Lung Adenocarcinoma, Mixed Papillary-acinar Type, Metastatic to the Ovary Julie A. Irving, MD, FRCPC Department of Pathology, Vancouver General Hospital Vancouver , Canada

39 year old female with a 15.0 cm unilateral solid-cystic ovarian mass. Total hysterectomy had been performed 13 years ago for carcinoma of the cervix. History: A 39-year old woman was found to have a pelvic mass on routine physical examination. A chest X-ray taken during work-up showed a right upper lobe nodule. A history of heavy smoking was noted; she had also had a total abdominal hysterectomy for squamous cell carcinoma of the cervix 13 years previously. The patient underwent left salpingo-oophorectomy, pelvic lymph node dissection, and omentectomy. Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathological findings : The left ovarian tumor was a smooth surfaced, multiloculated cystic mass measuring 15 cm in maximum dimension. The cysts ranged in size from 1 to 13 cm, and papillary excrescences were present within the inner cyst linings. Focal solid areas were also identified. Histologically, intracystic tumor showed a striking papillary architecture, characterized by large bulbous fronds with stromal cores. In the subjacent cyst wall, irregular nests and glands infiltrated the stroma. In solid areas, the tumor showed a multinodular growth pattern; focal ovarian surface involvement and vascular invasion were present. Moderately differentiated glandular elements infiltrated between normal ovarian structures. The tumor cells showed positive immunoreactivity for thyroid transcription factor (TTF)-1. Peritoneal fluid washings were positive for adenocarcinoma; pelvic lymph nodes and omentum were negative for malignancy. Diagnosis: Lung adenocarcinoma, mixed papillary-acinar type, metastatic to the ovary Follow-up: Brain metastases were detected 3 weeks post-operatively. The patient received chemotherapy but died of disease 8 months later. Discussion: An ovarian tumor is a metastasis in approximately 5-10% of cases. [1] Of these, the majority are adenocarcinomas from elsewhere in the female genital tract (contralateral ovary, uterine corpus) or from extragenital sites, usually the gastrointestinal tract and breast. [1, 2, 3, 4] Primary lung carcinoma accounts for less than 1% of metastatic ovarian tumors. Despite this low overall frequency, increasing numbers of cases of lung carcinoma metastatic to the ovary have been encountered, often in relatively young women. [5] Presumably, this is a consequence of statistical trends, as lung carcinoma in females in the United States and Canada is now second in overall incidence and first in mortality due to cancer-related deaths. [6, 7] All major histologic subtypes of lung carcinoma can metastasize to the ovary and potentially mimic a primary ovarian neoplasm. [5, 8, 9, 10, 11, 12] Most tumors are small cell carcinoma, adenocarcinoma, or large cell carcinoma; in our experience, squamous cell carcinoma metastatic from the lung is rare. [5, 12] In our recent study, in most cases with a preceding history of lung carcinoma, the ovarian tumor was detected within one year of the initial diagnosis. [5] Absence of such history, however, does not exclude the possibility of a primary lung carcinoma, as a small but significant proportion of ovarian tumors are detected prior to the lung tumor. Awareness of other sites of involvement can provide very helpful information, as spread to locoregional pulmonary lymph nodes, mediastinum, chest wall, brain, and bone is much more indicative of a primary lung tumor. Conversely, distant metastasis from a primary ovarian tumor to lung in the absence of peritoneal extension would be uncommon. Differing features from those of the common primary ovarian carcinomas highlights that when an ovarian tumor exhibits unusual histologic features, a metastasis should always be strongly considered. General features suggestive of metastasis, including multinodular growth and lymphovascular invasion, are commonly present in metastatic lung carcinomas. [5] Bilateral ovarian involvement is present in one-third of cases, a lower frequency than usually encountered for metastatic ovarian tumors in general. Ovarian surface involvement, although identified in the present case, is infrequent in metastatic lung carcinomas, suggesting that the mode of spread is usually hematogenous or lymphangitic, rather than peritoneal seeding as occurs in many metastases of gastrointestinal origin. [5] Adenocarcinoma comprises approximately one-third of lung carcinomas metastatic to the ovary, and as a group these tumors show significant morphologic diversity. Metastatic lung adenocarcinomas have a propensity to mimic surface epithelial-stromal tumors of endometrioid, serous, clear cell, and mucinous type, but exhibit sufficient unusual features to prompt consideration of a metastasis. [5] In the present case, gross and microscopic features, including prominent stromal papillae with clusters of eosinophilic cells tufting from the papillae, mimicked an ovarian serous borderline tumor. Papillae with fibrovascular stromal cores have also been described in a case report of papillary adenocarcinoma of lung origin metastatic to the ovary. [8] Irregular, variably shaped glandular formations, and either extensive necrosis or lymphovascular invasion, are typical of a metastatic adenocarcinoma; such areas of frank adenocarcinoma would be exceptionally uncommon in a serous borderline tumor. The infiltrative glands of metastatic adenocarcinoma have malignant nuclei, often with coarse nuclear membranes and prominent nucleoli. In contrast, foci of microinvasion in primary serous borderline tumors are typically single cells or small discrete nests, often lying in empty spaces and with no associated stromal reaction. Cytologic features of the microinvasive foci are similar to those of the adjacent borderline tumor. The rare serous carcinoma arising in serous borderline tumor typically consists of papillae and sheets of malignant cells, often with slit-like spaces, in contrast to the irregularly infiltrative glands of metastatic adenocarcinoma. Thyroid transcription factor-1 is positive in approximately 75% of primary lung adenocarcinomas. [13, 14] Sixty percent of metastatic lung adenocarcinomas in our series were positive for TTF-1, but immunohistochemistry was performed in only 5 cases. [5] In a recent study specifically addressing the issue of TTF-1 immunoreactivity in ovarian surface epithelial carcinomas, Graham and co-workers reported only 2 of 166 cases positive for TTF-1. [15] The TTF-1 positive tumors were both high grade serous carcinomas, one with an admixed endometrioid component; neither case had radiological or clinical evidence of a pulmonary lesion. [15] None of the ovarian carcinomas in other recent studies showed TTF-1 positivity. [16, 17, 18] However, another study of TTF-1 expression in ovarian carcinomas reported 28.3% of cases positive for TTF-1, including 3/8 endometrioid, 6/25 serous, 4/10 clear cell, and 2/10 mucinous carcinomas. [19] Differential cytokeratin staining is of essentially no use in the distinction of primary ovarian carcinoma and metastatic lung adenocarcinoma, as both will often show a CK7-positive and CK20-negative immunophenotype. [16] In summary, the morphologic spectrum of lung adenocarcinoma metastatic to the ovary encompasses a wide range of histologic appearances, and can prompt consideration of a number of primary and metastatic ovarian neoplasms. Attention to clinical history, other sites of metastasis, and histologic recognition that the tumor shows morphology more typical of a primary lung carcinoma facilitate the correct diagnosis. 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