Current Status and Progress of Diagnostic Techniques for Cancer of Unknown Primary / 肿瘤防治研究

Cancer of unknown primary (CUP) is a heterogeneous tumor type that has been diagnosed as a metastatic tumor by pathological examination, but the primary tumor cannot be identified through comprehensive clinical examination. The incidence of CUP accounts for approximately 1%–2% of all tumors. CUP progresses rapidly and has a short course. The treatment and prognosis of patients with CUP are closely linked to the primary site. In clinical settings, identifying the primary tumor remains challenging. Scholars have focused on improving the detection rate. Novel technologies, such as gene expression profiling, high-throughput sequencing, epigenetics, and liquid biopsy, have been successively applied to identify the primary tumor of CUP accurately, sensitively and specifically. With the guidance of molecular diagnosis, targeted therapy, immunotherapy, and combination therapy will usher in the era of precision treatment for CUP, which may become a typical example for individualized therapy.

Swedish National Multicenter Study on Head and Neck Cancer of Unknown Primary: Prognostic Factors and Impact of Treatment on Survival

Abstract Introduction Head and neck cancer of unknown primary (HNCUP) is a rare condition whose prognostic factors that are significant for survival vary between studies. No randomized treatment study has been performed thus far, and the optimal treatment is not established. Objective The present study aimed to explore various prognostic factors and compare the two main treatments for HNCUP: neck dissection and (chemo) radiation vs primary (chemo) radiation. Methods A national multicenter study was performed with data from the Swedish Head and Neck Cancer Register (SweHNCR) and from the patients' medical records from 2008 to 2012. Results Two-hundred and sixty HNCUP patients were included. The tumors were HPV-positive in 80%. The overall 5-year survival rate of patients treated with curative intent was 71%. Age (p< 0.001), performance status (p= 0.036), and N stage (p= 0.046) were significant factors for overall survival according to the multivariable analysis. Treatment with neck dissection and (chemo) radiation (122 patients) gave an overall 5-year survival of 73%, and treatment with primary (chemo) radiation (87 patients) gave an overall 5-year survival of 71%, with no significant difference in overall or disease-free survival between the 2 groups. Conclusions Age, performance status, and N stage were significant prognostic factors. Treatment with neck dissection and (chemo) radiation and primary (chemo) radiation gave similar survival outcomes. A randomized treatment study that includes quality of life is needed to establish the optimal treatment.

Neoplasia de sítio primário desconhecido: abordagem diagnóstica e terapêutica / Cancer of onknown primary site: diagnostic and therapeutic approach

Introdução: As neoplasias de sítio primário desconhecido (NSPD) são responsáveis por 3-5% de todas as neoplasias malignas, definidas pela falha de identificação do sítio primário após a investigação diagnóstica. Métodos: Revisão bibliográfica da literatura entre abril e maio de 2018, em artigos de revisão, seminários e artigos originais, em inglês, dos últimos 20 anos. Resultados: A investigação diagnóstica das NSPD envolve uma extensa anamnese, exame físico, exames laboratoriais, exames de imagem, análise anatomopatológica e imuno-histoquímica da lesão metastática. Com base nessa investigação, são classificadas de acordo com critérios clínico-patológicos para melhor conduta terapêutica. Conclusão: As NSPD são um grande desafio para o clínico e oncologista, é imprescindível a investigação adequada dessas neoplasias para o melhor tratamento da doença.

Introduction: Cancer of unknown primary site (CUP) accounts for 3-5% of all malignant neoplasms, which is defined when the anatomical site of origin remains occult after detailed investigations. Methods: Review articles, seminars, and original articles in English for the last 20 years. Results: The diagnostic investigation of CUP involves an extensive anamnesis, physical examination, laboratory exams, imaging, anatomopathological and immunohistochemical analysis of the metastatic lesion. Based on this investigation, the neoplasms are classified according to clinical pathological criteria. Conclusion: CUP can be a challenge for the clinician and medical oncologist, it is essential to adequately investigate these neoplasms in order to define the best treatment approach.

FDG PET/CT and Conventional Imaging Methods in Cancer of Unknown Primary: an Approach to Overscanning / 대한핵의학회잡지

PURPOSE: To compare the performance of fluorine-18 fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) with conventional imaging methods (CIM), including computed tomography (CT), magnetic resonance imaging (MRI), and mammography (MMG) in cancer of unknown primary (CUP).METHODS: A total of 36 patients with CUP, who referred to our clinic for a FDG PET/CTscan, were enrolled in this study. Thirty of the patients were also examined through either diagnostic CT/MRI and/or MMG. The diagnostic performance of both methods for the primary cancer location was analyzed. The results of FDG PET/CT and CIM were compared based on the standard reference of the histopathology and/or clinical and laboratory follow-up.RESULTS: The primary cancer locations were detected in 24 patients (66.6%, 24/36) by FDG PET/CT, whereas CIM identified the locations in 16 patients (53.3%, 16/30). Sensitivity, specificity, PPV, NPV, and accuracy rates of the detection of the primary tumor localizations were as follows: 83, 70, 89, 58, and 79% for FDG PET/CT; 70, 62, 84, 42, and 68% for CIM, respectively. There was no statistical significance between modalities regarding any of the categories in 30 patients.CONCLUSION: FDG PET/CT detected the primary tumors of the patients with CUP more than CIM did. However, the difference between them was not found to be statistically significant. It may be considered that FDG PET/CT scan can be performed as a first-line tool in the initial diagnosis of the patients with CUP and to add radiodiagnostic imaging in selective cases.We conclude that if the first-line examination of a CUP patient has been already performed by a CIM and the result was negative or inconclusive, FDG PET/CT can be considered to avoid unnecessary imaging procedures.

Advances in the diagnosis and treatment of cancer of unknown primary in the genom-ic era / 中国肿瘤临床

A cancer of unknown primary (CUP), defined as a histologically confirmed metastatic cancer for which the primary site could not be identified after detailed investigations,accounts for 3%-10% of all malignancies.The diagnostic work-up in CUP relies mainly on imaging and histopathology with specific immunohistochemistry,while approaches of gene expression profiling and epig-enomics help precisely identify the primary site in the genomic era.Nevertheless,these approaches have not been widely used in clini-cal practice.Hence,essential and crucial steps are necessary to facilitate the use of such approaches in clinical practice.CUP is a het-erogeneous group of cancers,with low efficiency under traditional empirical treatment.However,identification of favorable subsets (accounting for 15%-20%)and organ-specific treatments could improve patients' survival.Moreover,molecular detection and applica-tion of next-generation sequencing offer the prospect of individualized targeted therapy with novel agents in CUP.Recently,with the development of immunotherapy,we are looking forward to breakthroughs in targeted therapy and immunotherapy for CUP.

Advances in gene expression profiling of metastases from unidentified primary tumor / 实用肿瘤学杂志

Primary lesions unknown metastatic cancer ( CUP) is a class of histopathologically confirmed metastases. However,a variety of clinical diagnosis and treatment can not clear the primary tumor. The identifica-tion of tumor primary site is the first step in the diagnosis of CUP. The histopathology,immunohistochemistry and PET /CT are commonly used clinical diagnosis and treatment. Gene expression profiling technique is a new meth-od for the diagnosis of primary tumor in recent years. It has high diagnostic accuracy,sensitivity and specificity, and is expected to achieve individual treatment of patients with CUP.

Identiifcation and validation of a novel gene expression signature for diagnosing tumor tissue origin / 中国癌症杂志

Background and purpose:Cancer of unknown primary (CUP) represents approximately 5%~10%of malignant neoplasms. For CUP patients, identiifcation of tumor origin allows for more speciifc therapeutic regimens and improves outcomes.Methods:By retrieving the gene expression data from ArrayExpress and Gene Expression Omnibus data repositories, we established a comprehensive gene expression database of 5 800 tumor samples encom-passing 22 main tumor types. The support vector machine-recursive feature elimination algorithm was used for feature selection and classiifcation modelling. We further optimized the RNA isolation and real-time quantitative polymerase chain reaction (RTQ-PCR) methods for candidate gene expression proifling and applied the RTQ-PCR assays to a set of formalin-fixed, paraffin-embedded tumor samples.Results:Based on the pan-cancer transcriptome database, we identiifed a list of 96-tumor speciifc genes, including common tumor markers, such as cadherin 1 (CDH1), kallikrein-re-lated peptidase 3 (KLK3), and epidermal growth factor receptor (EGFR). Furthermore, we successfully translated the microarray-based gene expression signature to the RTQ-PCR assays, which allowed an overall success rate of 88.4% (95%CI: 83.2%-92.4%) in classifying 22 different tumor types of 206 formalin-fixed, paraffin-embedded samples. Conclusion:The 96-gene RTQ-PCR assay represents a useful tool for accurately identifying tumor origins. The assay uses RTQ-PCR and routine formalin-ifxed, paraffn-embedded samples, making it suitable for rapid clinical adoption.

A Case of Metachronous Human Papilloma Virus-Associated Squamous Cell Carcinomas in Head and Neck / 대한이비인후과학회지

Synchronous or metachronous head and neck cancer is known to occur in up to 20% of patients, negatively affecting long-term prognosis. We experienced a case of metachronous head and neck cancers in a Human papillomavirus (HPV)-positive patient without a history of smoking, initially presenting with as a cancer of unknown primary (CUP), and then with a contralateral tonsil cancer with metastatic lymphadenopathy five years later. This report highlights the clinical usefulness of HPV typing to determine the optimal extent of surgery and the follow-up strategy in CUP.

Perfil dos pacientes com diagnóstico de câncer de sítio primário desconhecido em um centro terciário de atenção oncológica / Profile of patients with diagnosis of cancer of unknown primary site in a tertiary cancer center

Introdução: O câncer de sítio primário desconhecido caracteriza-se pela presença de doença metastática ao diagnóstico, sem localização do tumor primário. Objetivo: Conhecer o perfil dos pacientes com diagnóstico de câncer de sítio primário desconhecido em um centro de oncologia terciário. Material e método: Estudo retrospectivo e descritivo no qual foram analisados os prontuários dos pacientes com câncer de sítio primário oculto entre 2002 e 2012. Resultados: Entre os 68 prontuários analisados, observou-se que o adenocarcinoma é o tipo histológico mais frequente (39,71%) seguido pelo carcinoma espinocelular (29,41%). Os sítios de metástases mais recorrentes foram a região cervical (38,23%), fígado (20,58%) e peritônio (16,71%). A imuno-histoquímica foi realizada em 44,12%, os pacientes com acometimento cervical não se beneficiaram da elucidação diagnóstica por este meio, devido à falta de marcadores específi cos para este sítio. Em relação ao tratamento, 60,29% dos pacientes foram submetidos a alguma modalidade terapêutica, sendo a quimioterapia a mais comum, onde a cisplatina foi o antineoplásico mais utilizado de forma isolada (11,76%) e o esquema etoposídeo e cisplatina mais realizado em combinação (7,35%). Conclusão: O estudo está em consonância com os dados da literatura sobre o perfil destes pacientes; entretanto, apesar dos avanços nas técnicas diagnósticas, esta síndrome ainda representa um desafio na prática oncológica.

Introduction: Cancer is characterized by the presence of metastatic disease at diagnosis, without location of the primary tumor. Aim: To know the profile of patients diagnosed with cancer of unknown primary site in a tertiary cancer center. Methods: A retrospective study in which the medical records of patients with cancer of unknown primary site were analyzed between 2002 and 2012. Results: From the 68 charts analyzed adenocarcinoma was found to be the most common histological type (39.71 %), followed by squamous-cell carcinoma (29.41%). The most frequent metastasis sites were the cervical region (38.23%), liver (20.58%) and peritoneum (16.71%). Immunohistochemistry was performed on 44.12%, patients with cervical involvement did not benefi t from such diagnostic clarification due to lack of specific markers for this site. Regarding treatment, 60.29% of patients underwent some form of therapy, the most common being chemotherapy, where cisplatin was the most often antineoplastic used alone (11.76%) and etoposide plus cisplatin the most often used regimen used in combination (7.35%). Conclusion: The study is consistent with published data on the profile of these patients. Despite the advances in diagnostic techniques, however, this syndrome is still a challenge in oncology practice.

Endobronchial Ultrasound-guided Transbronchial Needle Biopsy for Diagnosis of Mediastinal Lymphadenopathy in Patients with Extrathoracic Malignancy

Mediastinal lymphadenopathy associated with extrathoracic malignancy or a metastasis of unknown origin (MUO) requires pathological verification. Surgical exploration or endoscopic ultrasound-guided fine needle aspiration is limited to application. We investigated the effectiveness of endobronchial ultrasound-guided transbronchial needle biopsy (EBUS-TBNA) for evaluating mediastinal lymphadenopathy in patients with an extrathoracic malignancy. We retrospectively analyzed data from 59 patients who underwent EBUS-TBNA with a core biopsy because of a suspected mediastinal metastasis between September 2008 and August 2010. All patients had previously been diagnosed with an extrathoracic malignancy (n = 39, 66.1%) or a suspected MUO without a thoracic lesion (n = 20, 33.9%). A total of 88 lymph nodes was analyzed. EBUS-TBNA findings indicated malignancies in 34 patients (57.6%). The EBUS-TBNA sensitivity and specificity for the detection of mediastinal malignancy in patients with a previous extrathoracic malignancy were 96.3% and 100%, respectively. For MUO patients without a thoracic lesion, the sensitivity and specificity were 61.5% and 100%, respectively. The overall sensitivity and specificity were 81.0% and 100%, respectively (P = 0.053). EBUS-TBNA is a safe and effective modality for evaluating mediastinal lymphadenopathy in patients with a previous extrathoracic malignancy or a MUO without a thoracic lesion. The application of this diagnostic tool is likely to have significant clinical implications.

Cancer of Unknown Primary Finally Revealed to Be a Metastatic Prostate Cancer: A Case Report / Journal of the Korean Cancer Association, 대한암학회지

The vast majority of patients with metastatic prostate cancer present with bone metastases and high prostate specific antigen (PSA) level. Rarely, prostate cancer can develop in patients with normal PSA level. Here, we report a patient who presented with a periureteral tumor of unknown primary site that was confirmed as prostate adenocarcinoma after three years with using specific immunohistochemical examination. A 64-year old man was admitted to our hospital with left flank pain associated with masses on the left pelvic cavity with left hydronephrosis. All tumor markers including CEA, CA19-9, and PSA were within the normal range. After an exploratory mass excision and left nephrectomy, the pelvic mass was diagnosed as poorly differentiated carcinoma without specific positive immunohistochemical markers. At that time, we treated him as having a cancer of unknown primary site. After approximately three years later, he revisited the hospital with a complaint of right shoulder pain. A right scapular mass was newly detected with a high serum PSA level (101.7 ng/ml). Tissues from the scapular mass and prostate revealed prostate cancer with positive immunoreactivity for P504S, a new prostate cancer-specific gene. The histological findings were the same as the previous pelvic mass; however, positive staining for PSA was observed only in the prostate mass. This case demonstrates a patient with prostate cancer and negative serological test and tissue staining that turned out to be positive during progression. We suggest the usefulness of newly developed immunohistochemical markers such as P504S to determine the specific primary site of metastatic poorly differentiated adenocarcinoma in men.

A case of inguinal lymph node squamous cell carcinoma of unknown origin, accompanied with carcinoma in situ of cervix / 부인종양

Metastatic Cancer of Unknown Primary Site (CUP) accounts for approximately 3-5% of all malignant neoplasms. CUP represents a heterogeneous group of metastatic tumors for which no primary site can be detected following a thorough medical history, careful clinical examination, and extensive diagnostic work-up. Several authors have reported poor prognosis of this malignancy, because there is no consensus on diagnostic guidelines and optimal therapy. Historically, chemotherapy has been the cornerstone of treatment for patients with CUP. We experienced a case of inguinal lymph node squamous cell carcinoma of unknown origin, accompanied with carcinoma in situ of the cervix. We report this case with a brief review of the literatures.