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Occult breast cancer presenting as metastatic adenocarcinoma of unknown primary: clinical presentation, immunohistochemistry, and molecular analysis.

ABSTRACT: We report a rare presentation of a 66-year-old female with diffuse metastatic adenocarcinoma of unknown primary involving liver, lymphatic system and bone metastases. The neoplastic cells were positive for CK7 and OC125, while negative for CK20, thyroid transcription factor 1, CDX2, BRST-2, chromogranin, synaptophysin, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu). Fluorescence in situ hybridization showed no amplification of the HER2/neu gene. Molecular profiling reported a breast cancer origin with a very high confidence score of 98%. The absence of immunohistochemistry staining for ER, PR, and HER2/neu further classified her cancer as triple-negative breast cancer. Additional studies revealed high expression levels of topoisomerase (Topo) I, androgen receptor, and ribonucleoside-diphosphate reductase large subunit; the results were negative for thymidylate synthase, Topo II-a and O6-methylguanine-DNA methyltransferase. The patient was initially treated with a combination regimen of cisplatin and etoposide, and she experienced a rapid resolution of cancer-related symptoms. Unfortunately, her therapy was complicated by a cerebrovascular accident (CVA), which was thought to be related to cisplatin and high serum mucin. After recovery from the CVA, the patient was successfully treated with second-line chemotherapy based on her tumor expression profile. We highlight the role of molecular profiling in the diagnosis and management of this patient and the implication of personalized chemotherapy in this challenging disease.

SUBMITTER: Wang J

PROVIDER: S-EPMC3290025 | biostudies-other | 2012 Jan

REPOSITORIES: biostudies-other

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Occult breast cancer presenting as metastatic adenocarcinoma of unknown primary: clinical presentation, immunohistochemistry, and molecular analysis.

Wang Jue J Talmon Geoffrey G Hankins Jordan H JH Enke Charles C

Case reports in oncology 20120107 1

We report a rare presentation of a 66-year-old female with diffuse metastatic adenocarcinoma of unknown primary involving liver, lymphatic system and bone metastases. The neoplastic cells were positive for CK7 and OC125, while negative for CK20, thyroid transcription factor 1, CDX2, BRST-2, chromogranin, synaptophysin, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu). Fluorescence in situ hybridization showed no amplification of the HER2 ...[more]

PMID: 22379471

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Project description:Cancer of unknown primary (CUP) is an umbrella term used to classify a heterogeneous group of metastatic cancers based on the absence of an identifiable primary tumor. Clinically, CUPs are characterized by a set of distinct features comprising early metastatic dissemination in an atypical pattern, an aggressive clinical course, poor response to empiric chemotherapy and, consequently, a short life expectancy. Two opposing strategies to change the dismal prognosis for the better are pursued. On the one hand, following the traditional tissue-gnostic approach, more and more sophisticated tissue-of-origin (TOO) classifier assays are employed to push identification of the putative primary to its limits with the clear intent of allowing tumor-site specific treatment. However, robust evidence supporting its routine clinical use is still lacking, notably with two recent randomized clinical trials failing to show a patient benefit of TOO-prediction based site-specific treatment over empiric chemotherapy in CUP. On the other hand, with regards to a tissue-agnostic strategy, precision medicine approaches targeting actionable genomic alterations have already transformed the treatment for many known tumor types. Yet, an unmet need remains for well-designed clinical trials to scrutinize its potential role in CUP beyond anecdotal case reports. In the absence of practice changing results, we believe that the emphasis on finding the presumed unknown primary tumor at all costs, implicit in the term CUP, has biased recent research in the field. Focusing on the distinct clinical features shared by all CUPs, we advocate adopting the term primary metastatic cancer (PMC) to denominate a distinct cancer entity instead. In our view, PMC should be considered the archetype of metastatic disease and as such, despite accounting for a mere 2-3% of malignancies, unraveling the mechanisms at play goes beyond improving the prognosis of patients with PMC and promises to greatly enhance our understanding of the metastatic process and carcinogenesis across all cancer types.

Project description:BackgroundMetastatic adenocarcinoma of unknown primary site (MACUP) is the most common cancer of unknown primary site, and shows worse prognosis. Prediction of its tumor site origin attracts a growing attention. However, the site determined by gene expression profiling does not have a significant impact on the survival. Some other special method might need to be found out.MethodsWe reviewed 1011 MACUP patients diagnosed by pathological examination and immunohistochemistry based on the Surveillance, Epidemiology, and End Results (SEER) database during 2010-2016. Kaplan-Meier curves and Cox proportional hazard model were analyzed to compare the survival. Logistic regression models and relevant nomograms were performed to predicting the probability of the primary site which including digestive system, respiratory system, and female breast. The validation and clinical utility of models were measured with relevant statistical approaches.ResultsAbout 324 (32.1%), 299 (29.6%), and 203 (20.1%) of MACUP patients were identified as the primary sites of digestive system, respiratory system, and female breast, respectively. Patients derived from digestive system and respiratory system showed poorer survival than these with other sites. Digestive system was significantly associated with liver (Odds ratio =13.21 [95% confidence interval =8.48-21.02]) or lung (2.36 [1.40-3.97]) metastasis, while respiratory system was linked to brain (11.68 [6.68-21.26]) or lymph node (3.39 [2.26-5.13]) metastasis. Patients identified as female breast were prone to occur bone metastasis (5.85 [3.68-9.45]). Logistic regression nomograms were developed to help clinicians intuitively predict the probabilities of tumor site origin with 0.867, 0.824, and 0.753 of the C-index, respectively. Decision curve analysis and clinical impact curves both revealed the clinical effectiveness.ConclusionsWe profiled different tumor site origin of MACUP patients and established prediction models. These features might be significant for clinicians to improve the probabilities of predicting the primary sites, and to decide subsequent treatment strategy.

Project description:To determine if immunohistochemistry is useful to distinguish between primary and metastatic hepatic carcinoma.Cases of hepatocellular and adenocarcinoma of liver from surgical and autopsy pathology files as diagnosed on routine histopathology with the help of haematoxylin-eosin stain.Thirty four patients with hepatic space - occupying lesions (a single lesion in 6 patients, multiple lesions in 5 patients and unspecified in remaining 23 patients). The histopathology diagnosis included 14 hepatocellular carcinoma (HC), 10 cholangiocarcinoma (CC), 7 metastatic carcinoma (MC) (colonic: n=4, pancreatic: n=2, mammary: n=l) and three cases were unclassified.The paraffin embedded blocks of biopsy and autopsy cases were taken out and sections of 4 µm thickness were cut. The immunohistochemistry staining was carried out by using a panel of 7 monoclonal antibodies. The monoclonal antibodies which were used were as follows - a fetoprotein (AFP), α 1 antitrypsin (AAT), monoclonal carcinoembryonic antigen (MCEA), myelomonocytic antigen (Leu-Ml), tumour associated glycoprotein (B72-3), A-subunit coagulation Factor XIII (Factor XIIIa) and blood group substance (Lex).Sections were defined as immunohistochemically 'positive' if definitive crisp labelling was seen in atleast 10% of tumour cells by two observers. The positive staining was classified as either predominantly cytoplasmic or membranous or both. The presence or absence of nuclear staining was also noted.The typical immunoreactivity of HCs included positivity for AAT, AFP and factor XIIIa and no staining for B 72-3 and Leu-Ml. Of 14 patients who were originally diagnosed as having HC, AAT was expressed in 86% and AFP was expressed in cytoplasm in half of the patients. Factor XIIIa displayed cytoplasmic reactivity in 71% cases of HC. Lex was present focally in 3 cases of HC, as was monoclonal CEA. These 3 cases showed features of hepatocholangiocarcinoma. In all 10 cases of CC there was staining for both Leu-Ml and Lex. The pattern of reactivity was cytoplasmic for Leu-Ml and it was both cytoplasmic and membranous for Lex. In 6 cases there was expression of B72-3 and monoclonal CEA in cytoplasm. None of the cases of CC showed staining for AFP and AAT only one case showed staining for AAT and factor XIIIa. As far as MC is concerned, there was expression of both Leu-M, and Lex in a cytoplasmic distribution in all the seven cases. The membranous accentuation of Lex seen in all cases of CC was not present in the cases of MC. Four of the 7 cases of MC showed reactivity for B72-3 as well and the staining pattern of Leu-M, and B72-3 was predominantly both cytoplasmic and membranous. In 3 of the 7 cases of MC, there was expression of monoclonal CEA, in 1 case there was expression of AAT and in 2 cases there was expression of factor XIIIa.Histologic differentiation of HC from CC and MC can be greatly aided by immunohistochemical studies. Using a panel of 7 antibodies, cases of HC displayed cytoplasmic reactivity for AAT, AFP and factor XIIIa. Cases of CC showed membranous and cytoplasmic reactivity for Lex but only cytoplasmic reactivity for Leu-M, and B72-3. On the other hand cases of MC showed only cytoplasmic staining but not membranous accentuation for Lex but Leu-M, and B72-3 showed membranous as well as cytoplasmic staining. The antibody MCEA showed variable results and hence was considered not useful. Therefore the results strongly suggest that a panel of 6 monoclonal antibodies (except MCEA) will greatly help in differentiating between primary and metastatic carcinoma.

Dataset Information

Occult breast cancer presenting as metastatic adenocarcinoma of unknown primary: clinical presentation, immunohistochemistry, and molecular analysis.

Publications

Occult breast cancer presenting as metastatic adenocarcinoma of unknown primary: clinical presentation, immunohistochemistry, and molecular analysis.

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