraumeni JFJr. , et al Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet 1982; 2: 795-7
• 27 Roh MH, Kindelberger D, Crum CP. Serous tubal intraepithelial carcinoma and the dominant ovarian mass: Clues to serous tumor origin?. Am J Surg Pathol 2009; 33: 376-83
• 28 Semmel DR, Folkins AK, Hirsch MS, Nucci MR, Crum CP. Intercepting early pelvic serous carcinoma by routine pathological examination of the fimbria. Mod Pathol 2009; 22: 985-8
• 29 Pentheroudakis G, Pavlidis N. Serous papillary peritoneal carcinoma: Unknown primary tumour, ovarian cancer counterpart or a distinct entity? A systematic review. Crit Rev Oncol Hematol 2010; 75: 27-42
• 30 Baron PL, Moore MP, Kinne DW, Candela FC, Osborne MP, Petrek JA. et al. Occult breast cancer presenting with axillary metastases. Updated management. Arch Surg 1990; 125: 210-4
• 31 Khandelwal AK, Garguilo GA. Therapeutic options for occult breast cancer: A survey of the American Society of Breast Surgeons and Review of the Literature. Am J Surg 2005; 190: 609-13
• 32 Walker GV, Smith GL, Perkins GH, Oh JL, Woodward W, Yu TK. et al. Population-based analysis of occult primary breast cancer with axillary lymph node metastasis. Cancer 2010; 116: 4000-6
• 33 Tell DT, Khoury JM, Taylor HG, Veasey SP. Atypical metastasis from prostate cancer Clinical utility of the immunoperoxidase technique for prostate-specific antigen. JAMA 1985; 253: 3574-5
• 34 Richardson RL, Greco FA, Wolff S. Extragonadal germ cell malignancy: Value of tumor markers in metastatic carcinoma in young males (Abstr). Proc Am Assoc Cancer Res 1979; 20: 204-1979
• 35 Fox RM, Woods RL, Tattersall MH. Undifferentiated carcinoma in young men: The atypical teratoma syndrome. Lancet 1979; 1: 1316-8
• 36 Lapeyre M, Malissard L, Peiffert D, Hoffstetter S, Toussaint B, Renier S. et al. Cervical lymph node metastasis from an unknown primary: Is a tonsillectomy necessary?. Int J Radiat Oncol Biol Phys 1997; 39: 291-6
• 37 Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M. et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol 2009; 27: 4656-63
• 38 Hainsworth JD, Johnson DH, Greco FA. Poorly differentiated neuroendocrine carcinoma of unknown primary site. A newly recognized clinicopathologic entity. Ann Intern Med 1988; 109: 364-71
• 39 Varadhachary GR, Raber MN, Matamoros A, Abbruzzese JL. Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions. Lancet Oncol 2008; 9: 596-9
• 40 Varadhachary GR, Karanth S, Qiao W, Carlson HR, Raber MN, Hainsworth JD. et al. Carcinoma of unknown primary with gastrointestinal profile: Immunohistochemistry and survival data for this favorable subset. Int J Clin Oncol 2014; 19: 479-84
• 41 Sinha S, Greco FA. Therapy of adenocarcinoma of unknown primary: Are we making progress?. J Natl Compr Canc Netw 2008; 6: 1061-7
• 42 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. J Clin Oncol 2013; 31: 217-23