Cancer of unknown primary (CUP)

Critical Reviews in Oncology/Hematology 54 (2005) 243 250 Cancer of unknown primary (CUP) Nicholas Pavlidis a,, Karim Fizazi b a School of Medicine, Department of Medical Oncology, University of Ioannina, Greece b Institut Gustave Roussy, Villejuif, France Accepted 7 October 2004 Abstract Carcinoma of unknown primary (CUP) is one of the 10 most frequent cancers worldwide. It constitutes 3 5% of all human malignancies. Patients with CUP present with metastases without an established primary site. CUP manifests as an heterogenous group of mainly epithelial cancers recognised by distinct clinicopathological entities. The diagnostic work-up includes extensive histopathology investigations and modern imaging technology. Nevertheless, the primary tumour remains undetected most of the time. Certain clinicopathological CUP entities are considered as favourable subsets responding to systemic platinum-based chemotherapy or managed by locoregional treatment. These subsets are: the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, peritoneal papillary serous adenocarcinomatosis in females, poorly differentiated neuroendocrine carcinomas, isolated axillary node adenocarcinomas in females or cervical nodal involvement by a squamous cell carcinoma. Patients who belong to the non-favourable subsets have a worse prognosis. 2005 Published by Elsevier Ireland Ltd. Keywords: Carcinoma of unknown primary; Cancer; Tumour Contents 1. General information... 244 1.1. Epidemiology... 244 1.1.1. Incidence and mortality... 244 1.2. Aetiology and risk factors... 244 1.3. Early diagnosis... 244 1.4. Referral... 244 2. Pathology and biology... 244 2.1. Histological types... 244 2.2. Biology... 245 2.2.1. Chromosomal and molecular abnormalities... 245 3. Diagnosis... 245 3.1. Diagnostic evaluation for the identification of primary site and staging... 245 3.2. Diagnostic pathology... 245 3.3. Diagnostic radiology... 246 3.4. Diagnostic endoscopy... 246 3.5. Diagnostic value of serum tumour markers... 246 4. Staging... 246 4.1. Clinicopathological sub-sets... 246 Corresponding author. Tel.: +30 26510 99394; fax: +30 26510 99394. E-mail address: npavlid@cc.uoi.gr (N. Pavlidis). 1040-8428/$ see front matter 2005 Published by Elsevier Ireland Ltd. doi:10.1016/j.critrevonc.2004.10.002

244 N. Pavlidis, K. Fizazi / Critical Reviews in Oncology/Hematology 54 (2005) 243 250 5. Prognosis... 246 5.1. Prognostic and predictive factors... 246 6. Treatment... 247 6.1. Overall strategy... 247 6.2. Treatment of favourable groups... 247 6.2.1. Poorly differentiated carcinoma with midline distribution (extragonadal germ cell syndrome)... 247 6.2.2. Women with papillary adenocarcinoma of peritoneal cavity... 247 6.2.3. Women with adenocarcinoma involving only axillary lymph nodes... 247 6.2.4. Squamous cell carcinoma involving cervical lymph nodes... 247 6.2.5. Isolated inguinal lymphadenopathy from squamous cell carcinoma... 248 6.2.6. Poorly differentiated neuroendocrine carcinomas... 248 6.2.7. Men with blastic bone metastases and elevated PSA from an adenocarcinoma... 248 6.2.8. CUP patients with a single small metastasis... 248 6.3. Treatment of unfavorable groups... 248 6.4. Second-line chemotherapy... 248 7. Late sequelae... 248 7.1. Late sequelae related to surgery, radiation therapy and chemotherapy... 248 8. Follow-up... 248 References... 248 Biographies... 250 1. General information 1.1. Epidemiology 1.1.1. Incidence and mortality Cancer of unknown primary (CUP) is the seventh to eighth most frequently occurring cancer in the world and the fourth commonest cause of cancer death in both males and females [1]. CUP accounts for some 2.3 4.2% of cancer in both sexes. The annual age-adjusted incidence per 100.000 population in USA is 7 12 cases, in Australia 18 19 cases and in the Netherlands 5.3 6.7 cases. The median age for occurrence is around 60 years and CUP is marginally more frequent in males. Country Worldwide epidemiology of CUP Switzerland [2] 2.3 USA [3] 2.3 Finland [4] 2.5 Japan [5] 3.0 Russia [6] 3.6 Netherlands [7] 4.0 Australia [8] 4.2 1.2. Aetiology and risk factors Frequency (% of CUP among all cancers) In this heterogenous group of tumours, most of which follow an aggressive biological and clinical course, there are no obvious aetiological or risk factors that contribute to the pathogenesis of this syndrome. 1.3. Early diagnosis Early detection of CUP is not possible. Therefore, no current screening programmes are available. 1.4. Referral Referral of CUP patients from general medical settings to specialized institutions is recommended. 2. Pathology and biology 2.1. Histological types CUP is classified into the following histological types; the ICD-O 2000 morphology code is provided in brackets [9]: Adenocarcinoma [M 8140/3] Well to moderately differentiated Poorly or undifferentiated Squamous cell carcinoma [M 8070/3] Undifferentiated neoplasms Not specified carcinoma Neuroendocrine tumours [M-8246/3] Lymphomas [M 9590/3] Germ cell tumours [M-9064/3] Melanomas [M 8720/3] Sarcomas [M 8800/3] Embryonal malignancies [M-9070/3] Almost 50% of patients with CUP will be diagnosed with metastatic adenocarcinoma of well to moderate differentiation, 30% with undifferentiated or poorly differentiated

N. Pavlidis, K. Fizazi / Critical Reviews in Oncology/Hematology 54 (2005) 243 250 245 carcinomas, 15% with squamous cell carcinomas and the remaining 5% will have undifferentiated neoplasms. Immunohistopathological studies can be utilised to further characterize the undifferentiated neoplasms, poorly differentiated carcinomas, neuroendocrine tumours, lymphomas, germ cell tumours, melanomas, sarcomas and embryonal malignancies [10]. In children, embryonal malignancies make up the majority of the rare cases of disseminated malignancies without an identified primary tumour. 2.2. Biology CUP is a heterogeneous group of tumours. There is no evidence regarding whether CUP carries a distinct biological entity involving specific genetic and phenotypic alterations. The issue has not been extensively investigated on a molecular basis, and the limited information available is still controversial and inconclusive. In general, CUP follows an aggressive biological and clinical behaviour. 2.2.1. Chromosomal and molecular abnormalities Chromosonal abnormalities have been detected in the short arm of chromosome 1 including deletion of 1p, translocations with a breakpoint at 1p, isochromosome 1q and evidence for gene amplification. Identical results have also been reported in other advanced malignancies. Similar chromosomal abnormalities have been found in the short arm of chromosome 12. The isochromosome i(12)p or a deletion in 12p a germ cell chromosomal marker was observed in 25% of patients with poorly differentiated carcinoma and predominant lymph nodal disease [11,12]. Chromosomal instability (aneuploidy) was found in 70% of patients with metastatic adenocarcinoma or undifferentiated carcinoma [13]. In one study, overexpression of c-myc, ras and c-erb-b2, as demonstrated by immunohistochemistry, was reported in 96%, 92% and 65% of cases respectively. However, in another study c-erb-b2 expression was found in 11% of patients with poorly differentiated carcinomas [14,15]. Additionally, using immunohistochemistry bcl-2 and p53 were overexpressed in 40% and 53% of cases respectively, whereas using PCR only 26% of patients expressed p53 [16,17]. Furthermore, the incidence of p53 mutations was 26% of the cases studied [17]. No differences in angiogenesis, as measured by microvessel density, were detected between CUP patients with liver metastases and those with hepatic secondaries from known primaries [18]. 3. Diagnosis 3.1. Diagnostic evaluation for the identification of primary site and staging Despite extensive work-up, less than 20% of patients with CUP have a primary site of their cancer identified antemortem. Autopsy studies have reported that 70% of cases remained undiagnosed. 3.2. Diagnostic pathology An adequate sample of tumour tissue is essential for carrying out light microscopy examinations, immunohistochemical investigations, evaluating other markers or receptors as well as performing more specific investigations such as electron microscopy or genetic/molecular studies. Light microscopy can only characterize cell morphology and tumour differentiation. Immunohistochemical studies are of paramount importance. Several cell components can be identified by the immunoperoxidase technique using a series of monoclonal or polyclonal antibodies to enzymes, structural tissue components (i.e. cytokeratins), hormonal receptors, hormones, oncofetal antigens or other substances [10,19]. Tumour type Immunoperoxidase marker Carcinoma Cytokeratin, EMA Lymphoma CLA, EMA (±) Sarcoma Vimentin, desmin, factor VIII antigen Melanoma S-100, HMB-45, vimentin, NSE Neuroendocrine Chromogranin, synaptophysin, cytokeratin, EMA, NSE Germ-cell Cytokeratin, EMA, HCG, AFP Prostate cancer PSA, cytokeratin, EMA Breast cancer Cytokeratin, EMA, ER, PR Thyroid cancer Thyroglobulin, cytokeratin, EMA, calcitonin Organ Cytokeratins Colon CK7 /CK20+ Stomach CK7 /CK20+, CK7+/CK20+ Biliary tree CK7+/CK20, CK7+/CK20+ Pancreas CK7+/CK20, CK7+/CK20+ Lung CK7+/CK20 Ovary non-mucinous CK7+/CK20 Ovary, mucinous CK7 /CK20+, CK7+/CK20+ Breast CK7+/CK20 Urinary tract CK7+/CK20+ Endometrium CK7+/CK20 Prostate CK7 /CK20 Kidney CK7 /CK20 Liver CK7 /CK20 Electron microscopy should be considered in the evaluation of poorly differentiated neoplasms in young patients, particularly when immunnoperoxidase stains are inconclusive [10]. Cytogenetic analysis could be useful in the evaluation of young patients with poorly differentiated carcinomas or undifferentiated neoplasms potentially responsive to

246 N. Pavlidis, K. Fizazi / Critical Reviews in Oncology/Hematology 54 (2005) 243 250 chemotherapy i.e. identification of isochromosome i(12p) in poorly differentiated carcinoma with lymph nodal midline distribution, of translocation t[11, 22] [q24; q12] in peripheral neuroectodermal tumour and Ewing s sarcoma, of t [8; 14] [q24; q32] in non-hodgkin s lymphomas, of t[3; 13] in alveolar rhabdomyosarcoma or of 3p deletion in small cell lung carcinoma [20,21]. 3.3. Diagnostic radiology In terms of conventional radiology, a routine chest radiograph is part of the initial evaluation of the patient with CUP. Computed tomography (CT) of the abdomen and pelvis results in the detection of a primary site for the cancer in 30 35% of patients. CT of the chest has not been adequately studied. CT scans can also be helpful in evaluating the stage of the disease [22]. Mammography has been recommended for female patients with metastatic adenocarcinoma involving axillary lymph nodes. Magnetic resonance imaging was found to be very sensitive for the detection of mammographically occult breast cancer [23]. FDG-PET scans are a valuable modern imaging technique for patients with CUP, particularly for patients with squamous pathology involving the cervical lymph nodes [24,25]. 3.4. Diagnostic endoscopy Endoscopic studies should always be directed towards investigating specific symptoms or signs. For example, patients with pulmonary symptoms and/or indications for imaging should be offered fiberoptic bronchoscopy, or patients with abdominal symptoms or occult blood in the stool should be investigated with gastrointestinal endoscopies [26]. 3.5. Diagnostic value of serum tumour markers Serum b-chorionic gonadotropin, (b-hcg), a-fetoprotein (AFP) and prostate specific antigen (PSA) should be requested for male patients with CUP, in order to exclude treatable extragonadal germ cell tumours and metastatic prostate cancer. High levels of serum thyroglobulin in CUP patients with bone metastases is indicative of an occult thyroid cancer. In certain subsets, such as those with isolated axillary nodal metastatic disease and in peritoneal papillary adenocarcinomatosis, serum CA 15-3 and CA 125 could be of some help [27]. diagnostic approaches and to be able to offer optimal therapeutic management [27]. The classification of the different clinicopathological entities is shown bellow: Organ Liver (mainly) and/or other organs Lymph nodes Mediastinalretroperitoneal (midline distribution) Axillary Cervical Inguinal Peritoneal cavity Peritoneal adenocarcinomatosis in females Malignant ascites of other unknown origin Lungs Pulmonary metastases Pleural effusions Bones (solitary or multiple) Brain (solitary or multiple) Neuroendrocrine tumours Malignant melanoma Histology AdenoCa moderately or poorly differentiated Undifferentiated or poorly differentiated Ca AdenoCa well to poorly differentiated Squamous cell Ca Undifferentiated Ca, squamous, mixed squamous/adenoca Papillary or serous adenoca (±psammoma bodies) Mucin-producing adenoca moderately or poorly differentiated (±signet ring cells) AdenoCa of various differentiations AdenoCa moderately or poorly differentiated AdenoCa of various differentiations AdenoCa of various differentiations or squamous cell Ca Poorly differentiated Ca with neuroendocrine features (mainly), low-grade neuroendocrine Cas, small cell anaplastic Cas Undifferentiated neoplasm with melanoma features 4. Staging 4.1. Clinicopathological sub-sets It is very important to classify CUP patients into established clinicopathological sub-sets in order to guide 5. Prognosis 5.1. Prognostic and predictive factors Median survival in CUP patients enrolled in clinical studies ranges from 6 to 10 months, but in an unselected CUP

N. Pavlidis, K. Fizazi / Critical Reviews in Oncology/Hematology 54 (2005) 243 250 247 population outside a clinical trial, life expectancy is only 2 3 months [28]. The prognostic and predictive factors examined in two available studies include age, gender, performance status, weight loss, histopathology, tumour burden, tumour location, number of metastatic sites and serum markers. The factors characterized as significant were certain histopathological sub-sets (poorly differentiated carcinoma, squamous cell carcinoma, neuroendocrine carcinoma), number of metastatic lesions ( 2), female sex, performance status, weight loss and various serum markers (alkaline phosphatase, LDH, CEA). The detection of these prognostic and predictive factors helped to distinguish the favourable from the unfavourable groups of CUP patients [29 31]. 6. Treatment 6.1. Overall strategy Treatment recommendation for CUP patients are based on a type 3 level of evidence and available treatment options are considered as suitable for individual clinical use or investigational. For adequate therapeutic guidance CUP entities should be categorized into favourable or unfavourable sub-sets. Some favourable sub-sets require specific treatment approaches and have the potential for an excellent treatment outcome. The favourable and unfavourable sub-sets of CUP are illustrated below: Favourable sub-sets 1. Poorly differentiated carcinoma with midline distribution (extragonadal germ cell syndrome). 2. Women with papillary adenocarcinoma of the peritoneal cavity. 3. Women with adenocarcinoma involving only axillary lymph nodes. 4. Squamous cell carcinoma involving cervical lymph nodes. 5. Isolated inguinal adenopathy (squamous carcinoma). 6. Poorly differentiated neuroendocrine carcinomas. 7. Men with blastic bone metastases and elevated PSA (adenocarcinoma). 8. Patients with a single, small, potentially resectable tumour. Unfavourable sub-sets 1. Adenocarcinoma metastatic to the liver or other organs. 2. Non-papillary malignant ascites (adenocarcinoma). 3. Multiple cerebral metastases (adeno or squamous carcinoma). 4. Multiple lung/pleural metastases (adenocarcinoma). 5. Multiple metastatic bone disease (adenocarcinoma). 6.2. Treatment of favourable groups 6.2.1. Poorly differentiated carcinoma with midline distribution (extragonadal germ cell syndrome) This subset of CUP should be managed in a manner similar to poor prognosis germ cell tumours with platinum-based combination chemotherapy, on a type 3 level of evidence [32,33]. More than 50% response has been reported, with 15 25% complete responders and 10 15% long-term disease free survivors. 6.2.2. Women with papillary adenocarcinoma of peritoneal cavity These patients should optimally be treated as FIGO stage III ovarian cancer with aggressive surgical cytoreduction followed by platinum-based postoperative chemotherapy, on a type 3 level of evidence [34,35]. Survival is identical to FIGO stage III ovarian cancer patients. 6.2.3. Women with adenocarcinoma involving only axillary lymph nodes In these patients, locoregional treatment with or without systemic therapy is suggested. The management is similar to that of stage II or III breast cancer. In patients with N1 disease (mobile nodes) axillary clearance followed be either a simple mastectomy or breast radiotherapy is recommended. In premenopausal women with positive oestrogen receptors, adjuvant chemotherapy followed by tamoxifen administration is recommended. For postmenopausal patients with positive oestrogen receptors tamoxifen is still recommended. No data are available concerning adjuvant chemotherapy in these patients. In patients with N2 disease (fixed nodes), preoperative neoadjuvant chemotherapy is suggested following the guidelines for stage III breast cancer. However, in non-responding tumours or in elderly patients, radical radiotherapy should be the treatment of choice. Oestrogen receptor positive patients should continue on tamoxifen treatment. All the above data are on a type 3 level of evidence [36 38]. The reported 5- and 10-year overall survival rates are 75 and 60%, respectively. 6.2.4. Squamous cell carcinoma involving cervical lymph nodes These patients should be treated with locoregional management according to the guidelines for locally advanced head and neck cancer. The 5-year survival rates range from 35 to 50% with documented long-term disease-free survivors, on a type 3 level of evidence [39,40]. Surgery alone is inferior and can be recommended only in selected patients, particularly those with pn1 neck disease with no extracapsular extension. Radiotherapy to the ipsilateral cervical nodes alone is still inferior to extensive irradiation to both sides of the neck and the mucosa in the entire pharyngeal axis and larynx. Whether

248 N. Pavlidis, K. Fizazi / Critical Reviews in Oncology/Hematology 54 (2005) 243 250 such an intensive irradiation prolongs survival is still uncertain. Although the role of systemic chemotherapy remains undefined, concurrent chemoradiotherapy seems to be beneficial particularly in patients with an N2 or N3 lymph node disease. 6.2.5. Isolated inguinal lymphadenopathy from squamous cell carcinoma Inguinal node dissection, with or without local radiotherapy, is the recommended treatment for this sub-set of patients on a type R basis [41]. Long-term survivors have been reported. 6.2.6. Poorly differentiated neuroendocrine carcinomas This group of CUP patients should be treated with platinum-based or paclitaxel/carboplatin-based chemotherapy on a type 3 level of evidence [10,42,43]. The reported response rates are as high as 50 70% with 25% complete responders and 10 15% long-term survivors. 6.2.7. Men with blastic bone metastases and elevated PSA from an adenocarcinoma This rare sub-set of CUP patients, although still debatable, should be considered as having metastatic prostate cancer and endocrine treatment is recommended as the initial therapy on a type R basis [10,27]. 6.2.8. CUP patients with a single small metastasis Local treatment with either resection and/or radiotherapy should be recommended on a type R basis [27]. A considerable number of these patients enjoy palliative benefit and some of them a long disease-free survival. 6.3. Treatment of unfavorable groups No chemotherapy regimen has been found convincingly effective for the majority of CUP patients presenting with disseminated bone, liver or multi-organ metastases of adenocarcinoma. Despite some evidence of response, median survival is still in the range of 8 9 months. Chemotherapy regimens used include platinum or taxane/platinum combinations, on a type 3 level of evidence [10, 27]. Randomized studies have shown similar activity between platinum combined with gemcitabine or irinotecan as well as between platinum-based and taxane-based chemotherapy, on a type 2 level of evidence [31,44]. Only investigational treatment options apply to these patients. Alternatively, low toxicity chemotherapy of palliative intent or best supportive care should be considered. 6.4. Second-line chemotherapy Second-line chemotherapy with various regimens in patients who have failed platinum-based treatment has been reported to be ineffective, on a type 3 level of evidence [31,45]. 7. Late sequelae 7.1. Late sequelae related to surgery, radiation therapy and chemotherapy Clinically significant long-term sequelae related to surgery in specific CUP subsets, i.e. in women with adenocarcinoma involving axillary lymph nodes or in women with papillary adenocarcinoma of peritoneal cavity or in patients with squamous cell carcinoma involving cervical lymph nodes, are no different from the relevant surgical late complications of patients with known primary breast, ovarian or head-neck cancers of similar clinical stages. Clinically long-term sequelae related to radiation therapy in women with adenocarcinoma involving axillary lymph nodes or in patients with squamous cell carcinoma involving cervical lymph nodes are similar to those of known primary breast and head-neck cancers. In a majority of patients late sequelae attributable to chemotherapy do not represent a clinical problem since median survival is no longer than 1 year. In the minority of patients with long-term survival late toxicities are similar to those seen in patients treated with platinum and/or taxane based chemotherapy. 8. Follow-up The short life expectancy of CUP patients leaves little room for developing guideline recommendations for a follow up strategy. As a general rule, after completion of treatment, patients in sub-sets with a poor prognosis should attend outpatient clinics upon need, but patients with a favourable CUP sub-set diagnosis should be seen on a regular basis similar to that followed for the respective solid tumour, such as germ-line tumours for patients with middle line distribution, ovarian cancer for carcinomatosis peritonei in women and breast cancer for patients with axillary nodal metastases. References [1] Krementz ET, Cerise EJ, Foster DS, Morgan Jr LR. Metastases of undetermined source. Curr Probl Cancer 1979;4:4 37. [2] Levi F, Te VC, Erler G, Randimbison L, La Vecchia C. Epidemiology of unknown primary tumours. Eur J Cancer 2002;38:1810 2. [3] Muir C. Cancer of unknown primary site. Cancer 1995;75:353 6. [4] Parkin DM, Muir CS, Whelan S, Gao YT, Ferlay J, Powell J, et al. Cancer incidence in five continents, vol. VI. Lyon: IARC. Scientific Publication Number 120; 1992. [5] Parkin DM, Whelan S, Ferlay J, Raymond L, Young J. Cancer incidence in five continents, vol. VII. Lyon: IARC No. 143; 1991.

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250 N. Pavlidis, K. Fizazi / Critical Reviews in Oncology/Hematology 54 (2005) 243 250 Biographies Nicholas Pavlidis is Professor of Medical Oncology in the University of Ioannina, Greece, Member of the Educational and Guidelines Committees of ESMO and Program Coordinator of ESO for Balkans and Middle East. Karim Fizazi is a medical oncologist. He is the chairman of the genitourinary oncology group at Gustave Roussy Institute (IGR), Villejuif, France, which is the largest cancer center in Europe. He is currently the chairman of the French study group of Carcinomas of an Unknown Primary (GEF- CAPI).