Access the full text.
Sign up today, get DeepDyve free for 14 days.
Loading next page...
/lp/springer_journal/2018-consensus-statement-by-the-spanish-society-of-pathology-and-the-0Jaq1nQsI4
- Publisher
- Springer Journals
- Copyright
- Copyright © 2018 by The Author(s)
- Subject
- Medicine & Public Health; Oncology
- ISSN
- 1699-048X
- eISSN
- 1699-3055
- DOI
- 10.1007/s12094-018-1899-z
- Publisher site
- See Article on Publisher Site
Abstract
Cancer of unknown primary (CUP) is dene fi d as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They differ from other primary tumours in their biological features and how they spread, which means that they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, CUP can account for 2–9% of all cancer patients, mostly 60–75 years old. This article reviews the main clinical, pathological, and molecular studies conducted to analyse and determine the origin of CUP.The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed. Keywords Cancer of unknown primary · Diagnosis · Immunohistochemistry · Biopsy · Prognosis · Chemotherapy · Molecular pathology · Histopathology Introduction is regarded as CUP. The US National Cancer Institute (NCI), the National Comprehensive Cancer Network (NCCN), and Cancer of unknown primary (CUP) is defined as a heteroge - the European Society of Medical Oncology (ESMO) have neous group of tumours that present initially with metastasis, published minimum recommendations on this subject, with and in which a properly standardised diagnostic work-up a reminder that any cancer presenting with metastasis must cannot identify the original site of the malignancy [1, 2]. In undergo the initial testing before being regarded as CUP the last few years, various consensus statements and inter- [3, 4]. national clinical guidelines have tried to define more clearly CUP can be considered a separate entity, because its what diagnostic work-up should be performed before a case biological properties set it apart from other known primary * F. Losa Pathology Department, Hospital de la Santa Creu i Sant Pau, ferran.losa@sanitatintegral.org Barcelona, Spain Medical Oncology Department, Hospital Universitario Medical Oncology Department, Institut Català d’Oncologia Virgen Macarena, Seville, Spain ICO-Hospitalet/Hospital de Sant Joan Despí, Moisès Broggi, Sant Joan Despí, Carrer de Jacint Verdaguer, 90, Pathology Department, Hospital Universitario A Coruña, 08970 Sant Joan Despí, Barcelona, España La Coruña, Spain 2 9 Medical Oncology Department, Hospital Universitario Doce Medical Oncology Department, Institut Català d’Oncologia, de Octubre, Madrid, Spain Badalona, Barcelona, Spain 3 10 Pathology Department, Hospital Universitari de Bellvitge, Pathology Department, Hospital Universitario Arnau de L’Hospitalet de Llobregat, Barcelona, Spain Vilanova de Lleida y Hospital Universitari de Bellvitge, IRBLLEIDA, IDIBELL, CIBERONC, L’Hospitalet de Pathology Department, Hospital Clínico San Carlos, Madrid, Llobregat, Barcelona, Spain Spain Medical Oncology Department, Hospital Universitario de León, León, Spain Vol.:(0123456789) 1 3 1362 Clinical and Translational Oncology (2018) 20:1361–1372 tumours. In addition, it generally has atypical patterns of been shown to be cost-effective. In men, however, tests spread and clinical behaviour, which are inconsistent with for prostate-specific antigen (PSA), serum chorionic gon- the supposed site of origin [5]. There are two hypotheses adotropin (β-hCG), and alpha-fetoprotein (AFP) are recom- regarding CUP biology: the first suggests that the neoplasm mended, to rule out treatable extragonadal germ cell tumours might arise from a stem cell, without first producing a pre- or prostate cancer eligible for endocrine therapy. In the case malignant lesion or a primary tumour; the second maintains of adenocarcinomas with peritoneal involvement in women, that it represents rapid progression of metastasis from a very a CA 125 test should be done [2, 13]. early primary tumour [6]. As far as the initial radiological tests are concerned, Chromosomal instability was recently suggested as a patients should have a contrast-enhanced CT scan of the plausible explanation, or even a prognostic factor for more chest, abdomen, and pelvis. If there are cervical lymphad- aggressive presentation and chemoresistance of CUP [7]. enopathies, this should be accompanied by a CT scan of the It has been shown that, generally, CUP is not associated neck. Positron emission tomography (PET) can be useful in with specific mutations in oncogenes or suppressor genes. certain clinical presentations, for both diagnosis and staging Instead, it is characterised by angiogenesis activation [14]. It has 87% sensitivity and 71% specificity [15]. One (50–89%), oncogene over-expression (10–30%), a greater of the limitations of PET is its moderate precision regard- presence of hypoxia-related proteins and epithelial–mesen- ing anatomical sites or functional abnormalities, because of chymal transition markers (16–25%), and the activation of low tracer uptake by some tumour tissues. In these cases, it intracellular signals such as AKT or MAPK (20–35%) [8]. is more helpful to combine PET with CT. A meta-analysis Depending on the definition used and how exhaustive and systematic review of combined PET/CT in patients diag- the diagnostic procedures are, CUP can account for 2% to nosed with CUP found that primary tumours were detected 9% of all cancer patients [1]. Accordingly, the incidence of in 37% of patients, with 84% sensitivity and identical 84% CUP may change as new diagnostic technologies are imple- specificity [16]. This primary tumour detection rate is higher mented. In purely numerical terms, CUP is currently the in the case of specific metastatic scenarios, such as cervical eighth most frequent cancer diagnosis [1]. Its incidence is lymphadenopathies, and sensitivity is higher too [17]. How- highest in patients aged 60–75 years [9, 10]. The most com- ever, in the only prospective study done, PET/CT proved no mon underlying occult primary tumours are basically of lung superior to CT [18]. PET is, therefore, not recommended as and biliopancreatic origin, as observed in the pooled analysis the initial test. Its use should be confined to specific clini- of over 800 patients in 12 autopsy series [11]. cal presentations (single metastases and cervical lymphad- enopathies), and when local or regional therapy is being considered. Basic clinical work‑up In women, it is helpful to perform mammography, and/ or magnetic resonance imaging of the breasts if the mam- The initial clinical assessment of patients diagnosed with mography result is equivocal [13]. On the other hand, endos- CUP should not be exhaustive. Instead, it should aim to copy should not be routinely employed, because it rarely determine the extent of the disease, and to identify tumour detects the primary tumour in asymptomatic patients, and subtypes in which a specific therapy may have a positive false positives can cause confusion [19]. The choice of other impact on patient progress and prognosis. The basic clinical diagnostic procedures should be based on interpretation of investigations that should be done include history-taking and the histological sample obtained by biopsy. physical examination, basic laboratory tests, and computed tomography (CT) of the chest, abdomen, and pelvis. A full medical history and physical examination should Pathological diagnosis include genitourinary and rectal examination, as well as examining the breasts and pelvic region in women, and Optimising the sample the prostate in men. Special attention should be paid to the previous diseases, biopsies or lesions removed, spontane- Obtaining a sample of enough tissue is essential for diagnos- ously regressing lesions, previous imaging tests, and family ing and investigating CUP, both for tumour typing and for cancer history. The laboratory tests recommended are a full conducting additional molecular studies. The sample should blood count with differential white cell count, measurement be obtained using a procedure that provides as much tissue of electrolytes, creatinine and calcium, liver function tests, as possible but is not highly invasive for the patient [20]. and basic urinalysis [4, 12]. Although the minimum number of cells needed for histo- Serum tumour markers should not be tested routinely. logical and molecular investigations is not well established, Elevations in these markers are not highly sensitive or spe- samples containing at least 400 cells are recommended cific, and testing for them during CUP diagnosis has not [21]. Some studies show that cytology specimens can be 1 3 Clinical and Translational Oncology (2018) 20:1361–1372 1363 diagnostically useful [22, 23]. To enable all the necessary Epithelial/epithelioid: carcinoma, “epithelioid” sarcoma, tests to be done, however, solid tissue samples obtained by and melanoma; core-needle biopsy (CNB), incisional biopsy, or surgical Spindle cell: sarcoma, sarcomatoid carcinoma, and mela- resection are preferable. noma; On the other hand, it is essential to optimise the material Small cell: lymphoma, sarcoma, neuroendocrine tumour, obtained. The available material should be divided between primitive neuroectodermal tumour (PNET), and mela- multiple paraffin blocks, to conserve as much tissue as pos- noma; sible. Diagnostic immunohistochemical tests should be con- Pleomorphic: all. fined to reasonable panels, according to the available clinical and radiological evidence, to prevent unnecessary staining. Second classification: most likely primary tumour In cases likely to require molecular techniques, it is advis- able to prepare a few blank slides when serial sections are In poorly differentiated carcinomas and adenocarcinomas, cut for routine immunostaining. immunohistochemistry is essential. In squamous cell car- cinomas, morphology and immunohistochemistry are rela- Basic histopathology study and classification tively non-specific, although there are subtypes associated by morphological/histopathological subtype with human papillomavirus that have greater specificity. In some cases, relevant differences may exist between After the initial clinical assessment, the sample is examined primary tumours and their metastases. For example, com- using histopathological techniques, which may require a pared with primary tumours, melanoma metastases show basic immunohistochemical (IHC) panel. Preliminary clas- greater cytokeratin (CK) AE1/AE3 staining (22%) and less sification then becomes possible [2 , 24–26]: HMB45 staining (65%). The marker S100 may be expressed in adenocarcinomas of the lung, breast, endometrium, and Initial classification kidney (up to 80%), and other sites to a lesser extent [27]. Certain epithelioid or spindle cell sarcomas can be con- The most common initial classifications are: fused with carcinomas or melanomas. Many sarcomas have specific molecular alterations that can be demonstrated by Carcinoma/neuroendocrine tumour: immunohistochemistry or fluorescence in situ hybridisation (FISH) [28]. Molecular diagnostics are particularly recom- – adenocarcinoma (60%); mended for sarcomas of atypical morphology or site. – poorly differentiated carcinoma, including poorly dif- ferentiated adenocarcinoma (20%); Prognostic classification of CUP – squamous cell (epidermoid) and/or transitional cell carcinoma (5–10%); The prognosis is favourable in 15–20% of CUP cases [24, – neuroendocrine tumour (5%); 25]. These tumours are more chemosensitive and overall – undifferentiated carcinoma; survival is better. This category includes poorly differenti- lymphoma; ated midline carcinomas, peritoneal papillary adenocarci- extragonadal germ cell tumour; nomas in women, metastatic adenocarcinoma involving the melanoma; axillary lymph nodes only, metastatic squamous cell carci- sarcoma. noma in the cervical lymph nodes, single-node metastases, poorly differentiated neuroendocrine carcinoma, resectable In this first classification, it should be remembered that tumours, and germ cell tumours. In contrast, other cases of CUP may be due to tumours of atypical site, morphology, CUP have a poor prognosis. These include adenocarcinomas and immunophenotype. The most common metastases at that with liver metastases, non-papillary malignant ascites, and site have to be ruled out. Tumours that have effective spe- multiple brain, bone, or lung metastases. cific therapies must also be appropriately excluded, such as germ cell tumours, neuroendocrine tumours, lymphoma, and Specific histopathology study hormone-dependent tumours (prostate in men and breast in women). Moreover, IHC markers may have limited specific- Advisable minimum IHC panel ity and sensitivity in this first classification. The initial IHC panel should be based on the patient’s clini- General histopathological patterns cal details (age, sex, disease history, site, etc.) and morpho- logical examination of the mass. For a general approach to The general histopathological patterns are as follows: CUP, the basic IHC panel should mainly consist of epithelial 1 3 1364 Clinical and Translational Oncology (2018) 20:1361–1372 cell markers (CK AE1/AE3, CK Cam 5.2, EMA), S100, sarcomas, melanomas, and a good proportion of lymphomas. vimentin, and leucocyte common antigen (LCA or CD45) It tends to play a supportive role together with other markers. (Fig. 1). If epithelial origin of the lesion is confirmed (CK+ , The detection of tumours with neuroendocrine differenti- S100−, vimentin ± and LCA−), a combination of CK7 and ation and tumours of germ cell origin deserves special men- CK20 will give a first indication of the organ in which the tion. For neuroendocrine tumours, the panel should include tumour is most likely to have originated [29]. synaptophysin, chromogranin A, and CD56. For germ cell In general, although carcinomas express CK and mes- tumours, a specific panel should be considered, such as enchymal tumours express vimentin, the exceptions to that PLAP, alpha-fetoprotein, or OCT 3/4. When the tumour’s rule must be remembered. For example, poorly differentiated microscopic features show it to be clearly epithelial, some carcinomas can show an unpredictable CK expression pat- of the markers in this profile can be omitted. In that case, the tern, or CK expression may be lost completely (as in cases initial panel can be restricted to CK7 and CK20, and testing involving the kidney or adrenal gland), whereas some carci- completed with the extended panel. nomas co-express vimentin and CK (typically those found in the endometrium, thyroid, and kidney, among others). Optional extended IHC panel On the other hand, some types of sarcoma, such as epithe- lioid or synovial sarcomas, leiomyosarcomas or malignant First, the following points should be considered. Tumour peripheral nerve sheath tumours, can co-express vimentin types with widely differing phenotypic profiles arise in each and CK. This also occurs in polyphenotypic tumours/blas- organ. Therefore, this article refers to the most common and tomas, such as Ewing sarcoma/PNET, desmoplastic small most clinically relevant in each case. Phenotypic profiles of round cell tumour, or medulloblastoma. tumours of the same origin and histological type vary from Staining positive for CD45 and negative for CK suggests one case to another, according to their degree of differentia- a lesion of haematological origin, although some haematol- tion, and as they progress. This article, therefore, always ymphoid tumours (granulocytic sarcoma, myelomas, Hodg- refers to expression patterns in general, on the understand- kin’s lymphoma, or anaplastic lymphomas) may have very ing that each particular case may display atypical, aberrant, little or no CD45 expression and test positive for S100 or or exceptional phenotypes. As markers can be identified in EMA. S100 is highly specific for lesions of melanocytic or tumours of different histological types arising in different neural origin and may be expressed in a nuclear and cyto- organs, and practically no absolutely specific markers exist, plasmic pattern. Vimentin is an intermediate filament char - it is advisable to test for several markers simultaneously to acteristic of mesenchymal cells. It is found in almost all reach a conclusive diagnosis. Fig. 1 Advisable minimum IHC panel. IHC immunohistochem- istry 1 3 Clinical and Translational Oncology (2018) 20:1361–1372 1365 Once a first approximation has been obtained using an Platforms for identifying the organ harbouring initial panel (Fig. 1), combined with clinical details (age, the primary tumour gender, past medical and family history, lesion site, bio- chemistry, imaging, etc.) and the tumour’s histological pat- Various molecular platforms exist for evaluating gene tern, thereby confirming that it is a carcinoma and that other expression, microRNA profile or epigenetic pattern in tumour types (melanomas, lymphomas, germ line malignan- CUP [30–38]. Once a tumour’s molecular profile has been cies, etc.) can reasonably be ruled out, specific expression obtained, it is compared against database results from a patterns should be studied (Table 1). range of sites and histological types. The molecular profile of the tumour being tested is assessed for similarity to these patterns, and the diagnosis provided suggests one or more Molecular diagnostics sites, each with its estimated probability (similarity score). Table 2 lists the main features of these platforms. The choice Thanks to advances in immunohistochemistry, the propor- of one platform over another depends on several factors, tion of CUP cases in which the origin cannot be identified such as availability in different countries. Strategies of more has fallen to 15–20%. This is the patient group most reliant recent introduction tend to be more informative, because on the use of molecular platforms. Molecular techniques they analyse a larger number of possible sites. offer information for possible specific therapy. Strategies fall In general, these platforms correlate well with immu- into two categories: platforms for identifying the organ har- nohistochemistry, and reduce the number of CUP cases in bouring the primary tumour; and next-generation sequencing which the primary cannot be identified. The main difficulties to characterise the tumour’s mutation profile. involved in using them are: (1) detecting unusual tumours Table 1 Main phenotypic profiles of the most common tumours Tumour Markers Breast GATA3, mammaglobin, GCDFP-15, hormone receptors (oestrogens, progesterone, and androgens), CA 15-3, CK34BE12 Salivary gland Like breast, GFAP Skin appendages Like breast, S100 Thyroid PAX8, TTF1, thyroglobulin Parathyroid PTH, GATA3, synaptophysin, chromogranin A Lung (non-mucinous adenocarcinoma) TTF1, napsin A, CEA Lung (mucinous adenocarcinoma) TTF1, napsin A, CDX2, SATB2-, cadherin 17-, CEA Cervix (squamous cell) p40, p63, p16, HPV + , PAX8, 34BE12 Endocervix CEA, p16, ER/PR-, HPV + , PAX8, vimentin- Endometrium PAX8, ER/PR, vimentin, CEA-, WT1-, CA 125 Ovary/fallopian tube (serous) PAX8, WT1, ER/PR, vimentin, CA 125 Ovary (endometrioid) PAX8, ER/PR, vimentin, CA 125 Ovary (mucinous) PAX8, CDX2, WT1-, SATB2-, cadherin 17-, TTF1- Mesothelium calretinin, WT1, CK5/6, vimentin, podoplanin (D2-40), CEA- Colon/rectum CDX2, SATB2, cadherin 17, villin, AMACR, CEA, CA 19-9 Small intestine CDX2, cadherin 17, SATB± Pancreas/bile ducts CDX2, CK17, cadherin 17, SATB2 ± , CEA, CA 19-9, DPC4- Stomach CDX2, CK17-, cadherin 17, SATB± Liver arginase-1, Hep Par1, glypican 3 Kidney PAX8, RCC, carbonic anhydrase IX, glutathione reductase, vimentin, CD10, AMACR, c-KIT Adrenal SF1, melan-A, inhibin alpha, synaptophysin, chromogranin A, calretinin Prostate NKX3, PSA, AMACR , AR, prostatic acid phosphatase Squamous cell carcinomas p40, p63, 34BE12, p16/p53, HPV, MMP-13 Transitional cell carcinomas p40, p63, GATA3, uroplakin II, S100P, CK34BE12 + , CK8/18 Myoepithelial carcinomas p63, CK34BE12, myosin, EMA, S100, GFAP, CD10 Neuroendocrine tumours synaptophysin, chromogranin A, CD56/CD57, PGP9.5, neurofilaments Underlining indicates markers recommended for their greater specificity and usefulness 1 3 1366 Clinical and Translational Oncology (2018) 20:1361–1372 Table 2 Main molecular diagnostics platforms for cancer of unknown The main objection to using massively parallel sequenc- primary ing in CUP arises from the belief that the potential drug response conferred by a given mutation depends on the Platform Method No. of genes Sensitivity (%) type of tumour in which the mutation is found. That is, the Quest-Lab RT-PCR 92 – context of histological type and tumour site can affect the Veridex RT-PCR 6 76.0 response to the drug [43]. That assumption is based on stud- Pathwork cDNA array 2000 89.0 ies such as the SHIVA study, which showed that molecularly Cup-print cDNA array 495 85.0 targeted off-label drug use failed to improve patients’ dis- Rosetta miRNA array 64 90.0 ease-free survival [44]. Accordingly, sequencing techniques CancerType RT-PCR 92 89.0 are complementary to platforms for predicting the primary Epicup methylation array – 97.7 cancer site. Platforms available in Spain Targeted clinical work‑up and prognosis not always covered by the platforms, e.g., uncommon sites or exceptional histological types; (2) distinguishing between The median survival of patients with CUP is approximately tumours of similar morphology or origin, that may have very 9–10 months, similar to that seen in metastatic lung cancer similar molecular traits but different oncological manage- [45]. A gradual increase has been detected in CUP survival, ment; and (3) to date, these platforms are not funded by the probably because of improved therapy for malignancies of national health system. known origin and better management of metastatic disease, The results of these molecular techniques are highly as well as optimisation of diagnostic resources in general dependent on the quantity, quality, and percentage of tumour [46]. cells. Strategies, therefore, need to be established for obtain- Nevertheless, patients who present with metastasis of ing optimal material and preserving it after immunohisto- a known tumour have better survival than patients whose chemical testing has taken place. primary tumour is unknown [47]. Successfully identifying There are a few prospective studies to support the useful- tumour origin improves the patient’s prognosis, probably ness of these platforms. In a study involving 194 patients, because it enables better treatment selection and adjust- Hainsworth et al. showed that survival was better when the ment [48]. That was demonstrated in patients whose CUP platform predicted tumour types clinically associated with molecular profiling results proved consistent with colorectal a better response [39]. In general, molecular platforms are cancer, and who were treated accordingly (median survival regarded as complementary to immunohistochemistry, and 27 months and 50% response to specific therapy, similar to useful when a reasonable number of immunohistochemi- figures obtained in colon cancer) [49]. Therefore, the factor cal stains have failed to predict tumour origin, especially in most likely to improve the prognosis of a patient with CUP poorly differentiated tumours [34]. is actually not having CUP any more. That is why the algo- rithm for diagnosing and managing CUP looks for “great- est similarity” to known tumours, in terms of IHC, clinical Next‑generation sequencing to characterise features, and/or molecular findings. the tumour’s mutation profile In the absence of a definitive diagnosis, the clinical work- up should aim to identify tumours that can be treated accord- Sequencing with gene panels enables mutations associated ing to consensus guidelines because of similarity to known with responses to specific drugs (actionable mutations) to primary tumours [2, 25, 50]. Patients with “favourable” be identified. This strategy has been tested in several stud - CUP have a better prognosis. These cases should be treated ies. Gatalica et al. evaluated 1806 CUP cases by immuno- with locoregional or systemic therapies, because the sur- histochemistry (23 markers), sequencing (47 genes) and vival achieved will be longer and/or similar to their known in situ hybridisation (7 genes) [40]. They found actionable homologues [51] (Table 3). Unfortunately, these patients alterations in 96% of cases. In another study, Ross et al. only account for 22–23% of cases [52]. studied formalin-fixed, paraffin-embedded specimens from The remainder are categorised in the “unfavourable” CUP 200 patients with CUP, 125 of whom had adenocarcinomas group, and their prospects depend on various prognostic [41]. These authors examined 236 genes and the introns of factors. Their median survival ranges from 3 to 10 months. 19 genes often altered in cancer. At least one actionable Clinical, laboratory, and histological prognostic factors mutation was identified in 96% of cases. Tothill et al. used have been documented. Poor clinical prognostic factors panels representing 701 genes and identified actionable of particular note are: presenting with multiple metastases mutations in 12 out of 16 cases [42]. (especially at more than 3 sites); and liver, bone, or adrenal 1 3 Clinical and Translational Oncology (2018) 20:1361–1372 1367 Table 3 Favourable cancers of unknown primary and specific therapy Histology Clinical subset Further investigation Therapy Adenocarcinoma Female + axillary lymphadenopathies Breast MRI ER/PR/HER-2 = Breast cancer Female + peritoneal carcinomatosis CA 12.5 = Ovarian cancer Male with blastic bone M1 and raised PSA PSA = Prostate cancer Clinical/pathological features consistent with a IHC: CK20 +/CK7- and CDX2+ = Colon cancer primary colorectal tumour Single M1 lesion PET Local therapy ± CT Squamous cell Cervical lymph nodes Endoscopy/PET? = Head and neck cancer Tonsillectomy Inguinal lymph nodes LND ± RT ± CT Undifferentiated Young male, mediastinum and/or retroperitoneum hCG, AFP = Extragonadal germ cell cancer Neuroendocrine Low or high grade Octreotide scan = Neuroendocrine tumour AFP alpha-fetoprotein, CK cytokeratin, CT chemotherapy, ER oestrogen receptors, hCG human chorionic gonadotropin, IHC immunohisto- chemistry, LND lymph node dissection, M1 metastasis, MRI magnetic resonance imaging, PET positron emission tomography, PR progesterone receptors, PSA prostate-specific antigen, RT radiotherapy Breast cancer: females with adenocarcinoma and axillary lymphadenopathy should be treated as if they had stage II breast cancer Ovarian cancer: females with peritoneal carcinomatosis should be treated as if they had stage III ovarian cancer, especially in the case of raised CA 12.5, known adenocarcinoma histology, and if gastrointestinal origin has been ruled out Prostate cancer: males with blastic bone metastases and raised serum prostate-specific antigen should be treated as if they had metastatic pros- tate cancer Colorectal cancer: patients whose clinical and pathological features are consistent with a primary colorectal tumour should be treated using the same protocols as for metastatic colorectal cancer, especially in the case of known adenocarcinoma histology and CK20+/CK7- or CDX2+ immunohistochemical staining Tumours of the head and neck, and anogenital tumours: in patients with squamous cell carcinoma involving the cervical or inguinal lymph nodes only, locoregional approaches based on chemotherapy/radiotherapy strategies are warranted Extragonadal germ cell tumours: young males with poorly differentiated mediastinal or retroperitoneal tumours should be treated as if they had extragonadal germ cell tumours metastases [53, 54]. Single sites confer a better prognosis, Prognostication, I-SCOOP). Those factors were: leucocy- as do lymph node metastases with no visceral involvement tosis, CUP subset (visceral disease), and performance status [45]. If only lymph nodes are affected, patients with just the [60]. Using advanced statistical methods, they constructed cervical, axillary, and/or inguinal lymph nodes involved have an algorithm that gave a 5-tier point score. This enabled a better prognosis than those with lymph node metastases patients to be categorised into three risk levels: low, inter- in pelvic or abdominal locations. Other factors that worsen mediate, and high. Other algorithms have been published the prognosis are impaired performance status and previous by various authors, but no consensus has ever been reached, weight loss [55, 56]. probably because of the heterogeneous nature of the cases As far as laboratory tests are concerned, common poor included in each series. prognostic factors are mainly increased lactate dehydro- genase (LDH) and hypoalbuminemia, probably related to weight loss [55, 56]. In terms of haematological findings, Treating cancer of unknown primary leucocytosis and anaemia also constitute independent poor prognostic factors [57]. It is possible that the “inflamma- Treatment strategies for CUP are quite challenging, because tion-based” Glasgow Prognostic Score, calculated from the these malignancies represent an extremely heterogeneous neutrophil/lymphocyte ratio (NLR), may predict with more group of metastatic tumours with, in general, a dismal prog- certainty how a particular case will behave [58]. nosis. Nevertheless, some subsets of CUP patients, who may Among histological factors, adenocarcinomas and undif- harbour chemosensitive and potentially curable tumours, ferentiated tumours have a worse prognosis (3.5% 3-year have a favourable risk (about 20%) [25]. Favourable-risk survival) than squamous cell carcinomas (41.6% 3-year sur- CUP can be identified on the basis of clinical and patho- vival) [59]. logical features, so every effort should be made to identify Petrakis et al. described a prognostic algorithm based on such cases. factors that, in their series, independently affected patient To establish a rational approach to treatment in this sce- survival (Ioannina Score for CUP Outpatient Oncologic nario, two main groups can be identified: a) CUP in which 1 3 1368 Clinical and Translational Oncology (2018) 20:1361–1372 the primary site of tumour origin is strongly suspected from dromes may be displayed due to production of hor- the clinical and pathological features; and b) tumours for mones or vasoactive substances. Low-grade tumours which no suspicion can be formulated regarding the origin are often slow-growing, so managing them like well- of the primary tumour [2] (Fig. 2). differentiated neuroendocrine tumours of the gastro- In the first case, the treatment plan should be based on the intestinal tract is recommended. At advanced stages, same standard strategies established for tumours thought to the preferred approach is simple observation (asympto- be primaries [2, 61] (Table 3). As well as the subsets men- matic patients) or symptomatic treatment with somato- tioned above, other cases of CUP inviting no suspicions as statin analogues (octreotide). Intensive platinum-based to primary origin may show a favourable prognosis. That is chemotherapy seems unhelpful in this context [62]; true of the following patient subsets: however, sunitinib or everolimus therapy may be con- sidered when a functioning pancreatic neuroendocrine (a) Poorly differentiated malignancies: up to 60% of these tumour is suspected [63, 64]. On the other hand, poorly cases are accounted for by lymphomas, which can be differentiated neuroendocrine tumours are always suspected on detection of widespread involvement of high-grade tumours (grade 3), with aggressive clinical lymph node territories and organs, such as the liver, and behaviour and a poor prognosis. These tumours require especially the spleen. In these cases, it can be useful rapid evaluation and therapy. They typically respond to conduct appropriate analysis, including a PET scan to chemotherapy, so they are treated like disseminated and repeated biopsies, if feasible, to guide the use of small cell lung cancer. The treatment of choice is specific therapies [61]. chemotherapy cycles of cisplatin and etoposide. This (b) Involvement of a single site: locoregional strategies, provides overall response rates in the 70–80% range. including surgery, is highly advisable. The use of PET Other more intensive regimens show a similar response is strongly recommended in this situation, provided not rate but have greater toxicity [62]. only that limited locoregional CUP is suspected, but also that treatment with curative intent is feasible [3]. Although more consistent evidence is needed, retrospec- (c) Low/intermediate/high-grade neuroendocrine tumours: tive studies have revealed that favourable-risk CUP patients these tumours represent a heterogeneous group of show clinical behaviour and responses resembling those seen malignancies. Well-differentiated neuroendocrine in patients with metastatic tumours of known primary origin tumours (low and intermediate grades) share similar [65]. The great majority of CUP patients are categorised approaches to diagnosis and treatment. Clinical syn- in the poor-risk subset. Unfortunately, these patients share Fig. 2 Summary of proposed management of cancer of unknown primary 1 3 Clinical and Translational Oncology (2018) 20:1361–1372 1369 a rather dismal prognosis, with median overall survival of with immunotherapy, such as tumour mutational burden, are 8–12 months from diagnosis [66]. Chemotherapy combina- being tested intensively and may play an important role in tions studied in this context show no evidence of superiority CUP treatment strategies [71]. using any regimen [67]. Most of the combinations tested have been based on platinum salts (cisplatin, carboplatin, and oxaliplatin) with other drugs (taxanes, gemcitabine, Conclusions etoposide, irinotecan, etc.) [68, 69]. However, very mod- est outcomes have been documented with this approach. It Because of the biological features of CUP, the way in which provides symptom relief at best, with no clear overall impact it spreads, and its aggressive, chemoresistant nature in some on survival confirmed. Because of its high toxicity and rel- cases, it is very important to diagnose it promptly and accu- atively low efficacy in CUP, chemotherapy should always rately. Attempts should be made to determine its extent and be used judiciously, once other potentially more effective identify the tumour subtype to which it belongs, to enable options have been reasonably ruled out (Fig. 2). use of a specific therapy that has a positive impact on the In the era of personalised medicine, efforts have also been patient. However, identifying the origin of these tumours is made to confirm whether there may be a role for targeted not easy, especially because the same organ can give rise to therapies in CUP management. The modern gene expres- different tumour types, and tumours with the same origin sion profile assays on the market can identify the origin of can vary in phenotypic profile from case to case. Moreover, CUP tissues in up to 80% of cases [32]. One method for the literature evidence is sometimes confusing or contradic- elucidating the origin of a tissue is to select a therapy of tory, because the diagnostic methods used are not always proven effectiveness in a class of tumours, and/or to use the same, and results may be interpreted in different ways. that information to implement personalised therapies in each It is, therefore, important to have standardised protocols for patient. This has not yet been tested in clinical trials, but a diagnosis and interpretation of the results. Phase III prospective trial is being conducted (GEFCAPI04, On the other hand, it is important to obtain a good biopsy, clinicaltrials.gov NCT01540058). ensuring adequate numbers of tumour cells, and to plan As well as determining tissue origin based on tumour tissue use to obtain as much information as possible. The tissue samples, another promising strategy involves liquid algorithm proposed by the Spanish Society of Pathology biopsies that detect circulating tumour DNA in patients with (SEAP) is shown in Fig. 3. The recommendation is to use a CUP. In a recent study of 442 CUP patients, liquid biopsy basic IHC panel based on the tumour’s clinical and micro- detected a genomic alteration in 65.6% of cases. The most scopic features, and a specific advanced IHC panel. A lim- common mutations were in TP53, KRAS, and PIK3CA [70]. ited number of techniques should be performed with both EGFR abnormalities, ERBB2 alterations, and BRAF V600E panels, so that a suitable amount of tissue is preserved for mutations were found in 5.9, 3.6, and 1.6% of cases, respec- using a molecular platform, if thought necessary. Molecular tively. Changes in a mismatch repair (MMR) gene were diagnostics and gene expression platforms are considered also detected in 1.6% of cases, making immune checkpoint helpful when used to complement IHC testing, because the inhibitor therapy an option. A trial is currently in progress results which they provide can be compared against many using pembrolizumab in patients with rare tumours, includ- databases, allowing more accurate diagnosis and specifica- ing CUP (clinicaltrials.gov NCT02721732). As well as tion of tumour origin. MMR mutations, other promising biomarkers that may help 1 3 1370 Clinical and Translational Oncology (2018) 20:1361–1372 Fig. 3 SEAP diagnostic algorithm. Sample material should be basic immunohistochemical panel, according to morphology, and an obtained by imaging or surgical techniques, preferably in the form advanced immunohistochemical panel, based on information obtained of a core-needle, incisional or excisional biopsy. In the pathology from the basic panel, clinical features, and microscopy findings. The department, optimal use of the material should be ensured. This may recommended number of stains is approximately 7. The aim is to pre- mean separating fragments into different paraffin blocks to save mate- serve material for possible use of a molecular platform rial for future use, if necessary. Tests should then be done using a Acknowledgements The authors are grateful for the editorial assis- creativecommons.org/licenses/by/4.0/), which permits unrestricted use, tance of Dr. Fernando Sánchez-Barbero of HealthCo (Madrid, Spain) distribution, and reproduction in any medium, provided you give appro- in the production of this manuscript. SEOM and SEAP are grateful for priate credit to the original author(s) and the source, provide a link to the financial support for this project in the form of unrestricted grants the Creative Commons license, and indicate if changes were made. from Ferrer Diagnostic, OncoDNA and Foundation Medicine/Roche. Compliance with ethical standards References Conflict of interest The authors declare that, when writing and revis- ing the text, they did not know the names of the pharmaceutical com- 1. Pavlidis N, Fizazi K. Cancer of unknown primary (CUP). Crit Rev panies that provided financial support for this project, so this support Oncol Hematol. 2005;54:243–50. has not influenced the content of this article. 2. Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet. 2012;379:1428–35. Ethical approval The study has been performed in accordance with the 3. Fizazi K, Greco FA, Pavlidis N, Daugaard G, Oien K, Penther- ethical standards of the Declaration of Helsinki and its later amend- oudakis G, et al. Cancers of unknown primary site: ESMO Clini- ments. This article does not contain any studies with human partici- cal Practice Guidelines for diagnosis, treatment and follow-up. pants or animals performed by any of the authors. Ann Oncol. 2015;26:v133–8. 4. National Comprehensive Cancer Network. NCCN Clinical Informed consent For this type of study formal consent is not required. Practice Guidelines in Oncology. Occult Primary (Cancer of Unknown Primary [CUP]) Version 1.2018–November 9, 2017. https ://www .nccn.or g/pr ofe ssion als/ph y si cian_g ls/pdf/occul Open Access This article is distributed under the terms of the t.pdf. Accessed 2 Jan 2018. Creative Commons Attribution 4.0 International License (http:// 1 3 Clinical and Translational Oncology (2018) 20:1361–1372 1371 5. Greco FA, Hainsworth J. Cancer of unknown primary site. Can- of tumor subtyping and feasibility of EGFR and KRAS molecular cer: principles and practice of oncology. Philadelphia: Lippin- testing. J Thorac Oncol. 2011;6:451–8. cott Williams and Wilkins; 2011. 24. Fizazi K, Greco FA, Pavlidis N, Pentheroudakis G, ESMO Guide- 6. Klein CA. Parallel progression of primary tumours and metas- lines Working Group. Cancers of unknown primary site: ESMO tases. Nat Rev Cancer. 2009;9:302–12. Clinical Practice Guidelines for diagnosis, treatment and follow- 7. Vikesa J, Moller AK, Kaczkowski B, Borup R, Winther O, up. Ann Oncol. 2011;22:vi64–8. Henao R, et al. Cancers of unknown primary origin (CUP) are 25. Massard C, Loriot Y, Fizazi K. Carcinomas of an unknown characterized by chromosomal instability (CIN) compared to primary origin - diagnosis and treatment. Nat Rev Clin Oncol. metastasis of know origin. BMC Cancer. 2015;15:151. 2011;8:701–10. 8. Pentheroudakis G, Stoyianni A, Pavlidis N. Cancer of unknown 26. National Institute for Health and Clinical Excellence. Metastatic primary patients with midline nodal distribution: midway malignant disease of unknown primary origin in adults: diagnosis between poor and favourable prognosis? Cancer Treat Rev. and management. Clinical guideline [CG104]. https ://www.nice. 2011;37:120–6.org.uk/guida nce/cg104 . Accessed 2 Jan 2018. 9. Brewster DH, Lang J, Bhatti LA, Thomson CS, Oien KA. 27. Herrera GA, Turbat-Herrera EA, Lott RL. S-100 protein expres- Descriptive epidemiology of cancer of unknown primary site sion by primary and metastatic adenocarcinomas. Am J Clin in Scotland, 1961–2010. Cancer Epidemiol. 2014;38:227–34. Pathol. 1988;89:168–76. 10. Levi F, Te VC, Erler G, Randimbison L, La Vecchia C. Epidemiol- 28. Hornick JL. Novel uses of immunohistochemistry in the diag- ogy of unknown primary tumours. Eur J Cancer. 2002;38:1810–2. nosis and classification of soft tissue tumors. Mod Pathol. 11. Pentheroudakis G, Golfinopoulos V, Pavlidis N. Switching 2014;27:S47–63. benchmarks in cancer of unknown primary: from autopsy to 29. Kandukuri SR, Lin F, Gui L, Gong Y, Fan F, Chen L, et al. Appli- microarray. Eur J Cancer. 2007;43:2026–36. cation of Immunohistochemistry in undifferentiated neoplasms: a 12. Collado Martín R, García Palomo A, de la Cruz Merino L, Bor- practical approach. Arch Pathol Lab Med. 2017;141:1014–32. rega García P, Barón Duarte FJ, Spanish Society for Medical 30. Economopoulou P, Mountzios G, Pavlidis N, Pentheroudakis G. Oncology. Clinical guideline SEOM: cancer of unknown primary Cancer of unknown primary origin in the genomic era: elucidating site. Clin Transl Oncol. 2014;16:1091–7. the dark box of cancer. Cancer Treat Rev. 2015;41:598–604. 13. Pavlidis N, Fizazi K. Carcinoma of unknown primary (CUP). Crit 31. Talantov D, Baden J, Jatkoe T, Hahn K, Yu J, Rajpurohit Y, et al. Rev Oncol Hematol. 2009;69:271–8. A quantitative reverse transcriptase-polymerase chain reaction 14. Rades D, Kuhnel G, Wildfang I, Borner AR, Schmoll HJ, Knapp assay to identify metastatic carcinoma tissue of origin. J Mol W. Localised disease in cancer of unknown primary (CUP): the Diagn. 2006;8:320–9. value of positron emission tomography (PET) for individual thera- 32. Varadhachary GR, Spector Y, Abbruzzese JL, Rosenwald S, Wang peutic management. Ann Oncol. 2001;12:1605–9. H, Aharonov R, et al. Prospective gene signature study using 15. Delgado-Bolton RC, Fernández-Pérez C, González-Maté A, Car- microRNA to identify the tissue of origin in patients with carci- reras JL. Meta-analysis of the performance of 18F-FDG PET in noma of unknown primary. Clin Cancer Res. 2011;17:4063–70. primary tumor detection in unknown primary tumors. J Nucl Med. 33. Dumur CI, Lyons-Weiler M, Sciulli C, Garrett CT, Schrijver 2003;44:1301–14. I, Holley TK, et al. Interlaboratory performance of a microar- 16. Kwee TC, Kwee RM. Combined FDG-PET/CT for the detection ray-based gene expression test to determine tissue of origin in of unknown primary tumors: systematic review and meta-analysis. poorly differentiated and undifferentiated cancers. J Mol Diagn. Eur Radiol. 2009;19:731–44. 2008;10:67–77. 17. Zhu L, Wang N. 18F-fluorodeoxyglucose positron emission 34. Handorf CR, Kulkarni A, Grenert JP, Weiss LM, Rogers WM, tomography-computed tomography as a diagnostic tool in patients Kim OS, et al. A multicenter study directly comparing the diag- with cervical nodal metastases of unknown primary site: a meta- nostic accuracy of gene expression profiling and immunohisto- analysis. Surg Oncol. 2013;22:190–4. chemistry for primary site identification in metastatic tumors. Am 18. Moller AK, Loft A, Berthelsen AK, Pedersen KD, Graff J, Chris- J Surg Pathol. 2013;37:1067–75. tensen CB, et al. A prospective comparison of 18F-FDG PET/CT 35. Azueta A, Maiques O, Velasco A, Santacana M, Pallares J, Novell and CT as diagnostic tools to identify the primary tumor site in A, et al. Gene expression microarray-based assay to determine patients with extracervical carcinoma of unknown primary site. tumor site of origin in a series of metastatic tumors to the ovary Oncologist. 2012;17:1146–54. and peritoneal carcinomatosis of suspected gynecologic origin. 19. Pavlidis N, Khaled H, Gaafar R. A mini review on cancer of Hum Pathol. 2013;44:20–8. unknown primary site: a clinical puzzle for the oncologists. J Adv 36. Kerr SE, Schnabel CA, Sullivan PS, Zhang Y, Singh V, Carey B, Res. 2015;6:375–82. et al. Multisite validation study to determine performance char- 20. Ofiara LM, Navasakulpong A, Beaudoin S, González AV. Opti- acteristics of a 92-gene molecular cancer classifier. Clin Cancer mizing tissue sampling for the diagnosis, subtyping, and molecu- Res. 2012;18:3952–60. lar analysis of lung cancer. Front Oncol. 2014;4:253. 37. Erlander MG, Ma XJ, Kesty NC, Bao L, Salunga R, Schnabel CA. 21. Johnson DB, Dahlman KH, Knol J, Gilbert J, Puzanov I, Means- Performance and clinical evaluation of the 92-gene real-time PCR Powell J, et al. Enabling a genetically informed approach to cancer assay for tumor classification. J Mol Diagn. 2011;13:493–503. medicine: a retrospective evaluation of the impact of comprehen- 38. Morán S, Martínez-Cardus A, Sayols S, Musulén E, Balana C, sive tumor profiling using a targeted next-generation sequencing Estival-González A, et al. Epigenetic profiling to classify cancer panel. Oncologist. 2014;19:616–22. of unknown primary: a multicentre, retrospective analysis. Lancet 22. Malapelle U, Bellevicine C, Zeppa P, Palombini L, Troncone G. Oncol. 2016;17:1386–95. Cytology-based gene mutation tests to predict response to anti- 39. Hainsworth JD, Rubin MS, Spigel DR, Boccia RV, Raby S, Quinn epidermal growth factor receptor therapy: a review. Diagn Cyto- R, et al. Molecular gene expression profiling to predict the tissue pathol. 2011;39:703–10. of origin and direct site-specific therapy in patients with carci- 23. Rekhtman N, Brandt SM, Sigel CS, Friedlander MA, Riely GJ, noma of unknown primary site: a prospective trial of the Sarah Travis WD, et al. Suitability of thoracic cytology for new thera- Cannon research institute. J Clin Oncol. 2013;31:217–23. peutic paradigms in non-small cell lung carcinoma: high accuracy 40. Gatalica Z, Millis SZ, Vranic S, Bender R, Basu GD, Voss A, et al. Comprehensive tumor profiling identifies numerous biomarkers 1 3 1372 Clinical and Translational Oncology (2018) 20:1361–1372 of drug response in cancers of unknown primary site: analysis of adults: clinicopathological features, prognostic factors and sur- 1806 cases. Oncotarget. 2014;5:12440–7. vival outcomes. PLoS ONE. 2016;11:e0154985. 41. Ross JS, Wang K, Gay L, Otto GA, White E, Iwanik K, et al. Com- 57. Randen M, Helde-Frankling M, Runesdotter S, Gunven P. Unfa- prehensive genomic profiling of carcinoma of unknown primary vorable cancers of unknown primaries: presentation and prognos- site: New routes to targeted therapies. JAMA Oncol. 2015;1:40–9. tic factors. A population-based 8-year experience. Med Oncol. 42. Tothill RW, Li J, Mileshkin L, Doig K, Siganakis T, Cowin P, 2013;30:706. et al. Massively-parallel sequencing assists the diagnosis and 58. Mohamed Z, Pinato DJ, Mauri FA, Chen KW, Chang PM, Sharma guided treatment of cancers of unknown primary. J Pathol. R. Inflammation as a validated prognostic determinant in carci- 2013;231:413–23. noma of unknown primary site. Br J Cancer. 2014;110:208–13. 43. Horlings HM, Shah SP, Huntsman DG. Using somatic mutations 59. Kim CS, Hannouf MB, Sarma S, Rodrigues GB, Rogan PK, Mah- to guide treatment decisions: Context matters. JAMA Oncol. mud SM, et al. Identification and survival outcomes of a cohort 2015;1:275–6. of patients with cancer of unknown primary in Ontario, Canada. 44. Le Tourneau C, Delord JP, Goncalves A, Gavoille C, Dubot Acta Oncol. 2015;54:1781–7. C, Isambert N, et al. Molecularly targeted therapy based on 60. Petrakis D, Pentheroudakis G, Voulgaris E, Pavlidis N. Prognos- tumour molecular profiling versus conventional therapy for tication in cancer of unknown primary (CUP): development of advanced cancer (SHIVA): a multicentre, open-label, proof-of- a prognostic algorithm in 311 cases and review of the literature. concept, randomised, controlled phase 2 trial. Lancet Oncol. Cancer Treat Rev. 2013;39:701–8. 2015;16:1324–34. 61. Hainsworth JD, Fizazi K. Treatment for patients with unknown 45. Hemminki K, Riihimaki M, Sundquist K, Hemminki A. Site- primary cancer and favorable prognostic factors. Semin Oncol. specific survival rates for cancer of unknown primary according 2009;36:44–51. to location of metastases. Int J Cancer. 2013;133:182–9. 62. Spigel DR, Hainsworth JD, Greco FA. Neuroendocrine carcinoma 46. Riihimaki M, Hemminki A, Sundquist K, Hemminki K. Time of unknown primary site. Semin Oncol. 2009;36:52–9. trends in survival from cancer of unknown primary: small steps 63. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard- forward. Eur J Cancer. 2013;49:2403–10. Bohas C, et al. Sunitinib malate for the treatment of pancreatic 47. Riihimaki M, Thomsen H, Hemminki A, Sundquist K, Hem- neuroendocrine tumors. N Engl J Med. 2011;364:501–13. minki K. Comparison of survival of patients with metastases from 64. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, known versus unknown primaries: survival in metastatic cancer. et al. Everolimus for advanced pancreatic neuroendocrine tumors. BMC Cancer. 2013;13:36. N Engl J Med. 2011;364:514–23. 48. Greco FA, Lennington WJ, Spigel DR, Hainsworth JD. Molecu- 65. Levy A, Massard C, Gross-Goupil M, Fizazi K. Carcinomas lar profiling diagnosis in unknown primary cancer: accuracy and of an unknown primary site: a curable disease? Ann Oncol. ability to complement standard pathology. J Natl Cancer Inst. 2008;19:1657–8. 2013;105:782–90. 66. Culine S, Kramar A, Saghatchian M, Bugat R, Lesimple T, 49. Hainsworth JD, Schnabel CA, Erlander MG, Haines DW 3rd, Lortholary A, et al. Development and validation of a prognostic Greco FA. A retrospective study of treatment outcomes in patients model to predict the length of survival in patients with carcinomas with carcinoma of unknown primary site and a colorectal cancer of an unknown primary site. J Clin Oncol. 2002;20:4679–83. molecular profile. Clin Colorectal Cancer. 2012;11:112–8. 67. Golfinopoulos V, Pentheroudakis G, Salanti G, Nearchou AD, 50. Pavlidis N. Optimal therapeutic management of patients with dis- Ioannidis JP, Pavlidis N. Comparative survival with diverse chem- tinct clinicopathological cancer of unknown primary subsets. Ann otherapy regimens for cancer of unknown primary site: multiple- Oncol. 2012;23:x282–5. treatments meta-analysis. Cancer Treat Rev. 2009;35:570–3. 51. Pavlidis N, Petrakis D, Golfinopoulos V, Pentheroudakis G. Long- 68. Culine S, Lortholary A, Voigt JJ, Bugat R, Theodore C, Priou term survivors among patients with cancer of unknown primary. F, et al. Cisplatin in combination with either gemcitabine or Crit Rev Oncol Hematol. 2012;84:85–92. irinotecan in carcinomas of unknown primary site: results of a 52. Matsubara N, Mukai H, Nagai S, Itoh K. Review of primary randomized phase II study–trial for the French Study Group on unknown cancer: cases referred to the National Cancer Center Carcinomas of Unknown Primary (GEFCAPI 01). J Clin Oncol. Hospital East. Int J Clin Oncol. 2010;15:578–82. 2003;21:3479–82. 53. Fehri R, Rifi H, Alboueiri A, Malouche D, Ayadi M, Rais H, 69. Gross-Goupil M, Fourcade A, Blot E, Penel N, Negrier S, Culine et al. Carcinoma of unknown primary: retrospective study S, et al. Cisplatin alone or combined with gemcitabine in carci- of 437 patients treated at Salah Azaiez Institute. Tunis Med. nomas of unknown primary: results of the randomised GEFCAPI 2013;91:205–8. 02 trial. Eur J Cancer. 2012;48:721–7. 54. Hemminki K, Bevier M, Hemminki A, Sundquist J. Survival in 70. Kato S, Krishnamurthy N, Banks KC, De P, Williams K, Williams cancer of unknown primary site: population-based analysis by site C, et al. Utility of genomic analysis in circulating tumor DNA and histology. Ann Oncol. 2012;23:1854–63. from patients with carcinoma of unknown primary. Cancer Res. 55. Lu HJ, Chen KW, Tzeng CH, Liu JH, Chiou TJ, Yen CC, et al. 2017;77:4238–46. Evaluation of prognosis for carcinoma of unknown origin in 71. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, elderly patients. Oncology. 2012;83:24–30. Miller V, et al. Tumor mutational burden as an independent pre- 56. Raghav K, Mhadgut H, McQuade JL, Lei X, Ross A, Matamoros dictor of response to immunotherapy in diverse cancers. Mol Can- A, et al. Cancer of unknown primary in adolescents and young cer Ther. 2017;16:2598–608. 1 3
Journal
Clinical and Translational Oncology – Springer Journals
Published: May 28, 2018