MODERATELY TO POORLY DIFFERENTIATED NON-SMALL CELL NEUROENDOCRINE CARCINOMA
The microscopic features of this epithelial neoplasm are consistent with a non-small cell neuroendocrine carcinoma, which was supported by the positive chromogranin and synaptophysin stainings. This is a very challenging case with respect to determining the primary site of origin for this neoplasm. As revealed in the immunohistochemical panel, the carcinoma expresses TTF-1 and CK7; it fails to express all other markers specific to other potential primary sites of origin including CDX2 and CK20.
TTF-1 is a nuclear homeodomain transcription factor that is thought to be expressed in pulmonary and thyroid neoplasms. Particularly, neuroendocrine tumors of the lung, including typical and atypical carcinoids and large cell neuroendocrine carcinomas, show > 90% positivity with TTF-1 (Folpe et al., 1999). TTF-1 is rarely expressed in extrapulmonary neuroendocrine tumors except for small cell carcinomas that can have as high as 44-80% positivity (Agoff, et al., 2000; Kaufmann and Dietel, 2000). For a non-small cell neuroendocrine carcinoma staining positive with TTF-1, the most likely site of origin is lung. Moreoever, a TTF-1+ / CK7+/CK20- immunopanel (as in this case) has been suggested to be moderately sensitive and highly specific for a diagnosis of pulmonary origin in carcinoid tumors (Cai, et al., 2001). However, no discrete pulmonary mass was present on CT scan in this case. Without a pulmonary lesion, one must strongly consider other potential sites of origin. In fact, Kaufmann and Dietel demonstrated positive TTF-1 expression in 1 of 4 extrapulmonary large cell neuroendocrine carcinomas, and concluded that TTF-1 should not be used as a marker for pulmonary carcinomas before excluding small cell carcinoma as well as large cell neuroendocrine carcinoma. They also demonstrated rare cases of positive TTF-1 staining in genitourinary and gastrointestinal neuroendocrine tumors.
In the absence of a pulmonary mass, the most likely original site would be gastrointestinal tract, particularly in the clinical picture of this case. In the "right adnexa", there is a luminal, mural and serosal involvement of the appendix by the neuroendocrine tumor although the appendiceal mucosa itself appears to be largely intact. The most common appendiceal malignancy is carcinoid tumor and it is the most common neuroendocrine neoplasm in the abdomen outside of pancreas. Although the appendix as a primary site is relatively uncommon, primary malignant GI tract tumors metastasizing to ovaries is a well described clinicopathologic condition such that any time one has bilateral tumor involvements of the ovary it directs the clinician to exclude metastases (McBroom, et al., 2000). As for the immunohistochemical markers, carcinoids of GI tract unfortunately have low frequencies of positive CDX2 staining, unlike other GI neoplasms (We rling, et al., 2003). In addition, GI neuroendocrine tumors including carcinoids have low incidence of CK20 expression, despite the high frequency of CK20 positivity in colorectal carcinomas (Chu, et al., 2000). In light of the clinical presentation and immunohistochemical profile, we would favor the appendix as the primary site of origin for this neuroendocrine carcinoma.
On the other hand, it is worth noting that ovarian metastases from cancer of the lung (as well as the appendix and other GI sites) might precede the detection of a primary neoplasm (Young and Scully, 1985). The possibility of an undetected pulmonary tumor cannot be completely excluded.
In summary, this 76-year-old woman who presented with pelvic masses had a widely spreading moderately to poorly differentiated neuroendocrine carcinoma. The neoplasm expresses chromogranin and synaptophysin, as well as TTF-1 and CK7, with the exclusion of CK20, CDX2 and all the other markers. In the absence of a pulmonary mass, the appendix is favored as the site of origin based on the clinicopathologic correlation. The prognosis of patients with appendiceal neuroendocrine malignancy metastasizing to the ovaries is poor especially when the primary and metastatic lesions are identified simultaneously or intraperitoneal spreading is present (Mandai, et al., 2001).
(The follow-up information on this case will be updated if available.)
We thank Dr. Samuel Yousem for the consultation and comments.
Contributed by Jing Yu, MD, PhD, Giuliana Trucco, MD