Preliminary Immunohistochemistry Panel in Evaluating Carcinomatous Deposits in Brain from Unknown Primary: A Cross-sectional Study

Abstract

Introduction: Metastasis to the brain as a first presentation is very rare and challenging. Metastatic tumours are ten times more common in the brain than primary intracranial neoplasms. Brain metastasis to brain causes severe neurological morbidity in a patient with cancer. In such cases, histopathology plays a pivotal role in the analysis of metastatic carcinomatous deposits, especially when they present as Cancer of Unknown Primary (CUP) site. A panel of immunohistochemical markers, especially Cytokeratin 7 (CK7), Cytokeratin 20 (CK20) and Thyroid Transcription Factor1 (TTF-1), helps in delineating the primary site of the tumour in cases of CUP. Aim: To evaluate the use of three basic immunohistochemistry markers-CK7, CK20 and TTF-1-in identifying the unknown primary source of brain metastasis. Materials and Methods: This is a cross-sectional study conducted over a period of two years, from June 2016 to June 2018, in the Department of Pathology at the Institute of Neurosurgery, Rajiv Gandhi Government General Hospital, Chennai, Tamil Nadu, India. The aim of the study was to formulate an algorithm for the initial work-up of CUP in the Central Nervous System (CNS). The analysis of the origin of the occult primary tumour was performed using a panel of immunohistochemistry markers, including CK7, CK20 and TTF1, on paraffin-embedded blocks of patients with metastatic carcinoma deposits in the CNS with an occult primary site. The results were compared with the corresponding squash cytology preparations. The parameters studied included imaging, squash cytology, histomorphology and immunohistochemical analysis. The results were analysed using the IBM Statistical Package for the Social Sciences (SPSS) software version 20.0, using Chi-square test and Fisher’s-exact test. Results: The incidence of metastatic deposits in the CNS in our institute was 5.2% (82 out of 1553 cases). Squash cytology done intraoperatively was sensitive in identifying metastatic carcinomatous deposits in the CNS, as compared to the corresponding histopathological slides. Squash cytology was able to detected 41 cases prior to histopathological examination, resulting in a sensitivity of 82%. In the histopathological examination, adenocarcinoma was the most commonly observed morphology, accounting for 45 (90%) cases of the total. The most common pattern of staining was CK7+ CK20- TTF1+, which was found in 21 (42%) cases. Of these, 18 cases were confirmed to be lung carcinoma on follow-up, indicating a sensitivity of 85.7% for this staining pattern in detecting lung carcinoma. Additionally, there was one case in which lung primary was suggested, but no primary was detected, hence the positive predictive value of 94.7% for the test in detecting lung carcinoma; however, the specificity was only 50%. The next most common pattern of staining, CK+ CK20- TTF1-, accounted for 16 (32%) cases. The second most common tumours that was found to metastases to the brain from an unknown primary site were from the Gastrointestinal Tract (GIT). Conclusion: The results indicate that immunohistochemical analysis of CK7, CK20 and TTF1 is valuable for classifying the probable primary site in patients with metastasis from Cancers of Unknown Primary (CUP) in the CNS, especially in a resource-limited set-up. This panel provides a window for the rational use of organ-specific markers, serving as a cost-effective method of investigation. The authors also found that once histomorphology is indicative of carcinomatous deposits and this readily available basic panel is applied, it hastens the search for the primary. Hence, the present study helps initiating the treatment at the earliest especially in public sector hospitals where there is dearth of wide range of advanced immunohistochemical markers.

Keywords

• carcinoma of unknown primary
• cytokeratin 7
• cytokeratin 20
• thyroid transcription factor 1