Immunohistochemical profile for unknown primary adenocarcinoma

Abstract

Background: Development of tailored treatment based on immunohistochemical profiles (IPs) of tumors for cancers of unknown primary is needed.

Methodology/principal findings: We developed an algorithm based on primary known adenocarcinoma for testing sensitivity and specificity. Formalin-fixed paraffin-embedded tissue samples from 71 patients of unfavorable subsets of unknown primary adenocarcinoma were obtained. We examined 15 molecular markers using the algorithm incorporating these IPs and classified the tumours into 9 subsets based on the primary tumour site. The sensitivity and specificity of this algorithm were 80.3% and 97.6%, respectively. Apparent primary sites were lung in 17 patients, digestive organs in 13, gynecological organs in 9, prostate in 7, liver or kidney in 6, breast in 4, urothelial organ in 2, biliary tract and pancreatic profile in none, and unclassified in 13. The response rate to chemotherapy was highest for the gynecological IPs. Patients with gynecological or lung cancer IPs had longer median progression-free survival than those with others: 11.2 months for gynecological IPs (p<0.001) and 6.8 months for lung IPs (p = 0.05). Lung, digestive, prostate, and gynecological profiles were associated with significantly longer median survival time than the other profiles. Multivariate analysis confirmed that the IPs were independent prognostic factors for survival.

Conclusions/significance: The IPs identified in this study can be used to further stratify patient prognosis for unfavorable subsets of unknown primary adenocarcinoma.

Figure 1. Identification of the primary tumor site by immunohistochemistry and gene analysis.

Thirteen patients were not sorted to specific profiles and an additional 8 patients were not classified into the profiles in the manner defined by the algorithm. Two patients presenting with both CK7− and CK20-positive were classified into an unclassified profile. Ten patients with CK7-positive and CK20-negative were classified into an unclassified profile. Three patients with CK7-positive and CK20-negative were classified into the digestive (n = 1) and urothelial (n = 2) profiles. One patient with both CK7− and CK20-negative was classified into the unclassified profile. Four patients with both CK7− and CK20-negative were classified into the digestive (n = 3) and lung (n = 1) profiles. Footnote: * Estrogen receptor- or progesterone receptor-positive with CK19-positive.

Figure 2. An adenocarcinoma showing typical presentation of the breast profile by immunohistochemistry.

Hematoxylin-eosin stain (left upper), cytokeratin (CK)7 (right upper), CK20 (left lower), and mammaglobin (right lower). CK7 and mammaglobin are positive in the cytoplasm of tumor cells (original magnification ×200).

Figure 3. An adenocarcinoma showing typical presentation of the lung profile by immunohistochemistry.

Hematoxylin-eosin stain (left upper), cytokeratin (CK)7 (right upper), CK20 (left lower), and thyroid transcription factor-1 (TTF-1) (right lower). CK7 and TTF-1 are positive in the cytoplasm and nuclei of tumor cells, respectively (original magnification ×200).

Figure 4. Progression-free survival curve by the Kaplan-Meier method for the groups with each primary site as classified by the immunohistochemistry profiles.

Figure 5. Overall survival curve by the Kaplan-Meier method for the groups with each primary site as classified by the immunohistochemistry profiles.