Long-term survivors among patients with cancer of unknown primary

Critical Reviews in Oncology/Hematology 84 (2012) 85 92 Long-term survivors among patients with cancer of unknown primary Nicholas Pavlidis, Dimitrios Petrakis, Vassilios Golfinopoulos, George Pentheroudakis Department of Medical Oncology, Medical School, University of Ioannina, 451 10 Ioannina, Greece Accepted 1 February 2012 Contents 1. Introduction... 85 2. Pathology and immunochemistry profiling of cup... 86 3. Cup clinicopathological subsets... 86 4. The favorable cup subsets... 87 4.1. Women with serous papillary adenocarcinoma of the peritoneal cavity (primary peritoneal adenocarcinoma)... 87 4.2. Women with isolated axillary nodal metastases from adenocarcinoma... 87 4.3. Poorly differentiated carcinoma with midline distribution... 88 4.4. Neuroendocrine carcinoma of unknown primary... 88 4.5. Squamous cell carcinoma involving cervical lymph nodes... 89 4.6. Adenocarcinoma with a colon cancer profile... 89 4.7. Metastatic melanoma of unknown primary site (MUP)... 89 4.8. Men with osteoblastic metastases and elevated serum PSA... 89 4.9. Patients with limited CUP disease... 89 5. Discussion... 90 Conflict of interest... 91 Reviewers... 91 References... 91 Biography... 92 Abstract There is a general conception among oncologists that CUP patients behave poorly to treatment and carry a dismal survival. In this paper we are trying to elucidate the different groups of CUP patients and to describe in details the diagnostic and therapeutic management of the prognostically favorable patients. Clinicians should be aware that the favorable CUP cases must be treated according to recent guidelines with either specific locoregional and/or systemic therapy and that they commonly enjoy a long survival. Survival data of 219 CUP patients treated at Ioannina University Hospital from 1995 until 2011 are also presented. 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Cancer of unknown primary; Favorable subsets; Survival 1. Introduction Corresponding author at: University Hospital of Ioannina, 451 10 Ioannina, Greece. Tel.: +30 26510 99394; fax: +30 26510 99394. E-mail address: npavlid@uoi.gr (N. Pavlidis). Cancer of unknown primary (CUP) is a clinicopathological syndrome of patients who presented with histologically confirmed metastatic cancer without a primary site at diagnosis. The primary tumor remains undetectable despite a 1040-8428/$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2012.02.002

86 N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 84 (2012) 85 92 careful medical history and physical examination, laboratory investigations including blood, urine, stool tests, CT-scans, mammogram, MRI, PET-Scan and endoscopies as well as extensive immunohistochemical studies [1]. During the last few years diagnostic molecular tools such as gene profiling microarrays or micrornas led to the high accuracy of identification of the primary tumors [2,3]. CUP accounts for 3 5% of all cancer patients and is recognized as the 7th 8th most common malignant tumor and the fourth most frequent cause of death. Median age at diagnosis is 65 years with a slight predilection for males [4]. CUP is generally considered as an aggressive disease with an early dissemination of metastatic sites and a peculiar natural history in most of the cases. CUP s unique natural history is characterized by a short history of symptoms and signs which is attributed to an unpredictable metastatic pattern that is different from that of known primary cancers [1]. The biology and pathogenesis of CUP remains poorly understood despite some research efforts on oncogene, suppressor gene, receptor or signal transduction pathway expression as well as on angiogenesis or metalloproteinase level [5]. In this paper we are presenting to the oncology community the existing information on the favorable CUP subsets by reviewing the clinical picture, histopathology, therapeutic management and prognosis of these patients. We hope this endeavour will provide them with the best of knowledge about treatable patients with CUP. 2. Pathology and immunochemistry profiling of cup Pathologically CUP patients are divided into the following histological subtypes: (a) adenocarcinomas of well or moderate differentiation (50%), (b) undifferentiated or poorly differentiated adenocarcinomas (30%), (c) squamous cell carcinomas (15%), and (d) undifferentiated neoplasms (5%) [1]. Immunochemistry studies are considered as the cornerstone of CUP diagnostic approach. Immunoperoxidase techniques using a series of monoclonal or polyclonal antibodies can help in differentiating epithelial from nonepithelial tumors, in diagnosing adenocarcinomas from other solid cancers and in identifying the tissue of origin among adenocarcinoma cases [6,7]. Table 1 demonstrates the most commonly used immunoperoxidase markers. 3. Cup clinicopathological subsets Thirteen subsets of CUP patients have been recognized based mainly on the sites of metastases and the histopathological type. Clinically, they involve lymph nodal, serosal or osseal tissues as well as various vital organs i.e. liver, lungs or brain. Histologically, they belong to adenocarcinomas, squamous cell carcinomas, poorly differentiated carcinomas, neuroendocrine carcinomas or melanomas [1] (Table 2). Table 1 Immunochemistry studies used in the diagnostic algorithm of CUP. Immunoperoxidase stains Tumor type Carcinoma Pan-Cytokeratin, EMA Lymphoma CLA, (CD45RB), occasionally EMA Sarcoma Vimentin, desmin, S100, alpha-smooth muscle actin, myod1, CD34, c-kit, CD99 Melanoma S100, HMB45, Melan-A Carcinoma type Adenocarcinoma Light microscopy, PAS, CK7, CK20 Squamous cell carcinoma CK5/6, p63 Neuroendocrine carcinoma Chromogranin, synaptophysin, PGP9.5, CD56 Germ-cell carcinoma PLAP, OCT4, AFP, HCG Adenocarcinoma type Breast cancer ER, GCDFP-15, mamaglobulin, CK7+/CK20- Prostate cancer PSA, PAP, CK7 /CK20 Ovarian cancer CA125, mesothelin, WT1, ER, CK7+/CK20 Endometrial cancer CK7+/CK20, CA125, ER Colon cancer CDX2, CEA, CK7 /CK20+ Stomach cancer CDX2, CK7 /CK20+ Pancreatic cancer CK7+/CK20±, CA125, mesothelin Liver cancer Hepar-1, AFP, polyclonal CEA, CD10, CD13 Lung cancer TTF1, CK7+/CK20 Kidney cancer RCC, CD10, CK7 /CK 20 Thyroid cancer TTF1, thyroglobulin In 2003 CUP subsets have clearly been categorized to two major prognostic groups [8]. The favorable (good prognosis) group and the unfavorable (poor prognosis) group. In the favorable subsets patients with considerable responses to Table 2 Clinicopathological subsets of CUP patients. Organ Histopathology Lymph nodes Mediastinal retroperitoneal UDF or PDF Axillary AdenoCa (WDF/MDF/PDF) Cervical SCC Inguinal UDF, SCC, mixed SCC/adenoCa Peritoneal cavity Primary peritoneal in females AdenoCa (papillary/serous) Ascites of other unknown origin AdenoCa (MDF/PDF, mucin, ±signed ring cells) Neuroendocrine tumors PDF with neuroendocrine features, low-grade neuroendocrine Cas, small cell anaplastic Cas Liver (mainly) and/or other organs AdenoCa (MDF/PDF) Lungs Pulmonary metastases AdenoCa (WDF/MDF/PDF) Pleural effusions AdenoCa (MDF/PDF) Bones (solitary or multiple) AdenoCa (WDF/MDF/PDF) Brain (solitary or multiple) AdenoCa (WDF/UDF/PDF), SCC Malignant melanoma UDF neoplasm with melanoma features AdenoCa: adenocarcinoma, Cas: carcinomas, UDF: undifferentiated, WDF: well undifferentiated, MDF: moderately differentiated, PDF: poorly differentiated, SCC: squamous cell carcinoma.

N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 84 (2012) 85 92 87 Table 3 Favorable subsets of CUP. 1. Women with serous papillary adenocarcinoma of the peritoneal cavity. 2. Women with isolated axillary nodal metastases from adenocarcinoma. 3. Poorly differentiated carcinoma with midline distribution. 4. Neuroendrocrine carcinoma of unknown primary. 5. Squamous cell carcinoma involving cervical lymph nodes. 6. Adenocarcinoma with a colon - cancer profile. 7. Metastatic melanoma of unknown primary site. 8. Men with osteoblastic metastases and elevated serum PSA. 9. Patients with limited disease. systemic or locoregional treatments and longer survival are incorporated. Most of these patients are treated similarly to the hidden primaries i.e. breast cancer stage II III, ovarian cancer stage II III or locally advanced head and neck cancer. But also other CUP subtypes exhibit encouraging predictive and prognostic features i.e. neuroendrocrine tumors or adenocarcinomas with colon-cancer profile [9] (Table 3). Unfortunately, the unfavorable group of CUP patients represents the 70 80% of all CUP cases. 4. The favorable cup subsets 4.1. Women with serous papillary adenocarcinoma of the peritoneal cavity (primary peritoneal adenocarcinoma) Data on this issue are derived from a systematic review of 25 clinical series of a total of 579 patients with serous peritoneal papillary cancer [10]. Clinical picture: The incidence of this subset ranges between 7 and 20% of all women diagnosed with pelvic or peritoneal serous papillary malignancies. The median age is 55 65 years and seem to affect women 3 7 years older than those with ovarian cancer. The clinical picture resembles that of stage III/IV ovarian cancer characterized by abdominal pain and distention, palpable mass lesions, ascites or incomplete intestinal obstruction. Serum CA 125 levels are elevated in 70 90% of patients. Disease is more frequently multifocal and is predominantly located in the peritoneal, mesenteric and omental surfaces, followed by ovarian surface (70 95%), pelvic and retroperitoneal nodes (20 70%) and visceral organs (<15%). Histopathology: Histologically, all cases are diagnosed as serous papillary adenocarcinoma with or without the presence of psammoma bodies, while 40 60% of them carry poorly differentiated histology. Immunohistochemical expression is similar to ovarian cancer with positive pancytokeratins, epithelial membrane antigen, CA125, B72.3, S100, LN1, LN2, MB2 and Leu M1, however PLAP, amylase and CEA is expressed is a lesser degree. Therapeutic management: The recommended treatment of women with primary serous peritoneal carcinoma is optimal surgical debulking (residual lesions < 1 cm) following by platinum/taxane combination chemotherapy (Table 4). Table 4 Recommended therapeutic management for favorable CUP subsets. CUP subset Recommended treatment Women with serous papillary adenocarcinoma of the peritoneal cavity Women with isolated axillary nodal metastases from adenocarcinoma Poorly differentiated carcinoma with midline distribution Neuroendrocrine carcinoma of unknown primary Squamous cell carcinoma involving cervical lymph nodes Adenocarcinoma with a colon-cancer profile Metastatic melanoma of unknown primary site Men with osteoblastic metastases and elevated serum PSA Patients with limited disease Optimal surgical debulking followed by platinum-based chemotherapy Axillary nodal dissection, mastectomy or breast irradiation and adjuvant chemohormonotherapy Platinum-based combination chemotherapy Platinum-etoposide combination chemotherapy Neck dissection and/or irradiation of bilateral neck and head-neck axis for advanced stages induction chemotherapy with platinum-based combination or chemotherapy Colorectal chemotherapy regimen Surgical treatment for localized disease followed by chemoimmunotherapy. Systemic treatment for disseminated disease. Local radiotherapy is optional as postoperative treatment Hormonal therapy with LHRH agonists and/or antiandrogons. Local excision with or without radiotherapy Median response rate is similar to serous ovarian cancer around 80% (53 100%), with a clinical complete response rates of 50 70% and of 10 15% pathological complete responders. Optimal surgical cytoreduction (<1 2 cm) was reported to be feasible in 13 79% of patients. Prognosis: Mean overall survival is around 30 months (15 42 months). Optimal debulking is necessary for longterm survival (Table 5). 4.2. Women with isolated axillary nodal metastases from adenocarcinoma The present data are coming from a systematic review of 24 clinical studies with 689 patients with axillary lymph nodal involvement from an adenocarcinoma of unknown primary origin [11]. Clinical picture: The incidence of this subset is <0.7% of all cancers and the mean age is 52 years. Patients are presented with axillary lymphadenopathy of either N1 (48%) or N2 3 (52%) disease. The majority of patients are postmenopausal women (66%), the localization is equally distributed between left or right axilla and almost 24% of them carry a positive family history for malignancy. The detection rate by mammography is around 20%, while by magnetic resonance imaging increases to 60%. Following mastectomy an occult breast primary can histologically been identified in 70% of the cases.

88 N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 84 (2012) 85 92 Table 5 Prognostic features of favorable CUP subsets. Subset Prognostic features Women with serous adenoca of peritoneal cavity Women with isolated axillary nodal metastases from adenoca Poorly differentiated carcinoma with midline distribution Neuroendrocrine carcinoma of unknown primary Squamous cell carcinoma involving cervical lymph nodes AdenoCa with a colon-cancer profile Metastatic melanoma of unknown primary site Survival is 2 6 months less compared to primary ovarian cancer Mean overall survival: 30 months Optimal debulking is feasible and necessary for long-term survival (15 42 months) Mean 5 year overall survival: 72% Impact of adjuvant systemic therapy: 22% at 3-yr survival Median survival 12 months (8 15 months) Long term disease free survivors: 10 15% High-grade tumors: median survival 15.5 months, 2-yr survival:33 50% Low-grade tumors: median survival 40 months, 5-yr survival: 35 45% 5-year survival or disease control: 50 60% Majority considered cured Median overall survival: 20 24 months Nodal disease: median survival: 24 165 months, 5-year survival: 29 76% and 10-year survival 19 63% Visceral disease: median survival: 3 13 months and 5-year survival: 6 18% Histopathology: The most common histology is ductal carcinoma (83%), while lobular carcinoma accounts for only 13%. Almost 90% of cases belong to good or moderate differentiation histology. Estrogen and progesterone receptors are positive in 43% and 41%, respectively. There is a limited experience regarding HER2/neu protein over-expression with 31% positivity among 13 reported cases. Therapeutic management: Although therapeutic results are derived from level III evidence based data, the recommended guidelines suggest: (a) axillary lymph node dissection, (b) mastectomy in patients accepting mutilating surgery or breast irradiation as alternative, and (c) adjuvant systemic chemotherapy, hormonotherapy or trastuzumab according to indications for node-positive breast cancer. Prognosis: Prognosis is similar to stage II III breast cancer. Locoregional failure in patients treated with local radiotherapy is between 15% and 25%. Number of involved axillary lymph nodes and absence of residual gross disease are important prognostic factors. Mean 5-year overall survival is 72% with a median followup of 62 months. The impact of adjuvant systemic therapy at 3-year overall survival is estimated around 22%. 4.3. Poorly differentiated carcinoma with midline distribution A systematic review of 10 published papers and 703 patients provided the data presented below [12]. Clinical picture: This subset was initially considered as resembling extragonadal germ cell tumor. It affects mainly males with median age of 56 years and is characterized as tumor with rapid growth. They present with dominant nodal disease of midline distribution (mediastinal, retroperitoneal and supraclavicular) and occasionally with peripheral nodal enlargement, lung or pleural deposits. Serum germ cell markers (AFP and HCG) are elevated in less than 20% of the patients. Histopathology: Histologically, the diagnostic features are compatible with poorly differentiated or undifferentiated carcinoma. There are no immunoperoxidase stains that are entirely specific. Probably this subset hides more than one histogenetically derived malignancies including germ cell or high-grade neuroendocrine tumors with atypical pathologic features. Therefore, specific markers for the latter tumors might be helpful. Also, in some patients the presence of an i(12p) chromosomal abnormality is in favor of an atypical germ cell tumor. Therapeutic management: These patients should be treated with platinum-based chemotherapy. Response rates range around 50% (42 64%) with 20 25% complete responders. Prognosis: Median survival clustered around 12 months (8 15 months). Low tumor burden, absence of visceral disease, good performance status, females and poorly differentiated carcinoma or neuroendocrine differentiation, are considered as favorable prognostic factors. Almost 10 15% of these patients can enjoy long term disease free survival. 4.4. Neuroendocrine carcinoma of unknown primary A recent systematic review analyzed 39 studies with 500 patients diagnosed with neuroendrocrine carcinoma of unknown primary. Data presented below are based on this particular analysis [13]. Clinical picture: This subset accounts for less than 5% of CUP patients and represents the 13% of all neuroendrocrine tumors. It is characterized by the presence of diverse tumors with variable clinical picture predicted by tumor differentiation. There are two different variants the low-grade and the high-grade neuroendrocrine tumors. Low grade tumors have an indolent course and usually involve the liver or present with symptoms due to the secretion of vasoactive peptides. High grade or poorly differentiated neuroendocrine tumors exhibit a rapidly growing behavior. Histopathology: On routine light microscopy neuroendocrine tumors are recognized as small cells with little cytoplasm and dark nuclei. Immunohistochemically, they are positive for neuroendocrine markers such as in chromogranin, synaptophysin, PGP9.5 and CD56. Therapeutic management: Patients with high grade neuroendrocrine tumors are treated with platinum-based combination chemotherapy mainly with etoposide. Overall response rates range between 50 and 70% with 15 and 20%

N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 84 (2012) 85 92 89 complete responders. Patients with low-grade tumors could be treated with somatostatin analogues or chemoembolization. Prognosis: Median overall survival for high grade neuroendrocrine tumors is around 15.5 months (range 12 40 months) and for low-grade tumors is 40 months. Good performance status and low-grade histology are favorable prognostic factors. Thirty-three to fifty percent of high grade neuroendrocrine tumors could reach 2-year survival, while low grade tumors could enjoy 35 45%, 5-year survival. 4.5. Squamous cell carcinoma involving cervical lymph nodes Clinical picture: SCCLN accounting for approximately 5% of all CUP patients. It affects mainly middle-aged or elderly male patients with history of tobacco and alcohol abuse. Clinically, they are presented with unilateral involvement of upper or middle cervical lymph nodes. Histopathology: Light microscopy reveals a typical squamous cell carcinoma, while histochemistry has not proven particularly helpful in the diagnostic work-up. Detection of Epstein Barr virus (EB) or Human Papilloma virus (HPV) by advanced molecular technology could be useful in differentiating a nasopharyngeal or an oropharyngeal primary cancer. Therapeutic management: Patients should be treated according to locally advanced squamous carcinoma of the head and neck, with local radiotherapy to the pharyngeal axis and bilateral neck with or without radical neck dissection. Concurrent chemoradiotherapy is also used in many centers. Prognosis: Five-year survival or long term disease control can be achieved in 50 60% of patients. The majority of these patients are considered as cured. Two prognostic factors are the most prominent ones, the lymph node stage and the extracapsular spread. Other prognostic favorable factors are also used such as good performance status, young age, absence of weight loss and low grade histology [14,15]. 4.6. Adenocarcinoma with a colon cancer profile Clinical picture: The mean age is 58 years (42 75 years) and there is no sex predilection. Most patients are presented with liver or peritoneal metastases but also other metastatic sites are present i.e. lungs, pleura, bones, ovary, etc. Colonoscopy remains normal in all patients. Histopathology: Histology shows adenocarcinoma or poorly differentiated adenocarcinoma with positive immunohistochemical staining for CK20, CDX2 and CEA. Therapeutic management: These patients should be treated with colorectal chemotherapy regimens. Although the data are still premature the overall response rate is around 70% with some complete responders. Prognosis: The median survival is 20 24 months [16 18]. 4.7. Metastatic melanoma of unknown primary site (MUP) The data presented in this subset originates from a systematic review of 4348 patients diagnosed between 1952 and 2009 with melanoma of unknown primary [19]. Clinical picture: The incidence of this subset is 3.2%. Clinical presentation includes either only a local lymphadenopathy or symptoms and signs from disseminated disease such as lungs or liver as well as general symptoms like fever, weight loss or anemia. Histopathology: Histopathology reveals features of a melanoma. Therapeutic management: Patients with local disease should have surgical intervention. Adjuvant chemoimmunotherapy can be recommended. Patients with disseminated disease should be treated with systemic treatment. Local radiotherapy is advocated mainly as postoperative management. Prognosis: Various favorable prognostic factors have been reported including lymph node number, female gender, age or surgical management. A considerable number of these patients enjoy a longdisease free survival. Concerning survival two groups of patients have been recognized. The nodal involvement group and the visceral metastatic disease. In patients who belong to the nodal group the median survival ranges between 24 and 165 months, while the 5-year and 10-year survival between 29 76% and 19 63%, respectively. On the contrary, patients with visceral disease have a median survival ranged between 3 and 13 months and the 5-year survival between 6 and 18%. 4.8. Men with osteoblastic metastases and elevated serum PSA Clinical picture: Patients are presented with blastic bone metastases with localized or diffuse bone pains and elevated serum levels of PSA. Histopathology: Histopathology reveals an adenocarcinoma with positive immunohistochemistry staining for PSA. Therapeutic management: These patients should be treated on an empirical trial of androgen suppression therapy [1,4,9,20 22]. 4.9. Patients with limited CUP disease Clinical picture: These patients are diagnosed with a single lesion in a variety of sites, including lymph nodes, skin, liver, bone, lung, brain or adrenal gland. Histopathology: This subset includes adenocarcinoma of various differentiation, squamous cell carcinoma or poorly differentiated carcinoma. Therapeutic management: These patients should be managed with local excision with or without radiotherapy [1,4,9,20].

90 N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 84 (2012) 85 92 5. Discussion The intention of the present work was to offer a comprehensive update to the daily practice oncologists who are probably not very familiar on how to manage diagnostically or therapeutically CUP patients. CUP is characterized as a heterogeneous bunch of clinicopathological entities with different predictive and prognostic outcomes. Historically, the recognition of treatable CUP subsets became possible after the discovery of platinum compounds as well as after the advances in immunohistochemistry. There is no doubt that the recently established clinicopathological classification of CUP subsets into favorable and unfavorable subsets has been achieved through the triad of clinical observation, immunochemistry technology and the availability of some effective chemotherapy compounds. Although the majority of CUP patients belong to the unfavorable subsets, a 20 30% of them are included to the good prognosis group and could respond to locoregional or systemic treatment. Drastic locoregional treatment with surgery and/or radiotherapy in some subsets such as in women with isolated axillary nodal metastases or men with squamous cell carcinoma involving cervical lymph nodes, could offer 50 70% 5-year overall survival. On the other hand, chemosensitive subsets like women with serous peritoneal adenocarcinomatosis or neuoendocrine tumors could adequately respond to systemic chemotherapy and exhibit long survival [1,8,9,20]. Unfortunately, patients with poor prognosis CUP subsets although they might demonstrate moderate response rates to cytotoxic drugs, the overall survival is poor ranging between 6 and 9 months. These are mainly patients with liver metastatic disease from a poorly differentiated adenocarcinoma or undifferentiated carcinoma [2,3,11,24]. We recently reviewed survival data on 219 CUP patients treated at Ioannina University Hospital Fig. 1. Survival of favorable versus poor risk CUP patients treated at Ioannina University Hospital from 1995 to 2011. from 1995 until 2011 and confirmed published experience, as patients with squamous head neck, serous peritoneal and those with axillary nodal CUP enjoyed median survival times in excess of 23 months (unpublished data, Table 6). The median survival of patients in all favorable CUP subgroups exceeded 24 months versus only 6 months for those belonging in poor-risk CUP categories (Figs. 1 and 2). Although rare, long term survival potential is also present in the 80% of all CUP patients who harbour disease with unfavorable prognostic features and do not fit into any of the favorable subsets. There are ample data in the literature that there is a small minority of long-term survivors in this group of patients treated with standard empiric chemotherapy [23,24]. We have also noticed this phenomenon in our Table 6 Single-centre experience on outcome of 219 CUP patients treated at Ioannina University Hospital from 1995 to 2011. Time (months) Visceral CUP Squamous head neck CUP Axillary nodal CUP Midline nodal CUP Neuroendocrine CUP Serous peritoneal CUP Mucinous peritoneal CUP Median PFS 3 6 7 6 3 9 4 95% CI 2.5 3.5 3.4 8.6 4.8 9.2 2.2 9.8 0.5 5.6 4.6 13.3 2.1 5.9 Median OS 6 23 Not reached 11 15 32 8 95% CI 5 7 19.1 26.2 5.1 16.9 6.1 23.9 25 36.7 2.9 13.1 Multivariate analysis Parameter Hazard ratio 95% CI 2-sided p CUP subgroup 0.011 Visceral 1 HNSCC 0.21 0.08 0.54 0.01 Axillary 0.001 0.96 Midline nodal 0.65 0.31 1.38 0.26 Neuroendocrine 0.69 0.29 1.67 0.41 Serous peritoneal 0.36 0.16 0.80 0.01 Mucinous peritoneal 0.42 0.14 1.25 0.12 Leukocytosis 2.93 1.83 4.67 0.0005 Numbers in bold are the HR that are statistically significant (two-sided p < 0.05).

N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 84 (2012) 85 92 91 Conflict of interest The authors have no conflict of interests to declare. Reviewers F. Anthony Greco, MD, Sarah Cannon Cancer Center, 250 25th Avenue North, Suite 412, Nashville, TN 37203, United States. References Fig. 2. Overall survival of 219 CUP patients treated at Ioannina University Hospital from 1995 to 2011 according to clinicopathologic subgroup. series, as 10% of our poor-risk CUP patients were alive at 2 years and about half this number at 50 months of follow up. As shown in Fig. 2, rare patients belonging even in the worst subgroups, survived between 25 and 50 months. This observation highlights the complex biology of CUP and emphasizes the importance of treating fit patients, even those with poor-risk disease, with modern combination regimens. Molecular diagnosis for the identification of the primary tumor with either gene expression microarrays or with micrornas proven to be very efficient. The tissue of origin can be successfully detected in up to 90% of the cases. Molecular testing in CUP could play a potential role in accurately diagnosing the primary site and in treating patients accordingly [2,3]. However, the lack of appropriate randomized studies to show survival benefit, the high cost of the test, as well as the ability to easily recognize the specific favorable subsets through clinical and pathological tools, minimize the value of molecular diagnosis at least for patients with good prognosis [25]. Several prognostic factors have been identified for patients with CUP. From multivariate analysis the following variables are considered as the most important adverse prognostic indicators: male sex, age > 64, PS > 1, number of metastatic sites, liver metastases, poorly differentiated histology, weight loss lymphopenia, elevated serum LDH and alkaline phosphatase levels as well as low albumin levels [26]. In our recent review of 219 CUP patients from our institution we confirmed prognostic importance of several of these parameters in univariate analysis, however in multivariate analysis the only factors that retained independent prognostic significance were the clinicopathologic subgroup and the presence or absence of leukocytosis (Table 6). In conclusion, oncologists should be aware today of this distinction among CUP patients and should try to offer the optimal therapeutic management in order to improve outcome and to extend survival. In certain cases long term survival or even cure could be achieved [27]. [1] Hainsworth JD, Fizazi K. Treatment for patients with unknown primary cancer and favorable prognostic factors. Semin Oncol 2009;36(1):44 51. [2] Greco FA, Spigel DR, Yardley DA, et al. Molecular profiling in unknown primary cancer: accuracy of tissue or origin prediction. Oncologist 2010;15(5):500 6. [3] Ferracin M, Pedriali M, Veronese A, et al. MicroRNA profiling for the identification of cancer with unknown primary tissue-of-origin. J Pathol 2011;225(1):43 53. [4] Greco FA, Hainsworth JD. Cancer of unknown primary site. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice oncology. 8th ed. Philadelphia: Lippincott; 2008. p. 2363 87. [5] Pentheroudakis G, Briasoulis E, Pavlidis N. Cancer of unknown primary site: missing primary or missing biology? Oncologist 2007;12(4):418 25. [6] Dennis JL, Hvidsten TR, Wit EC, et al. Markers of adenocarcinoma characteristic of the site of origin: development of diagnostic algorithm. Clin Cancer Res 2005;11:3766 72. [7] Oien KA. Pathologic evaluation of unknown primary cancer. Semin Oncol 2009;36:8 37. [8] Pavlidis N, Briasoulis E, Hainsworth J, Greco FA. Diagnostic and therapeutic management of cancer of unknown primary. Eur J Cancer 2004;40(9):1454 5. [9] Pavlidis N. Forty years experience of treating cancer of unknown primary. Acta Oncol 2007;46(5):592 601. [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 2010;75:27 42. [11] Pentheroudakis G, Lazaridis G, Pavlidis N. Axillary nodal metastase from carcinoma of unknown primary (CUPAx): a systematic review of published evidence. Breast Cancer Res Treat 2010;119:1 11. [12] Pentheroudakis G, Stoyianni A, Pavlidis N. Cancer of unknown primary patients with midline nodal distribution: midway between poor and favourable prognosis? Cancer Treat Rev 2011;37(2):120 6. [13] Stoyianni A, Pentheroudakis G, Pavlidis N. Neuroendrocrine carcinoma of unknown primary. A systematic review of the literature and a comparative study with other neuroendrocrine tumors. Cancer Treat Rev 2011;37(5):358 65. [14] 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 Transl Oncol 2009;11:340 8. [15] Jereczek-Fossa BA, Jassem J, Orecchia R. Cervical lymph node metastases of squamous cell carcinoma from an unknown primary. Cancer Treat Rev 2004;30(2):153 64. [16] Varadhachaous GR, Raber MN, Matamoros A, et al. Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions. Lancet Oncol 2008;9:596 9. [17] Varadhachary G, Talantov D, Rober M, et al. Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol 2008;26:4442 8.

92 N. Pavlidis et al. / Critical Reviews in Oncology/Hematology 84 (2012) 85 92 [18] Greco FA, Hainsworth JD. Cancer of unknown primary site. In: Devita Hellman, Rosenberg, editors. Cancer, principles and practice of oncology. 9th ed. Lippincott, Williams and Wilkins; 2011. p. 2033 51. [19] Kamposioras K, Pentheroudakis G, Pectasides D, Pavlidis N. Malignant melanoma of unknown primary site: to make the long story short. A systematic review of the literature. Crit Rev Oncol Hematol 2011;78(2):112 26. [20] Pavlidis N, Pentheroudakis G. Cancer of unknown primary site: 20 questions to be answered. Ann Oncol 2010;21(Suppl. 7):vii 303 307. [21] Gentile PS, Carloss HW, Huant T-Y, et al. Disseminated prostate carcinoma simulating primary lung cancer. Cancer 1988;62:711 5. [22] Tell DT, Khoury JM, Taylor HG, Veasey SP. A typical metastasis from prostate cancer: clinical utility of the immunoperoxidase technique for prostate specific antigen. JAMA 1985;253:3574 5. [23] Lazaridis G, Pentheroudakis G, Fountzilas G, Pavlidis N. 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(8):693 700. [24] Greco FA, Pavlidis N. Treatment for patients with unknown primary carcinoma and unfavourable prognostic factors. Semin Oncol 2009;36(1):65 74. [25] Greco FA, Oien K, Erlander M, et al. Cancer of unknown primary: prognosis in the search for improved and rapid diagnosis leading forward superior patients outcomes. Ann Oncol 2012;23(2):298 304. [26] Culine S. Prognostic factors in unknown primary cancer. Semin Oncol 2009;36:60 4. [27] Pavlidis N, Briasoulis E, Pentheroudakis G. Cancer of uknown primary site: ESMO clinical practice guidelines for diagnosis, treatment and follow up. Ann Oncol 2010;21(Suppl. 5):V228 31. Biography Nicholas Pavlidis M.D., Ph.D. is chair of the Department of Medical Oncology in the Ioannina University Hospital and professor of Oncology in the Medical School of the University of Ioannina, Greece. He chairs the ESMO Minimum Clinical Recommendations Working Group, his clinic and research interests being cancer and pregnancy, cancer of unknown primary, adolescent/young adult oncology and translational research in breast, lung and gastrointestinal cancer.