Adenocarcinoma of unknown primary site
- John D Hainsworth, MD
John D Hainsworth, MD
- Chief Scientific Officer
- Sarah Cannon Research Institute
- F Anthony Greco, MD
F Anthony Greco, MD
- Medical Director
- Sarah Cannon Cancer Center
Cancer of unknown primary site (CUP) is a relatively common clinical entity, accounting for 4 to 5 percent of all invasive cancers . Within this category, tumors from many primary sites with varying biology are represented. This heterogeneity has made the design and interpretation of clinical studies difficult. (See "Overview of the classification and management of cancers of unknown primary site".)
Adenocarcinomas of unknown primary site comprise approximately 70 percent of CUPs. In these patients, the focus is on identifying specific subsets in which disease-oriented therapy may be more effective than empiric therapy; this is based upon a combination of clinical features, immunohistochemistry (IHC), and molecular tumor profiling.
The diagnosis and management of patients with adenocarcinoma of unknown primary are reviewed here. The diagnosis and management of the other CUPs are discussed separately. (See "Overview of the classification and management of cancers of unknown primary site".)
The incidence of adenocarcinoma of unknown primary site increases with age. The clinical presentation is determined by the sites of metastatic tumor involvement, which are frequently multiple and often include the liver, lungs, lymph nodes, and bones.
In autopsy series, the most frequently identified primary sites are lung, pancreas, hepatobiliary tree, and kidney, together accounting for approximately two-thirds of cases . However, tumors may arise from a wide variety of other primary sites. Adenocarcinomas of the breast and prostate are identified infrequently at autopsy, despite being the most common cancers in women and men, respectively. In 20 to 30 percent of patients, no primary site can be identified.
- Greco FA, Hainsworth JD. Introduction: unknown primary cancer. Semin Oncol 2009; 36:6.
- Pentheroudakis G, Golfinopoulos V, Pavlidis N. Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur J Cancer 2007; 43:2026.
- Hemminki K, Bevier M, Hemminki A, Sundquist J. Survival in cancer of unknown primary site: population-based analysis by site and histology. Ann Oncol 2012; 23:1854.
- Riihimäki M, Hemminki A, Sundquist K, Hemminki K. Time trends in survival from cancer of unknown primary: small steps forward. Eur J Cancer 2013; 49:2403.
- Dabbs D. Diagnostic immunohistochemistry, Churchill Livingstone, 2006.
- NCCN guidelines http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on June 26, 2014).
- Bohinski RJ, Bejarano PA, Balko G, et al. Determination of lung as the primary site of cerebral metastatic adenocarcinomas using monoclonal antibody to thyroid transcription factor-1. J Neurooncol 1998; 40:227.
- Kaufmann O, Dietel M. Thyroid transcription factor-1 is the superior immunohistochemical marker for pulmonary adenocarcinomas and large cell carcinomas compared to surfactant proteins A and B. Histopathology 2000; 36:8.
- Gomez-Fernandez C, Jorda M, Delgado PI, Ganjei-Azar P. Thyroid transcription factor 1: a marker for lung adenoarinoma in body cavity fluids. Cancer 2002; 96:289.
- Brown RW, Campagna LB, Dunn JK, Cagle PT. Immunohistochemical identification of tumor markers in metastatic adenocarcinoma. A diagnostic adjunct in the determination of primary site. Am J Clin Pathol 1997; 107:12.
- Kaufmann O, Deidesheimer T, Muehlenberg M, et al. Immunohistochemical differentiation of metastatic breast carcinomas from metastatic adenocarcinomas of other common primary sites. Histopathology 1996; 29:233.
- Lagendijk JH, Mullink H, Van Diest PJ, et al. Tracing the origin of adenocarcinomas with unknown primary using immunohistochemistry: differential diagnosis between colonic and ovarian carcinomas as primary sites. Hum Pathol 1998; 29:491.
- Tot T. Adenocarcinomas metastatic to the liver: the value of cytokeratins 20 and 7 in the search for unknown primary tumors. Cancer 1999; 85:171.
- Su AI, Welsh JB, Sapinoso LM, et al. Molecular classification of human carcinomas by use of gene expression signatures. Cancer Res 2001; 61:7388.
- Hammar SP. Metastatic adenocarcinoma of unknown primary origin. Hum Pathol 1998; 29:1393.
- Bender RA, Erlander MG. Molecular classification of unknown primary cancer. Semin Oncol 2009; 36:38.
- Erlander MG, Ma XJ, Kesty NC, et al. Performance and clinical evaluation of the 92-gene real-time PCR assay for tumor classification. J Mol Diagn 2011; 13:493.
- Pillai R, Deeter R, Rigl CT, et al. Validation and reproducibility of a microarray-based gene expression test for tumor identification in formalin-fixed, paraffin-embedded specimens. J Mol Diagn 2011; 13:48.
- Meiri E, Mueller WC, Rosenwald S, et al. A second-generation microRNA-based assay for diagnosing tumor tissue origin. Oncologist 2012; 17:801.
- Varadhachary GR, Talantov D, Raber MN, et al. Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol 2008; 26:4442.
- Horlings HM, van Laar RK, Kerst JM, et al. Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol 2008; 26:4435.
- Greco FA, Lennington WJ, Spigel DR, Hainsworth JD. Molecular profiling diagnosis in unknown primary cancer: accuracy and ability to complement standard pathology. J Natl Cancer Inst 2013; 105:782.
- Hainsworth JD, Schnabel CA, Erlander MG, et al. A retrospective study of treatment outcomes in patients with carcinoma of unknown primary site and a colorectal cancer molecular profile. Clin Colorectal Cancer 2012; 11:112.
- Hainsworth JD, Rubin MS, Spigel DR, 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.
- Ettinger DS, Handorf CR, Agulnik M, et al. Occult primary, version 3.2014. J Natl Compr Canc Netw 2014; 12:969.
- Hainsworth JD, Greco FA. Gene expression profiling in patients with carcinoma of unknown primary site: from translational research to standard of care. Virchows Arch 2014; 464:393.
- Shildt RA, Kennedy PS, Chen TT, et al. Management of patients with metastatic adenocarcinoma of unknown origin: a Southwest Oncology Group study. Cancer Treat Rep 1983; 67:77.
- Sève P, Billotey C, Broussolle C, et al. The role of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography in disseminated carcinoma of unknown primary site. Cancer 2007; 109:292.
- Moller AK, Loft A, Berthelsen AK, 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.
- Møller AK, Loft A, Berthelsen AK, 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.
- Currow DC, Findlay M, Cox K, Harnett PR. Elevated germ cell markers in carcinoma of uncertain primary site do not predict response to platinum based chemotherapy. Eur J Cancer 1996; 32A:2357.
- Pavlidis N, Kalef-Ezra J, Briassoulis E, et al. Evaluation of six tumor markers in patients with carcinoma of unknown primary. Med Pediatr Oncol 1994; 22:162.
- Dauplat J, Le Bouëdec G, Pomel C, Scherer C. Cytoreductive surgery for advanced stages of ovarian cancer. Semin Surg Oncol 2000; 19:42.
- Strnad CM, Grosh WW, Baxter J, et al. Peritoneal carcinomatosis of unknown primary site in women. A distinctive subset of adenocarcinoma. Ann Intern Med 1989; 111:213.
- Dalrymple JC, Bannatyne P, Russell P, et al. Extraovarian peritoneal serous papillary carcinoma. A clinicopathologic study of 31 cases. Cancer 1989; 64:110.
- Ransom DT, Patel SR, Keeney GL, et al. Papillary serous carcinoma of the peritoneum. A review of 33 cases treated with platin-based chemotherapy. Cancer 1990; 66:1091.
- Fromm GL, Gershenson DM, Silva EG. Papillary serous carcinoma of the peritoneum. Obstet Gynecol 1990; 75:89.
- Bloss JD, Liao SY, Buller RE, et al. Extraovarian peritoneal serous papillary carcinoma: a case-control retrospective comparison to papillary adenocarcinoma of the ovary. Gynecol Oncol 1993; 50:347.
- Katagiri H, Takahashi M, Inagaki J, et al. Determining the site of the primary cancer in patients with skeletal metastasis of unknown origin: a retrospective study. Cancer 1999; 86:533.
- Gentile PS, Carloss HW, Huang TY, et al. Disseminated prostatic carcinoma simulating primary lung cancer. Indications for immunodiagnostic studies. Cancer 1988; 62:711.
- 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.
- 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.
- Varadhachary GR, Karanth S, Qiao W, et al. Carcinoma of unknown primary with gastrointestinal profile: immunohistochemistry and survival data for this favorable subset. Int J Clin Oncol 2014; 19:479.
- Schorge JO, Muto MG, Welch WR, 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.
- Rades D, Kühnel G, Wildfang I, et al. Localised disease in cancer of unknown primary (CUP): the value of positron emission tomography (PET) for individual therapeutic management. Ann Oncol 2001; 12:1605.
- Nguyen LN, Maor MH, Oswald MJ. Brain metastases as the only manifestation of an undetected primary tumor. Cancer 1998; 83:2181.
- Salvati M, Cervoni L, Raco A. Single brain metastases from unknown primary malignancies in CT-era. J Neurooncol 1995; 23:75.
- Greco FA, Rubin MS, Boccia RV, et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients (pts) with carcinoma of unknown primary site (CUP): Results of a prospective Sarah Cannon Research Institute (SCRI) trial. J Clin Oncol 2012; 30: (suppl; abstr 10530).
- Greco FA, Pavlidis N. Treatment for patients with unknown primary carcinoma and unfavorable prognostic factors. Semin Oncol 2009; 36:65.
- Huebner G, Link H, Kohne CH, et al. Paclitaxel and carboplatin vs gemcitabine and vinorelbine in patients with adeno- or undifferentiated carcinoma of unknown primary: a randomised prospective phase II trial. Br J Cancer 2009; 100:44.
- Yonemori K, Ando M, Yunokawa M, et al. Irinotecan plus carboplatin for patients with carcinoma of unknown primary site. Br J Cancer 2009; 100:50.
- Palmeri S, Lorusso V, Palmeri L, et al. Cisplatin and gemcitabine with either vinorelbine or paclitaxel in the treatment of carcinomas of unknown primary site : results of an Italian multicenter, randomized, phase II study. Cancer 2006; 107:2898.
- Hainsworth JD, Spigel DR, Clark BL, et al. Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial. Cancer J 2010; 16:70.
- Hainsworth JD, Spigel DR, Burris HA 3rd, et al. Oxaliplatin and capecitabine in the treatment of patients with recurrent or refractory carcinoma of unknown primary site: a phase 2 trial of the Sarah Cannon Oncology Research Consortium. Cancer 2010; 116:2448.
- Hainsworth JD, Spigel DR, Farley C, et al. Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network. J Clin Oncol 2007; 25:1747.
- Hainsworth JD, Spigel DR, Raefsky EL, et al. Combination chemotherapy with gemcitabine and irinotecan in patients with previously treated carcinoma of an unknown primary site: a Minnie Pearl Cancer Research Network Phase II trial. Cancer 2005; 104:1992.
- Abbruzzese JL, Abbruzzese MC, Hess KR, et al. Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 1994; 12:1272.
- Hainsworth JD, Johnson DH, Greco FA. Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol 1992; 10:912.
- Saghatchian M, Fizazi K, Borel C, et al. Carcinoma of an unknown primary site: a chemotherapy strategy based on histological differentiation--results of a prospective study. Ann Oncol 2001; 12:535.
- van der Gaast A, Verweij J, Henzen-Logmans SC, et al. Carcinoma of unknown primary: identification of a treatable subset? Ann Oncol 1990; 1:119.
- Culine S, Kramar A, Saghatchian M, et al. Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site. J Clin Oncol 2002; 20:4679.
- Seve P, Ray-Coquard I, Trillet-Lenoir V, et al. Low serum albumin levels and liver metastasis are powerful prognostic markers for survival in patients with carcinomas of unknown primary site. Cancer 2006; 107:2698.
- Kodaira M, Takahashi S, Yamada S, et al. Bone metastasis and poor performance status are prognostic factors for survival of carcinoma of unknown primary site in patients treated with systematic chemotherapy. Ann Oncol 2010; 21:1163.
- Ross JS, Wang K, Gay L, et al.. Comprehensive genomic profiling of carcinoma of unknown primary site. Lancet Oncol 2015.
- CLINICAL COURSE
- Poorly differentiated adenocarcinoma
- Molecular tumor profiling
- INITIAL CLINICAL EVALUATION
- SPECIFIC PATIENT SUBGROUPS
- Women with peritoneal carcinomatosis
- - Pathology and pathogenesis
- - Management
- Women with axillary lymph node metastases
- Men with skeletal metastases
- Patients with a colon cancer profile
- Adenocarcinoma of unknown primary in a single site
- TREATMENT FOR PATIENTS NOT INCLUDED IN SPECIFIC SUBGROUPS
- Site-specific therapy directed by molecular tumor profiling
- - Empiric therapy
- - Prognostic factors
- - Experimental approaches
- - Summary
- SUMMARY AND RECOMMENDATIONS