Purpose: Accurate identification of carcinoma of unknown primary site (CUP) patients with colorectal sites of origin may improve outcomes by directing colorectal chemotherapy rather than empiric chemotherapy. Clinical features, standard pathologic evaluation, treatment response, and survival of CUP patients whose tumors had colorectal genetic signatures were examined. Patients and Methods: We prospectively tested paraffin-embedded biopsies from 213 CUP patients using mRNA-based RT-PCR assays, and identified patients with colorectal genetic signatures. Results: Assays were successful in 185 specimens (87%); 32 (17%) had colorectal genetic signatures. All 32 patients had carcinoma; colonoscopy was normal in 30 patients studied; 29 patients (90%) had typical metastatic sites; 17 (53%) had consistent IHC profiles (CK20+, CDX2+). Twenty-nine patients (90%) received first- and/or second-line colorectal chemotherapy regimens (response rates of 69% and 54%, respectively). Median, 2- and 4-year survivals for all 32 patients were 21 months, 42%, and 35%, respectively. Conclusion: The majority of CUP patients with colorectal molecular profile di- agnoses responded to site-specific chemotherapy; median survival was similar to patients with known advanced colo- rectal carcinoma and superior to expected survival of CUP patients receiving empiric chemotherapy. Molecular profile assays can identify CUP patients with colorectal carcinoma; colorectal chemotherapy appears to improve outcomes.
Abstract: Malignant pleural effusion in patients with cancers or malignant pleural mesothelioma may often appear at the late stage of disease and significantly affect the patients’ life quality and survival. However, there is still no very effective treatment to control malignant pleural effusion. Here we report that malignant pleural effusion in one patient was completely relieved for 15 months by the anti-tuberculosis therapy. Case presentation: A 54-year-old female patient complained of cough, dyspnea, chest pain, night sweat and light fever in the afternoon. Computed tomography (CT) of the chest revealed bilateral pleural effusion. But no tumor was found in the lung, pleura and in other sites. Blood test revealed serum carcinoembryonic antigen (CEA) level at 300 ng/mL. One week after we tried anti-tuberculosis combined therapy with isoniazid, pyrazinamide, rifapentine and ethambutol. The pleural effusion in patient was eliminated, along with decreasing CEA. But the CEA increased gradually again when the anti-tuberculosis treatment was forced to discontinuation. Sixteen months after anti-tuberculosis treatment, the symptoms of cough and breathing difficulty relapsed. Chest CT revealed left pleural effusion, pleural thickness and pericardium nodules. Thoracoscopy and biopsy were conducted. The pleural nodules specimen was pathologically diagnosed as squamous cell carcinoma. Conclusion We reported a rare case of successfully treating malignant pleural effusion caused by squamous cell carcinoma of unknown primary site with the anti-tuberculosis combined. This report provides useful evidences for that the anti-tubercular agents may have potential anticancer activity in some carcinomas.
relapsed after radiotherapy. After the initiation of TS-1 treatment, PET/CT revealed a marked decrease in LN size and in the FDG uptake of the cervicomediastinal lesions; a complete biological response was achieved (Figure 4). The serum levels of CA19-9 and CEA were maintained within almost the normal range during the 31-months after TS-1 treatment. Therefore, this regimen was considered to show clinical efficacy. At the 32nd month after TS-1 treatment, there was no exacerbation, and the quality of life has been maintained. TS-1 treatment for mediastinal LN carcinoma with an unknown primary site may be recommended as therapeutic strategy. To our knowledge, this is the first case report in the English-language medical literature to describe a patient successfully treated with TS-1 alone after the relapse of cervicomediastinal LN carcinoma with an unknown primary site.
AB: Alcian blue; CA125: Cancer antigen 125; CBDCA: Carboplatin; CDX2: Caudal type homeobox 2; CEA: Carcinoembryonic antigen; CK: Cytokeratin; CT: Computed tomography; CUP: Carcinoma of unknown primary site; ER: Estrogen receptor; GCDFP-15: Gross cystic disease fluid protein-15; HE: Hematoxylin-eosin; PTX: Paclitaxel; TTF-1: Thyroid transcription factor 1; US: Ultrasonography; PET: Positron emission tomography; WT-1: Wilms tumor gene 1.
Diagnostics of CUP is based on a detailed ENT exam- ination and panendoscopy with the collection of specimens from the altered airway mucosa. Tonsillectomy, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) are recommended. 6 The primary site is most often found in the oral part of the throat, ie, in the palatine tonsils and the root of the tongue. 7–9 According to the literature, CUP patients usually have positive HPV test results. 7–9 Despite of very thorough diagnostic procedures, a primary site is not found in 40% of patients. 10,11 The treatment of CUP requires cooperation of doctors of many medical specialties. The method of treatment depends on the histopathological type of the tumor located in the affected lymph nodes – their amount, location and the presence of distant metastases. The treatment involves the surgical removal of the neck lymph nodes, radiotherapy and/or chemotherapy. Radiotherapy usually covers a large area of the head and neck. Despite of the progress in numerous ﬁ elds of med- icine, such as histology, immunology, immunohistochem- istry and imaging diagnostics, it is still dif ﬁ cult to determine the location of the primary site. The appropriate oncological treatment can be implemented only after ﬁ nd- ing the primary site which gives incomparably better results. The worldwide incidence of CUP is decreasing, due to an improvement of diagnostic methods and faster diagnosis of the primary site. However, poor prognosis in this group of patients requires further studies on this subject.
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as poorly differentiated carcinoma with midline distribu- tion, papillary adenocarcinoma of the peritoneal cavity in women, adenocarcinoma involving only axillary lymph nodes in women, and squamous cell carcinoma involving cervical lymph nodes, achieves longer survival . How- ever, almost 85% of CUP patients fall into the unfavorable group, in which chemotherapy is controversial . In last 10 years, further categorization with newly identified prog- nostic factors, such as Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2, more than one organ metastasis, high serum LDH, and low albumin levels, reflects significantly poor survival within the unfa- vorable CUP category [7-11]. It remains unknown whether or not the unfavorable CUP patient with a good prognos- tic factors is a suitable candidate for palliative chemother- apy, which may further improve survival. One possible
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A 62-year-old woman of Norwegian ethnicity, previously healthy, presented in September 2012 with a large fast- growing nodal mass in her left groin; a computed tomog- raphy (CT) scan showed a 62 mm tumor infiltrating the subcutis. A clinical examination did not reveal any other pathological glands or any skin lesions. An magnetic resonance imaging (MRI) of her pelvis showed a solitary tumor, and subsequent CT of her thorax and abdomen, mammography, and endoscopy could not reveal or indi- cate the primary location of the tumor; in addition, the tumor markers we use in our screening were all within normal range: carcinoembryonic antigen (CEA), CA125, CA15-3, CA19-9, neuron-specific enolase (NSE), and chromogranin A (CgA). In November 2012 the tumor was still regarded as operable and surgery was performed. On macroscopic examination, the tumor was a 57 mm solid tumor. Histopathological examination revealed a tumor composed of malignant epithelioid cells, which on immu- nohistochemical examination stained positive for cytoker- atin (CK) AE1/AE3 (diffuse), CK7 (focally), CD10, vimentin, and epithelial membrane antigen (EMA; scat- tered tumor cells). S100 was positive in scattered cells with dendritic features and possibly in a few scattered tumor cells. Nearly 100 % of the tumor cells were positive for Ki67/MIB1. The cells were negative for BerEP4, CK20, CK5/6, p63, thyroid transcription factor 1 (TTF1), synap- tophysin, chromogranin, estrogen and progesterone receptors, human melanoma black 45 (HMB45), melan A, leukocyte common antigen (LCA), desmin, myogenin, smooth muscle actin (SMA), and CD30 (Fig. 1). We
Our study showed that the vast majority of druggable targets in CUPs were identified using established protein biomarkers using standard, widely available IHC techniques. These biomarkers can be used to tailor therapeutic modality utilizing conventional therapies, in addition to targeted biological drugs in CUPs. For example, we profiled a case of poorly differentiated carcinoma metastatic to liver (CK+/CK7-/CK20-/TTF1-/ p63+/SYN-/ CD56-) who, after 6 cycles of carboplatin/ paclitaxel had liver recurrence. Caris molecular profiling identified TOPO1+/Thymidylate synthase- immunoprofile of the tumor, indicating a potential therapeutic benefit from irinotecan/5-FU based chemotherapy. The patient was thus treated with FOLFIRI and at 6 months significant
Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor- specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable.
Between January 1 and December 31, 2014, a total of 286 patients were referred to the TBCC multidisciplinary head and neck clinic for consideration of head and neck malignancies. For purposes of this study the 68 patients referred with a diagnosis of “head and neck malignancy of unknown primary” were then retrospectively reviewed by two independent physicians. Patients were then excluded from analysis if they were treated elsewhere (3), refused further workup (2), did not have squamous pathology (3), had a non-head and neck primary (5; 3 skin and 2 lung) or a primary lesion was identified through imaging or clinical examination performed prior to refer- ral (26). This left 29 patients with pathologically confirmed squamous cell carcinoma diagnosed on cervical lymph node fine needle aspirate (25) or core/excisional biopsy (4) which forms the cohort of our analysis [Fig. 1]. To quan- tify the delay to treatment resulting from workup of un- known primaries, an additional, subsequent population consisting of the 145 patients referred to TBCC during the same time period and having known head and neck SCC with identifiable primaries at the time of referral was used to perform a comparative analysis.
Data were extracted in duplicate by two reviewers (T.F. & A.F.). The primary outcome was the identification rate of an unknown primary site using TORS, TLM, or lingual tonsillectomy performed using TORS/TLM. Information on study design, patient and tumor characteristics, diagnos- tic workup, margin status, and perioperative complications was also extracted. Subgroup analysis of identification rates were performed based on the presence or absence of posi- tive findings on preoperative investigations including : physical examination (PE) , diagnostic imaging (DI) con- sisting of computed tomography or magnetic resonance imaging (CT or MRI) , positron emission tomography- computed tomography (PET-CT) , a combination of PE/ DI/PET-CT, and  examination under anesthesia (EUA) with directed biopsies of the nasopharynx, hypopharynx, tonsil, and base of tongue. Data were aggregated using Microsoft Excel 2010 (Microsoft Corp., Redmond, Washington), and all statistical analyses were conducted using SPSS version 21.0 (SPSS Inc., Chicago, Illinois).
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We reviewed the medical records of all patients with CUP diagnosed at Kindai University Hospital between January 2009 and March 2017. CUP was defined as a pathologically diagnosed carcinoma in a patient present- ing with metastatic lesions for which the primary origin was not identifiable unequivocally on the basis of thor- ough physical examinations including a gynecological workup for females, serum markers, diagnostic imaging, and detailed pathological analysis with IHC when needed. Further clinical examinations such as esophago- gastroduodenoscopy, colonoscopy, and breast imaging were also performed at the discretion of the treating physician according to published clinical practice guide- lines [1, 2]. 18 F-fluoro-2-deoxy-d-glucose–based positron emission tomography combined with computed tomog- raphy (FDG-PET/CT) was performed in 96% of the cohort. The classification of patients into favorable and unfavorable subsets was based on published clinical practice guidelines [1, 2]. Patients with neuroendocrine carcinoma (NEC), squamous carcinoma limited to cer- vical lymph nodes (HNC-like), adenocarcinoma re- stricted to axillary lymph nodes (LNs) in females (breast cancer [BC]–like), extragonadal germ cell tumor syn- drome (GCT-like), peritoneal carcinomatosis in females (primary peritoneal cancer [PPC]–like), squamous car- cinoma limited to inguinal LNs (anal canal carcinoma [ACC]–like), or single resectable metastatic carcinoma were thus included in the favorable subset. Patients who did not meet these definitions were classified into the unfavorable subset. From this review, we identified 209 CUP patients, of whom 44 were ineligible because of insufficient medical information or treatment history (Fig. 1). Postmortem examination was not performed in this cohort. Among enrolled patients, only one individ- ual received ICI treatment during the study period; this patient was excluded from the main analyses, but her clinical course is presented as an independent evaluation of ICI efficacy. The remaining 164 patients were sub- jected to clinical profiling as the full-analysis set. In addition, 92 of these patients were included in the bio- marker-analysis set because they had pretreatment arch- ival formalin-fixed paraffin-embedded (FFPE) tumor tissue available for IHC and irGEP. Details of patient re- cruitment are shown in Fig. 1. The study was performed according to the Declaration of Helsinki and protocols approved by the Institutional Review Board and Ethical Committee of Kindai University Faculty of Medicine.
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CUP accounts for 3% to 5% of all human cancers, is reportedly the seventh to eighth most frequent malignant tumor, and is the fourth most common cause of cancer death in both sexes . CUP represents a heterogeneous group of cancer with a distinct biology and is classified depending on the patient characteristics, clinical exami- nation findings, site involvement, and histopathological findings. CUP may be divided into subsets of favorable and unfavorable prognoses. The favorable subset includes CUP with isolated axillary nodal involvement, carci- noma with a midline distribution in young men, and others. A treatment strategy has been established in the fa- vorable subset. Treatment response and survival are similar to those in patients with a relevant known primary tumor. In contrast, the optimal treatment for the unfavorable subset has not yet been determined. Lazaridis et al.  reported that the median survival of poor-prognosis CUP was 6 to 7 months.
Case Presentation: We report a case of 65 years old man who was found on routine Esophagogastroduodenoscopy to have gastric tumour. Histology revealed adenocarcinoma. Staging investigation with abdominal computed tomography (CT) and Positron emission tomography, fluorine-18 fluoro-2-2deoxy-D-glucose (PET-CT: F-18 FDG) Torso (Skull base to thigh) confirmed gastric cancer of the antrum with lymph node enlargement at hepatoduodenal ligament. The patient underwent laparoscopic assisted distal gastrectomy with D2 lymphadenectomy. Pathology revealed intestinal type moderately differentiated tubular adenocarcinoma invading lamina propria (pT1a). Four positive lymph nodes out of 34 did not show metastatic adenocarcinoma but rather Squamous Cell Carcinoma (SCC) and were positive for p63 and CK5/6 on immune histo chemistary. Primary site of SCC was not found. He received adjuvant chemotherapy with TS-1 60mg. After two years of follow-up he is asymptomatic and repeated EGD and abdominal CT Scan were normal.
This patient underwent an incisional biopsy of a left supraclavicular lymph node under general anaesthesia. The histology revealed replacement of normal node architecture by metastatic poorly diﬀerentiated carcinoma with probable squamoid diﬀerentiation. In order to find out the primary site she underwent panendoscopy of her upper aerodigestive tract which was normal. Further investigations failed to establish a possible primary site. This included gynae- cological and pelvic examinations, proctosigmoidoscopy, tumour marker study, and CT scan of paranasal sinuses.
Following the filtering process, biologically relevant and therapeutically actionable variants were identified in 81% (17/21) of the cohort. The mean number of variants was 1 per case (range 0–4) (Table 2 and Fig. 2). Hotspot mutations were identified in 59% (10/17) of cases. These were in genes associated with various cell signalling, cell cycle control and DNA repair pathways. The gene with the most common hotspot mutations was TP53 identi- fied in 47% (8/17) of cases, and the most common copy number variation (CNV) was MYC amplification identi- fied in 12% (2/17) of cases. Correlation with the tumour pathology showed that the CUP cases with morphol- ogy of adenocarcinoma and PD carcinoma had the larg- est number of cell signalling pathway variants (EGFR, MET, JAK3, KRAS, HRAS, BRAF, PIK3CA, PTPN11 and APC). In contrast, SCC tumours showed a higher num- ber of variants in cell cycle regulation genes (TP53 and CDKN2A). There were no associations with other clin- icopathological parameters (i.e. age, gender or anatomi- cal site of presentation).
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Neck cancer metastasis with an unknown primary site (NCUP) presents in patients with neck lymph node involvement in the absence of an identifiable primary tumor [1–3]. The histopathology of NCUP consists of squamous cell carcinoma, adenocarcinoma, and other undifferentiated carcinomas [1–3]. The often-extensive diagnostic workup to identify the primary site can include physical examination, chest X-ray, endoscopy, biopsy, computed tomography (CT) or magnetic resonance imaging (MRI), and positron emission tomography (PET). Nonetheless, in approximately 2% to10 % of NCUP cases the primary site remains unidentified [1–12].
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For patients presenting with uncertain primary tumors and who do not have a primary site identified even after exhaustive investigation empiric chemotherapy is rarely successful and often quite intolerable [7-9]. Better survi- val is achieved when tissue-specific treatment strategies are utilized [11,12,33]. Thus, availability of a test that identifies the tissue of origin would increase the chances of a patient receiving a more targeted and less toxic therapy. Depending on how such a test is integrated into the workup of uncertain primaries, it may also reduce the overall time and expense associated with the hunt for a primary tumor. In addition, as new tissue-tar- geted therapies are expected to be introduced, correct identification of the primary site will become even more important in guiding optimal patient management.
what broad type the cancer is, carcinoma, mel- anoma, lymphoma, or sarcoma? If not distin- guishable on morphology alone, then first-line IHC panel including AE1/3 (epithelial marker), S100 (melanocytic marker) and CLA (lymphoid marker) should be used. Third, if carcinoma, whether the subtype is adenocarcinoma, germ- cell tumor or solid organ tumors? In this case, tumor cell morphology and representative IHC markers play a significant role. Finally, a panel of specific IHC markers was applied to predict the primary site and to avoid errors. Recently, molecular diagnostic tools, ISH based on mRNA for example, have also shown a perfect perfor- mance, but are always unavailable .
Among the 20 patients, 11 underwent 18F-FDG PET scans, four of whom also underwent PET/CT scans sev- eral months after the initial PET scan was performed. The remaining nine out of the 20 patients only had a PET/CT. Data on the 20 patients are shown in Table 2. Neither the PET nor PET/CT detected the putative pri- mary site of the metastatic tumor in any of the 20 patients. In six cases, the initial presentation was cervical lymph node metastasis. Neither the PET nor PET/CT detected the primary site of cervical lymph node metas- tases. A 54-year-old male (patient no. 9) presented with right cervical lymph node metastasis from an unknown primary tumor. The patient had a radical neck dissec- tion, unilateral tonsillectomy, blind biopsy of the naso- pharynx and the tongue base. The pathology revealed metastatic squamous cell carcinoma in one out of 20