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Cancer of unknown primary site: 20 questions to be answered
symposium article
Annals of Oncology 21 (Supplement 7): vii303–vii307, 2010 doi:10.1093/annonc/mdq278
Cancer of unknown primary site: 20 questions to be answered N. Pavlidis* & G. Pentheroudakis Department of Medical Oncology, University of Ioannina, Greece
Cancer of unknown primary (CUP) is a common, well-recognized and heterogeneous clinical syndrome. Patients with CUP present with metastatic disease in the absence of an identifiable primary tumour despite a diagnostic work-up. Aetiologically, CUP might either harbor primaries that cannot be detected by the standardized diagnostic investigations or carry distinct genetic and epigenetic aberrations. In this article we try to clarify the clinical and pathological enigma of CUP by answering 20 important questions related to this entity.
Cancer of unknown primary (CUP) accounts for some 3–5% of cancer in both sexes and ranks among the 10 most common malignancies in developed societies. It is considered to be the seventh to eighth most frequent type of cancer and the fourth most common cause of cancer-related death. The annual age-adjusted incidence per 100 000 population in the USA is 7–12 cases, in Australia 18–19 cases and in The Netherlands 5.3–6.7 cases [1].
There is evidence that CUP does not follow a type 1 progression (from a pre-malignant lesion to malignant), but is malignant to begin with (type 2 progression). More than 50% of CUP patients present with multiple site involvement and carry a unique natural history which differs from that of patients with known primary cancers. This unique natural history includes some characteristics such as: (i) early dissemination; (ii) clinical absence of the primary tumour; (iii) unpredictability of metastatic pattern; and (iv) aggressiveness of the disease itself. The unpredictable metastatic pattern refers to the differences in the incidence of metastatic sites at diagnosis between known and unknown primary cancers. For example, pancreatic carcinoma presenting as CUP has a 4- to 5-fold higher incidence of bone and lung involvement compared with the known primary tumour [1, 2].
question 2: what is the definition of CUP? The clinical definition of CUP refers to patients who present with histologically confirmed metastatic cancer in whom medical history, physical examination, full blood count, basic biochemistry battery, urinalysis, stool occult blood testing, immunohistochemistry with specific markers, imaging technology with chest X-ray, computed tomography (CT) of the thorax, abdomen and pelvis, as well as mammography, magnetic resonance imaging (MRI) and positron emission tomography (PET) scan in certain cases, fail to detect the primary tumour [2].
question 3: what about aetiology and risk factors in CUP? In this heterogeneous group of malignancies, most of which follow an aggressive biological and clinical course, there are no obvious aetiological or risk factors that contribute to the pathogenesis of the syndrome [1, 2]. *Correspondence to: Prof. N. Pavlidis, Department of Medical Oncology, Ioannina University Hospital, 451 10 Ioannina, Greece. Tel:/Fax: +30-2651-99394; E-mail: [email protected]
question 5: what are the most common histopathological types of CUP? CUP is classified into four major histopathological subtypes: well or moderately differentiated adenocarcinomas (50%); undifferentiated or poorly differentiated adenocarcinomas or carcinomas (30%); squamous cell carcinomas (15%); and undifferentiated neoplasms (5%). Within the group of undifferentiated neoplasms neuroendocrine tumours are the most representative types, followed by other histopathological diagnoses such as those of not specified carcinomas, lymphomas, germ cell tumours, melanomas, sarcomas or embryonal carcinomas [3].
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
symposium article
question 4: is there any specific natural history in CUP patients?
Downloaded from http://annonc.oxfordjournals.org/ by guest on January 7, 2015
question 1: what is the incidence of CUP?
symposium article question 6: what is the optimal immunohistochemical diagnostic approach for CUP? The following steps of an immunohistochemical panel should be performed on CUP bioptic material.
Step 1 (detects broad type of cancer) Carcinoma (AE1/3 pancytokeratin), lymphoma [common leukocyte antigen (CLA)], melanoma (S100, HMB45), sarcoma (none of the above, S100 or vimentin positive).
Step 3 (detects origin of an adenocarcinoma) Prostate [PSA, prostate acid phosphatase (PAP)], lung (TTF1), breast [gross cystic disease fluid protein (GCDFP-15), mammaglobin, oestrogen receptor (ER)], colon (CDX2, CK20) pancreas/biliary (CDX2, CK20, CK7), ovary [ER, carbohydrate antigen 125 (CA 125), mesothelin] [4].
question 7: what diagnostic aid does molecular technology provide in CUP patients? Identification of the primary site by multiple gene expression profiling (by RT–PCR or DNA or microRNA microarray platforms) carries a relatively high specificity and sensitivity. In fact, the overall accuracy from 12 studies with several hundreds of tumour samples is 75–85% [5]. Nevertheless, their prognostic or predictive benefit remains unclear. Moreover, it is not known if molecular identification of a primary tissue of origin and administration of primary-specific therapy will result in improvement of patient outcome, which is the ultimate goal.
question 8: which of the available imaging radiographic studies contribute to the detection of the primary site? Routine chest radiograph has always been a part of the initial evaluation. CT scanning of the abdomen and pelvis is able to detect a primary site in 30–35% of patients. CT of the chest determines mainly the extent of metastatic disease. Mammography is useful for females with axillary metastatic adenocarcinoma; however MRI of the breast is more sensitive. 2-[18F]Fluoro-2-deoxy-D-glucose (FDG)-PET scan is valuable
vii304 | Pavlidis & Pentheroudakis
for CUP patients with hidden primaries in the head and neck area as well as in the lungs (sensitivity up to 45%) [1, 2].
question 9: how valuable are endoscopy studies for the identification of the primary site? Endoscopies should be used only if specific clinical symptoms or signs are present, i.e. ENT endoscopy is recommended in patients with isolated cervical nodal enlargement, gastrointestinal endoscopies in abdominal symptoms or occult blood in the stool, fibreoptic bronchoscopy in patients with pulmonary symptoms and/or imaging findings, and proctoscopy and/or colonoscopy in patients with inguinal lymph node involvement. In any other case the sensitivity is very low [1, 2].
question 10: do serum tumour markers contribute to the detection of the primary site? In general, routine evaluation of commonly used epithelial serum tumour markers [CA 19-9, CA 15-3, carcinoembryonic antigen (CEA), CA 125] has no diagnostic value in identifying the primary. However, it is important to request b-HCG, AFP and PSA in male CUP patients to rule out chemosensitive or hormone-sensitive neoplasms. Also, serum thyroglobulin, CA 15-3 and CA 125 are useful in certain CUP subsets such as suspected thyroid cancer, females with isolated axillary lymphadenopathy and adenocarcinoma, or women with primary peritoneal serous/papillary adenocarcinoma [1, 2].
question 11: how often can the primary tumour be identified? The antemortem frequency of detection of the primary site by imaging, endoscopy or immunohistochemistry studies remains 20–30%. Out of almost 1000 patients who underwent autopsies between 1944 and 2000, lung and pancreatic cancers were the most frequent primaries found (half of all autopsies). On the other hand, it is interesting to point out that the most frequent primaries assigned by molecular platforms were breast cancer (15%) followed by pancreatic cancer (12.5%), bowel cancer (12%) and lung cancer (11.5%) [1, 2, 6].
question 12: is CUP one or more diseases? CUP is a heterogeneous group of nosological entities based on histological, clinical, therapeutic and prognostic characteristics. It is classified into favourable and unfavourable subsets. The following subsets belong to the favourable entities: (i) poorly differentiated carcinoma with midline distribution; (ii) women with papillary adenocarcinoma of the peritoneal cavity; (iii) females with adenocarcinoma involving only axillary lymph nodes; (iv) squamous cell carcinoma involving cervical lymph nodes; (v) isolated inguinal adenopathy (squamous cell carcinoma); (vi)
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Step 2 (detects subtype of carcinoma) Adenocarcinoma [cytokeratin (CK) 7/20, prostate-specific antigen (PSA)], germ cell tumour [placental alkaline phosphatase (PLAP), OCT4, a-fetoprotein (AFP), human chorionic gonadotrophin (HCG], hepatocellular carcinoma (Hepar 1, canalicular pCEA/CD10/CD13), renal cell carcinoma (RCC, CD10), thyroid carcinoma [thyroid transcription factor 1 (TTF1), thyroglobulin], neuroendocrine carcinomas [chromogranin, synaptophysin, protein gene product 9.5 (PGP9.5), CD56], squamous carcinoma (CK5/6, p63).
Annals of Oncology
symposium article
Annals of Oncology
poorly differentiated neuroendocrine carcinomas; (vii) men with blastic bone metastases and elevated PSA (adenocarcinoma); and (viii) patients with a single, small and potentially resectable tumour. The unfavourable CUP group, which represents 80% of CUP patients, consists of: (i) adenocarcinoma metastatic to the liver or other organs; (ii) non-papillary malignant ascites (adenocarcinoma); (iii) multiple cerebral metastases; (iv) multiple lung/pleural metastases; and (v) multiple metastatic bone disease not expessing PSA in tumour/serum [1, 2].
question 13: what is the therapeutic management and prognosis of CUP patients with poorly differentiated carcinoma with midline distribution
question 14: how do we treat women with serous papillary adenocarcinoma of the peritoneal cavity? This entity is also called primary peritoneal carcinoma and it is treated as FIGO stage III–IV ovarian cancer with surgical cytoreduction and platinum-based postoperative chemotherapy. Overall response rate is up to 60%, with 30% complete responders. Median survival is 16 months with 10% 5-year survivors [1, 2]. In a recent systematic review it was reported that these patients have the following characteristics: (i) patterns of loss of heterozygosity at several chromosomal loci distinct from classical ovarian cancer patients; (ii) more
question 15: do we treat women with isolated adenocarcinoma of axillary nodes with a multidisciplinary approach? In general, these patients are managed similarly to those with stage II or III breast cancer. Patients with N1 disease (mobile nodes) should be treated with axillary clearance followed by either simple mastectomy or breast radiotherapy. Premenopausal patients with positive ERs should receive adjuvant chemotherapy followed by hormone treatment, while postmenopausal women should receive only endocrine treatment (tamoxifen or aromatase inhibitors). There are no adequate data concerning adjuvant chemotherapy in these patients. For N2 disease (fixed nodes), preoperative neoadjuvant chemotherapy is recommended followed by conventional guideline practice for stage III breast cancer. Mastectomy or radiotherapy provided locoregional disease control in 75–80% of cases. Mean 5- and 10-year survival is reported as 75% and 60%, respectively [1, 2, 11].
question 16: what is the therapeutic management and prognosis of CUP patients with squamous cell carcinoma involving the cervical lymph nodes? These patients should be treated with aggressive multimodal therapy similar to patients with locally advanced head and neck cancer. Surgery alone is not recommended except in patients with pN1 neck disease with no extracapsular extension. Extensive irradiation to both sides of the neck and the mucosa
Table 1. Optimal management of patients with CUP subgroups CUP subtype
Proposed treatment
Equivalent tumour
Poorly differentiated carcinoma, predominantly nodal disease Poorly differentiated neuroendocrine carcinomas Peritoneal adenocarcinomatosis of a serous papillary histological type in females Isolated axillary nodal metastases in females
Platinum-based combination chemotherapy
Extragonadal germ cell tumour
Platinum + etoposide combination chemotherapy Optimal surgical debulking followed by platinum-based chemotherapy Axillary nodal dissection, mastectomy or breast irradiation and adjuvant chemohormonotherapy Neck dissection and/or irradiation of bilateral neck and head–neck axis. For advanced stages, induction chemotherapy with platinum-based combination or chemoradiation Hormonal therapy with LHRH agonists and/or antiandrogens Palliative chemotherapy, clinical trial or best supportive care
Small cell lung cancer Ovarian cancer
Squamous carcinoma involving non-supraclavicular cervical lymph nodes
Metastases in bone adenocarcinoma and elevated serum PSA in males Poor-risk visceral CUP
Breast cancer Head and neck squamous cancer
Prostate cancer Unknown
CUP, cancer of unknown primary; LHRH, luteinizing hormone-releasing hormone; PSA, prostate-specific antigen.
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Generally, it was recognized and managed as an extragonadallike germ cell syndrome with platinum-based combination chemotherapy. Median response rate is 50%, with 25% complete responses. Despite high response rates the median survival clustered around 12 months with only 10% long survivors [7–9]. It is likely that only a minority of patients with midline nodal CUP harbour atypical extragonadal germ cell cancer (Table 1).
frequent HER2 oncogene overexpression; (iii) more advanced patient age; (iv) disease is more multifocal with diffuse micronodular spread difficult to debulk; and (vi) patient survival is inferior to that of ovarian cancer patients by 2–6 months [10].
symposium article in the entire pharyngeal axis and larynx should be given. Locoregional management offers long-term disease control in 50–60% of patients. Concurrent chemoradiotherapy seems to be beneficial especially in N2 or N3 disease patients [1, 2, 12].
questions 17: are poorly differentiated neuroendocrine carcinomas chemosensitive tumours?
question 19: is there any evidence that targeted systemic treatment is effective in CUP patients? There are only two completed studies using bevacizumab and erlotinib in CUP patients. The first was a phase II trial of bevacizumab and erlotinib in 51 patients with CUP treated in the second-line setting after chemotherapy or previously untreated patients with disease with poor prognosis. Only 10% had partial responses and 61% had stable disease. Median survival was 7.4 months, with 33% of patients alive at 1 year. The authors claimed superiority in survival in comparison with other second-line treatments. The second study was a first-line treatment with the combination of paclitaxel/carboplatin plus bevacizumab/ erlotinib. Chemotherapy was given for only four cycles; however, bevacizumab/erlotinib was continued until tumour progression. Fifty-three percent of the patients had major responses and 30% had stable disease. Median progression-free survival time was 8 months, with 38% of patients progression free at 1 year. Median survival was 12.6 months. Despite the results not being different from past regimens, the authors stated that this regimen is effective and well tolerated and needs further development [18, 19].
question 18: what is the optimal treatment and final outcome for CUP patients with unfavourable subsets?
question 20: are there any predictive or prognostic factors that we should know about in patients with CUP?
Patients with unfavourable CUP have dismal prognosis despite treatment with platinum- and/or taxane-based chemotherapy. Although chemotherapy can offer clinical benefit to some of these patients, overall survival remains poor. From mainly phase II studies as well as from some randomized trials the overall response rates range from 25% to 50%; however, median survival remains low at between 6 and 14 months [1, 2, 14]. Moreover, a multiple treatments meta-analysis of 10 randomized trials (683 subjects) showed no significant survival benefit for any chemotherapeutic regimen over others [15]. The subset of liver metastases is the most common and most representative subset of the unfavourable group. From a recent systematic review of a total of 711 patients from five studies treated with platinum and non-platinum combinations, the overall response rate was <20% with 0–4.7% complete responders and a median survival of 8–9 months [14]. Although gene profiling can detect the primary site in up to 85% of the cases, responses and survival when treated with cytotoxic combinations relevant to the primary tissue of origin-specific seem to be dissimilar to those with known primary tumours, i.e. irinotecan- or oxaliplatin-based chemotherapy activity between known metastatic colorectal cancer and CUP patients. Probably CUP patients carry a unique biological behaviour (genetic signature?) [16]. According to guidelines, patients of relatively young age and good performance status could be offered the chance of platinum-based chemotherapy or accrual in clinical trials. Alternatively, best supportive care could be recommended [17].
A few studies have elaborated predictive and prognostic factors in CUP patients by examining several clinicopathological parameters. The most significant favourable factors were categorized into: (i) histopathological features (poorly differentiated carcinoma, squamous cell carcinoma and neuroendocrine carcinoma); (ii) patients and clinical characteristics (female gender, good performance status, no weight loss, low number of metastatic sites, absence of liver and bone metastases); and (iii) serum markers (normal lactate dehydrogenase, alkaline phosphatase, CEA, no lymphopenia or low serum albumin) [20–22].
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epilogue CUP remains a diagnostic and therapeutic challenge for both patients and physicians. Patients with favourable risk CUP subsets harbour metastatic tumours from occult primaries with biology not drastically different from that of corresponding metastatic tumours from overt primaries. They should receive primary-specific therapy, matched to that of the equivalent known primary tumour, as they often enjoy long-term disease control. The majority (80%) of CUP patients with systemic visceral metastases are probably affected by a distinct clinical entity characterized by regression/dormancy of the primary, early high-volume systemic spread to uncommon sites and resistance to chemotherapy. These patients have a dismal outcome and should be treated in the context of trials evaluating new cytotoxic and targeted therapies. Poor-risk CUP, even when biologically assigned to a tissue of origin, often
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Neuroendocrine CUP are tumours arising from an occult primary site from several organs, i.e. pancreas, bronchus and stomach, and represents <5% of unknown primary cancers. Histologically, they are classified as either low-grade or well-differentiated neuroendocrine carcinomas (10%) with a slowly progressive outcome or as poorly differentiated, high-grade or anaplastic (90%) including small cell and large cell neuroendocrine neoplasms. Low-grade tumours should be managed locoregionally [resection, arterial chemoembolization, radiofrequency ablation (RFA)] or with symptomatic palliation with octreotide. High-grade tumours should be treated with platinum and etoposide or taxane combination chemotherapy. The response rate is 70%, with 20% complete responders and a median survival of 15 months (13% longterm survivors) [1, 2, 13].
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behaves differently from metastatic tumours of known origin. Whole-genome profiling studies may identify distinct molecular and epigenetic aberrations, unique for this heterogeneous group of systemic tumours.
disclosures The author has declared no conflict of interest.
references
Volume 21 | Supplement 7 | October 2010
11. Pentheroudakis G, Lazaridis G, Pavlidis N. Axillary nodal metastases from carcinoma of unknown primary (CUPAX): a sytematic review of published evidence. Breast Cancer Res Treat 2010; 119: 1–11. 12. Pavlidis N, Pentheroudakis G, Plataniotis G. Cervical lymph node metastases of squamous cell carcinoma from an unknown primary site: a favourable prognosis subset of patients with CUP. Clin Trans Oncol 2009; 6: 340–348. 13. Spiegel DR, Hainsworth JD, Greco FA. Neuroendrocrine carcinoma of unknown primary site. Semin Oncol 2009; 36: 52–59. 14. Lazaridis G, Pentheroudakis G, Fountzilas G et al. Liver metastases from cancer of unknown primary (CUPL): a retrospective analysis of presentation, management and prognosis in 49 patients and systematic review of the literature. Cancer Treat Rev 2008; 34: 693–700. 15. Golfinopoulos V, Pentheroudakis G, Salanti G et al. Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: multiple-treatments meta-analysis. Cancer Treat Rev 2009; 35: 570–573. 16. Pentheroudakis G, Greco FA, Pavlidis N. Molecular assignment of tissue origin of cancer to therapy or outcome: a systematic literature review. Cancer Treat Rev 2009; 35: 221–227. 17. Briasoulis E, Pavlidis N, Felip E. Cancers of unknown primary site: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; Suppl 4: 154–155. 18. 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: 1747–1752. 19. Hainsworth JD, Spigel DR, Thompson DS et al. Paclitaxel/carboplatin plus bevacizumab/erlotinib in the first-line treatment of patients with carcinoma of unknown primary site. Oncologist 2009; 14: 1189–1197. 20. Abruzzese SL, Abbruzzese MC, Hess KR et al. Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 1994; 12: 1272–1280. 21. Pasterz R, Savaraj N, Burgess M. Prognostic factors in metastatic carcinoma of unknown primary. J Clin Oncol 1986; 4: 1652–1657. 22. 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 systemic chemotherapy. Ann Oncol 2010; 21: 1163–1167.
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1. Pavlidis N, Fizazi K. Carcinoma of unknown primary. Crit Rev Oncol Hematol 2009; 69: 271–278. 2. Pavlidis N, Briasoulis E, Hainsworth J et al. Diagnostic and therapeutic management of cancer of unknown primary. Eur J Cancer 2003; 39: 1990–2005. 3. Fritz A, Percy C, Jack A et al. (eds). International Classification of Diseases for Oncology (ICD-O), 3rd edition. Geneva: World Health Organization 2000. 4. Oien KA. Pathologic evaluation of unknown primary cancer. Semin Oncol 2009; 36: 8–37. 5. Bender R, Erlander MG. Molecular classification of unknown primary cancer. Semin Oncol 2009; 36: 38–43. 6. Pentheroudakis G, Goflinopoulos V, Pavlidis N. Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur J Cancer 2007; 43: 2026–2036. 7. Greco FA, Vaughn WK, Hainsworth JD. Advanced poorly differentiated carcinoma of unknown primary site: recognition of a treatable syndrome. Ann Intern Med 1986; 104: 547–553. 8. Van der Gaast, Verweij J, Henzen-Logmans SC et al. Carcinoma of unknown primary: identification of a treatable subset? Ann Oncol 1990; 1: 119–122. 9. Penteroudakis G, Briasoulis E, Karavassilis V et al. Chemotherapy for patients with two favourable subsets of unknown primary carcinomas: active, but how effective? Acta Oncol 2005; 44: 155–160. 10. 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 2009 Nov 6. [Epub ahead of print].
symposium article
Annals of Oncology 21 (Supplement 7): vii303–vii307, 2010 doi:10.1093/annonc/mdq278
Cancer of unknown primary site: 20 questions to be answered N. Pavlidis* & G. Pentheroudakis Department of Medical Oncology, University of Ioannina, Greece
Cancer of unknown primary (CUP) is a common, well-recognized and heterogeneous clinical syndrome. Patients with CUP present with metastatic disease in the absence of an identifiable primary tumour despite a diagnostic work-up. Aetiologically, CUP might either harbor primaries that cannot be detected by the standardized diagnostic investigations or carry distinct genetic and epigenetic aberrations. In this article we try to clarify the clinical and pathological enigma of CUP by answering 20 important questions related to this entity.
Cancer of unknown primary (CUP) accounts for some 3–5% of cancer in both sexes and ranks among the 10 most common malignancies in developed societies. It is considered to be the seventh to eighth most frequent type of cancer and the fourth most common cause of cancer-related death. The annual age-adjusted incidence per 100 000 population in the USA is 7–12 cases, in Australia 18–19 cases and in The Netherlands 5.3–6.7 cases [1].
There is evidence that CUP does not follow a type 1 progression (from a pre-malignant lesion to malignant), but is malignant to begin with (type 2 progression). More than 50% of CUP patients present with multiple site involvement and carry a unique natural history which differs from that of patients with known primary cancers. This unique natural history includes some characteristics such as: (i) early dissemination; (ii) clinical absence of the primary tumour; (iii) unpredictability of metastatic pattern; and (iv) aggressiveness of the disease itself. The unpredictable metastatic pattern refers to the differences in the incidence of metastatic sites at diagnosis between known and unknown primary cancers. For example, pancreatic carcinoma presenting as CUP has a 4- to 5-fold higher incidence of bone and lung involvement compared with the known primary tumour [1, 2].
question 2: what is the definition of CUP? The clinical definition of CUP refers to patients who present with histologically confirmed metastatic cancer in whom medical history, physical examination, full blood count, basic biochemistry battery, urinalysis, stool occult blood testing, immunohistochemistry with specific markers, imaging technology with chest X-ray, computed tomography (CT) of the thorax, abdomen and pelvis, as well as mammography, magnetic resonance imaging (MRI) and positron emission tomography (PET) scan in certain cases, fail to detect the primary tumour [2].
question 3: what about aetiology and risk factors in CUP? In this heterogeneous group of malignancies, most of which follow an aggressive biological and clinical course, there are no obvious aetiological or risk factors that contribute to the pathogenesis of the syndrome [1, 2]. *Correspondence to: Prof. N. Pavlidis, Department of Medical Oncology, Ioannina University Hospital, 451 10 Ioannina, Greece. Tel:/Fax: +30-2651-99394; E-mail: [email protected]
question 5: what are the most common histopathological types of CUP? CUP is classified into four major histopathological subtypes: well or moderately differentiated adenocarcinomas (50%); undifferentiated or poorly differentiated adenocarcinomas or carcinomas (30%); squamous cell carcinomas (15%); and undifferentiated neoplasms (5%). Within the group of undifferentiated neoplasms neuroendocrine tumours are the most representative types, followed by other histopathological diagnoses such as those of not specified carcinomas, lymphomas, germ cell tumours, melanomas, sarcomas or embryonal carcinomas [3].
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
symposium article
question 4: is there any specific natural history in CUP patients?
Downloaded from http://annonc.oxfordjournals.org/ by guest on January 7, 2015
question 1: what is the incidence of CUP?
symposium article question 6: what is the optimal immunohistochemical diagnostic approach for CUP? The following steps of an immunohistochemical panel should be performed on CUP bioptic material.
Step 1 (detects broad type of cancer) Carcinoma (AE1/3 pancytokeratin), lymphoma [common leukocyte antigen (CLA)], melanoma (S100, HMB45), sarcoma (none of the above, S100 or vimentin positive).
Step 3 (detects origin of an adenocarcinoma) Prostate [PSA, prostate acid phosphatase (PAP)], lung (TTF1), breast [gross cystic disease fluid protein (GCDFP-15), mammaglobin, oestrogen receptor (ER)], colon (CDX2, CK20) pancreas/biliary (CDX2, CK20, CK7), ovary [ER, carbohydrate antigen 125 (CA 125), mesothelin] [4].
question 7: what diagnostic aid does molecular technology provide in CUP patients? Identification of the primary site by multiple gene expression profiling (by RT–PCR or DNA or microRNA microarray platforms) carries a relatively high specificity and sensitivity. In fact, the overall accuracy from 12 studies with several hundreds of tumour samples is 75–85% [5]. Nevertheless, their prognostic or predictive benefit remains unclear. Moreover, it is not known if molecular identification of a primary tissue of origin and administration of primary-specific therapy will result in improvement of patient outcome, which is the ultimate goal.
question 8: which of the available imaging radiographic studies contribute to the detection of the primary site? Routine chest radiograph has always been a part of the initial evaluation. CT scanning of the abdomen and pelvis is able to detect a primary site in 30–35% of patients. CT of the chest determines mainly the extent of metastatic disease. Mammography is useful for females with axillary metastatic adenocarcinoma; however MRI of the breast is more sensitive. 2-[18F]Fluoro-2-deoxy-D-glucose (FDG)-PET scan is valuable
vii304 | Pavlidis & Pentheroudakis
for CUP patients with hidden primaries in the head and neck area as well as in the lungs (sensitivity up to 45%) [1, 2].
question 9: how valuable are endoscopy studies for the identification of the primary site? Endoscopies should be used only if specific clinical symptoms or signs are present, i.e. ENT endoscopy is recommended in patients with isolated cervical nodal enlargement, gastrointestinal endoscopies in abdominal symptoms or occult blood in the stool, fibreoptic bronchoscopy in patients with pulmonary symptoms and/or imaging findings, and proctoscopy and/or colonoscopy in patients with inguinal lymph node involvement. In any other case the sensitivity is very low [1, 2].
question 10: do serum tumour markers contribute to the detection of the primary site? In general, routine evaluation of commonly used epithelial serum tumour markers [CA 19-9, CA 15-3, carcinoembryonic antigen (CEA), CA 125] has no diagnostic value in identifying the primary. However, it is important to request b-HCG, AFP and PSA in male CUP patients to rule out chemosensitive or hormone-sensitive neoplasms. Also, serum thyroglobulin, CA 15-3 and CA 125 are useful in certain CUP subsets such as suspected thyroid cancer, females with isolated axillary lymphadenopathy and adenocarcinoma, or women with primary peritoneal serous/papillary adenocarcinoma [1, 2].
question 11: how often can the primary tumour be identified? The antemortem frequency of detection of the primary site by imaging, endoscopy or immunohistochemistry studies remains 20–30%. Out of almost 1000 patients who underwent autopsies between 1944 and 2000, lung and pancreatic cancers were the most frequent primaries found (half of all autopsies). On the other hand, it is interesting to point out that the most frequent primaries assigned by molecular platforms were breast cancer (15%) followed by pancreatic cancer (12.5%), bowel cancer (12%) and lung cancer (11.5%) [1, 2, 6].
question 12: is CUP one or more diseases? CUP is a heterogeneous group of nosological entities based on histological, clinical, therapeutic and prognostic characteristics. It is classified into favourable and unfavourable subsets. The following subsets belong to the favourable entities: (i) poorly differentiated carcinoma with midline distribution; (ii) women with papillary adenocarcinoma of the peritoneal cavity; (iii) females with adenocarcinoma involving only axillary lymph nodes; (iv) squamous cell carcinoma involving cervical lymph nodes; (v) isolated inguinal adenopathy (squamous cell carcinoma); (vi)
Volume 21 | Supplement 7 | October 2010
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Step 2 (detects subtype of carcinoma) Adenocarcinoma [cytokeratin (CK) 7/20, prostate-specific antigen (PSA)], germ cell tumour [placental alkaline phosphatase (PLAP), OCT4, a-fetoprotein (AFP), human chorionic gonadotrophin (HCG], hepatocellular carcinoma (Hepar 1, canalicular pCEA/CD10/CD13), renal cell carcinoma (RCC, CD10), thyroid carcinoma [thyroid transcription factor 1 (TTF1), thyroglobulin], neuroendocrine carcinomas [chromogranin, synaptophysin, protein gene product 9.5 (PGP9.5), CD56], squamous carcinoma (CK5/6, p63).
Annals of Oncology
symposium article
Annals of Oncology
poorly differentiated neuroendocrine carcinomas; (vii) men with blastic bone metastases and elevated PSA (adenocarcinoma); and (viii) patients with a single, small and potentially resectable tumour. The unfavourable CUP group, which represents 80% of CUP patients, consists of: (i) adenocarcinoma metastatic to the liver or other organs; (ii) non-papillary malignant ascites (adenocarcinoma); (iii) multiple cerebral metastases; (iv) multiple lung/pleural metastases; and (v) multiple metastatic bone disease not expessing PSA in tumour/serum [1, 2].
question 13: what is the therapeutic management and prognosis of CUP patients with poorly differentiated carcinoma with midline distribution
question 14: how do we treat women with serous papillary adenocarcinoma of the peritoneal cavity? This entity is also called primary peritoneal carcinoma and it is treated as FIGO stage III–IV ovarian cancer with surgical cytoreduction and platinum-based postoperative chemotherapy. Overall response rate is up to 60%, with 30% complete responders. Median survival is 16 months with 10% 5-year survivors [1, 2]. In a recent systematic review it was reported that these patients have the following characteristics: (i) patterns of loss of heterozygosity at several chromosomal loci distinct from classical ovarian cancer patients; (ii) more
question 15: do we treat women with isolated adenocarcinoma of axillary nodes with a multidisciplinary approach? In general, these patients are managed similarly to those with stage II or III breast cancer. Patients with N1 disease (mobile nodes) should be treated with axillary clearance followed by either simple mastectomy or breast radiotherapy. Premenopausal patients with positive ERs should receive adjuvant chemotherapy followed by hormone treatment, while postmenopausal women should receive only endocrine treatment (tamoxifen or aromatase inhibitors). There are no adequate data concerning adjuvant chemotherapy in these patients. For N2 disease (fixed nodes), preoperative neoadjuvant chemotherapy is recommended followed by conventional guideline practice for stage III breast cancer. Mastectomy or radiotherapy provided locoregional disease control in 75–80% of cases. Mean 5- and 10-year survival is reported as 75% and 60%, respectively [1, 2, 11].
question 16: what is the therapeutic management and prognosis of CUP patients with squamous cell carcinoma involving the cervical lymph nodes? These patients should be treated with aggressive multimodal therapy similar to patients with locally advanced head and neck cancer. Surgery alone is not recommended except in patients with pN1 neck disease with no extracapsular extension. Extensive irradiation to both sides of the neck and the mucosa
Table 1. Optimal management of patients with CUP subgroups CUP subtype
Proposed treatment
Equivalent tumour
Poorly differentiated carcinoma, predominantly nodal disease Poorly differentiated neuroendocrine carcinomas Peritoneal adenocarcinomatosis of a serous papillary histological type in females Isolated axillary nodal metastases in females
Platinum-based combination chemotherapy
Extragonadal germ cell tumour
Platinum + etoposide combination chemotherapy Optimal surgical debulking followed by platinum-based chemotherapy Axillary nodal dissection, mastectomy or breast irradiation and adjuvant chemohormonotherapy Neck dissection and/or irradiation of bilateral neck and head–neck axis. For advanced stages, induction chemotherapy with platinum-based combination or chemoradiation Hormonal therapy with LHRH agonists and/or antiandrogens Palliative chemotherapy, clinical trial or best supportive care
Small cell lung cancer Ovarian cancer
Squamous carcinoma involving non-supraclavicular cervical lymph nodes
Metastases in bone adenocarcinoma and elevated serum PSA in males Poor-risk visceral CUP
Breast cancer Head and neck squamous cancer
Prostate cancer Unknown
CUP, cancer of unknown primary; LHRH, luteinizing hormone-releasing hormone; PSA, prostate-specific antigen.
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Generally, it was recognized and managed as an extragonadallike germ cell syndrome with platinum-based combination chemotherapy. Median response rate is 50%, with 25% complete responses. Despite high response rates the median survival clustered around 12 months with only 10% long survivors [7–9]. It is likely that only a minority of patients with midline nodal CUP harbour atypical extragonadal germ cell cancer (Table 1).
frequent HER2 oncogene overexpression; (iii) more advanced patient age; (iv) disease is more multifocal with diffuse micronodular spread difficult to debulk; and (vi) patient survival is inferior to that of ovarian cancer patients by 2–6 months [10].
symposium article in the entire pharyngeal axis and larynx should be given. Locoregional management offers long-term disease control in 50–60% of patients. Concurrent chemoradiotherapy seems to be beneficial especially in N2 or N3 disease patients [1, 2, 12].
questions 17: are poorly differentiated neuroendocrine carcinomas chemosensitive tumours?
question 19: is there any evidence that targeted systemic treatment is effective in CUP patients? There are only two completed studies using bevacizumab and erlotinib in CUP patients. The first was a phase II trial of bevacizumab and erlotinib in 51 patients with CUP treated in the second-line setting after chemotherapy or previously untreated patients with disease with poor prognosis. Only 10% had partial responses and 61% had stable disease. Median survival was 7.4 months, with 33% of patients alive at 1 year. The authors claimed superiority in survival in comparison with other second-line treatments. The second study was a first-line treatment with the combination of paclitaxel/carboplatin plus bevacizumab/ erlotinib. Chemotherapy was given for only four cycles; however, bevacizumab/erlotinib was continued until tumour progression. Fifty-three percent of the patients had major responses and 30% had stable disease. Median progression-free survival time was 8 months, with 38% of patients progression free at 1 year. Median survival was 12.6 months. Despite the results not being different from past regimens, the authors stated that this regimen is effective and well tolerated and needs further development [18, 19].
question 18: what is the optimal treatment and final outcome for CUP patients with unfavourable subsets?
question 20: are there any predictive or prognostic factors that we should know about in patients with CUP?
Patients with unfavourable CUP have dismal prognosis despite treatment with platinum- and/or taxane-based chemotherapy. Although chemotherapy can offer clinical benefit to some of these patients, overall survival remains poor. From mainly phase II studies as well as from some randomized trials the overall response rates range from 25% to 50%; however, median survival remains low at between 6 and 14 months [1, 2, 14]. Moreover, a multiple treatments meta-analysis of 10 randomized trials (683 subjects) showed no significant survival benefit for any chemotherapeutic regimen over others [15]. The subset of liver metastases is the most common and most representative subset of the unfavourable group. From a recent systematic review of a total of 711 patients from five studies treated with platinum and non-platinum combinations, the overall response rate was <20% with 0–4.7% complete responders and a median survival of 8–9 months [14]. Although gene profiling can detect the primary site in up to 85% of the cases, responses and survival when treated with cytotoxic combinations relevant to the primary tissue of origin-specific seem to be dissimilar to those with known primary tumours, i.e. irinotecan- or oxaliplatin-based chemotherapy activity between known metastatic colorectal cancer and CUP patients. Probably CUP patients carry a unique biological behaviour (genetic signature?) [16]. According to guidelines, patients of relatively young age and good performance status could be offered the chance of platinum-based chemotherapy or accrual in clinical trials. Alternatively, best supportive care could be recommended [17].
A few studies have elaborated predictive and prognostic factors in CUP patients by examining several clinicopathological parameters. The most significant favourable factors were categorized into: (i) histopathological features (poorly differentiated carcinoma, squamous cell carcinoma and neuroendocrine carcinoma); (ii) patients and clinical characteristics (female gender, good performance status, no weight loss, low number of metastatic sites, absence of liver and bone metastases); and (iii) serum markers (normal lactate dehydrogenase, alkaline phosphatase, CEA, no lymphopenia or low serum albumin) [20–22].
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epilogue CUP remains a diagnostic and therapeutic challenge for both patients and physicians. Patients with favourable risk CUP subsets harbour metastatic tumours from occult primaries with biology not drastically different from that of corresponding metastatic tumours from overt primaries. They should receive primary-specific therapy, matched to that of the equivalent known primary tumour, as they often enjoy long-term disease control. The majority (80%) of CUP patients with systemic visceral metastases are probably affected by a distinct clinical entity characterized by regression/dormancy of the primary, early high-volume systemic spread to uncommon sites and resistance to chemotherapy. These patients have a dismal outcome and should be treated in the context of trials evaluating new cytotoxic and targeted therapies. Poor-risk CUP, even when biologically assigned to a tissue of origin, often
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Neuroendocrine CUP are tumours arising from an occult primary site from several organs, i.e. pancreas, bronchus and stomach, and represents <5% of unknown primary cancers. Histologically, they are classified as either low-grade or well-differentiated neuroendocrine carcinomas (10%) with a slowly progressive outcome or as poorly differentiated, high-grade or anaplastic (90%) including small cell and large cell neuroendocrine neoplasms. Low-grade tumours should be managed locoregionally [resection, arterial chemoembolization, radiofrequency ablation (RFA)] or with symptomatic palliation with octreotide. High-grade tumours should be treated with platinum and etoposide or taxane combination chemotherapy. The response rate is 70%, with 20% complete responders and a median survival of 15 months (13% longterm survivors) [1, 2, 13].
Annals of Oncology
Annals of Oncology
behaves differently from metastatic tumours of known origin. Whole-genome profiling studies may identify distinct molecular and epigenetic aberrations, unique for this heterogeneous group of systemic tumours.
disclosures The author has declared no conflict of interest.
references
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