| Abstract|| |
Neuroendocrine tumors (NETs) are neoplasms arising from dispersed neuroendocrine cells, localized to the gastrointestinal tract (GIT), lungs, adrenal medulla, and other sites. The term “carcinoid tumor” is usually limited to NETs of the lung and GIT. Ovarian carcinoids are uncommon, accounting for 0.1% of ovarian malignancies and 5% of all NETs. Primary ovarian tumors arise in pure form or as a component of teratomas, while ovarian NET metastases are predominantly from gastrointestinal primaries. To the best of our knowledge, there are only two previous reports of bronchopulmonary carcinoids (PCs) metastasizing to the ovaries. We describe a case of PC in a 50-year-old woman, with bilateral ovarian tumors as the presenting manifestation of the disease, and discuss the clinical and pathobiologic significance of this presentation.
Keywords: Carcinoid, lung, metastases, neuroendocrine, ovarian, pulmonary
|How to cite this article:|
Mitra S, Jhunjhunwala A, Chakraborty H. Bilateral ovarian metastases as the presenting manifestation of lung carcinoid in a 50-year-old woman: Case study and review of literature. Indian J Pathol Microbiol 2017;60:396-8
|How to cite this URL:|
Mitra S, Jhunjhunwala A, Chakraborty H. Bilateral ovarian metastases as the presenting manifestation of lung carcinoid in a 50-year-old woman: Case study and review of literature. Indian J Pathol Microbiol [serial online] 2017 [cited 2020 Feb 29];60:396-8. Available from: http://www.ijpmonline.org/text.asp?2017/60/3/396/215366
| Introduction|| |
Neuroendocrine tumor (NET) metastases to ovary are a rarity, with approximately sixty cases being reported. These are usually bilateral and arise from gastrointestinal NETs. An uncommon case of pulmonary carcinoid (PC) presenting solely with ovarian disease requires differentiation from other primary ovarian tumors and identification of primary site of malignancy.,,,,,
| Case Report|| |
A 50-year-old female presented to the hospital with a complaint of an abdominal mass for 6–8 months and loss of appetite. There was no significant medical history. Physical examination revealed bilateral abdominal masses and no organomegaly. Routine laboratory investigations showed no significant alterations in hematological and biochemical parameters, apart from elevated lactate dehydrogenase, gamma-glutamyl transferase and alkaline phosphatase, and decreased serum protein level. Thyroid function tests were normal.
Serum beta-human chorionic gonadotropin (HCG), alpha fetoprotein, carcinoembryonic antigen, and CA 19-9 were normal, while serum CA125 was slightly elevated. Peritoneal wash cytology was negative for malignant cells. Computerized tomographic (CT) scan of the abdomen showed bilateral solid ovarian masses with some cystic areas.
Total abdominal hysterectomy was done with bilateral salpingo-oophorectomy. Intraoperative frozen section was done and diagnosed as malignant ovarian tumor, suggestive of adenocarcinoma. Bilateral ovarian tumors received for histopathological examination were large, solid tumors with smooth external surface. Cut surface was predominantly solid with few cystic spaces. Histology of the tumors revealed a distinctive organoid nesting pattern of large polygonal cells, separated by delicate fibrovascular septa. Individual tumor cells were polygonal, with round-to-oval hyperchromatic nuclei, granular chromatin, and moderate-to-abundant amount of granular eosinophilic cytoplasm. Moderate degree of nuclear pleomorphism was noted, along with occasional mitotic figures. Necrosis was present in few foci. There were no teratomatous components. Tumor was found to be infiltrating the capsule, though no transcapsular infiltration was present. There was tumor metastasis in pre- and para-aortic lymph nodes and common iliac lymph nodes. Other resected lymph nodes showed sinus histiocytosis [Figure 1].
|Figure 1: (a) Solid cut surface of ovarian tumor with variegated appearance. (b and c) Polygonal tumor cells in organoid nesting pattern, separated by fine fibrovascular septa (b - H and E, ×100, c - H and E, ×400). (d) Tumor metastasis in lymph node (H and E, ×100)|
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Immunohistochemistry (IHC) of the tumor cells showed pan-CK, synaptophysin, and chromogranin positivity, while CK7, CK20, and vimentin were negative. Thyroid transcription factor-1 (TTF-1) was widely expressed by tumor cells. There was focal expression of S-100 protein by tumor cells and sustentacular cells. Mib-1 index of tumor cells was 3%–4% [Figure 2].
|Figure 2: (a) Chromogranin positivity in tumor cells (immunoperoxidase, ×400). (b) Synaptophysin positivity in tumor cells (immunoperoxidase, ×400). (c) pan-CK positivity in tumor cells (immunoperoxidase, ×400). (d) Thyroid transcription factor-1 positivity in tumor cells (immunoperoxidase, ×400)|
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A diagnosis of bilateral carcinoid tumors of the ovary was made. TTF-1 positivity and bilaterality of tumor raised the possibility of metastasis.
Plasma chromogranin A levels were elevated at 770.79 ng/mL (N < 100 ng/mL). The patient was started on somatostatin therapy (20 mg monthly injections) and evaluated by positron emission tomography (PET) scan after 2 months. A preliminary whole body CT scan revealed supraclavicular lymph nodes and confluent lymph nodes in pretracheal, precarinal, subcarinal, and hilar regions. A soft tissue mass was detected in the left inferior hilar region of the lung, with peripheral consolidation and atelectasis. A whole body three-dimensional PET CT scan was done utilizing 68 Ga-DOTANOC, a radiolabeled somatostatin analog, as a marker. There was increased accumulation of the tracer molecule in the left perihilar mass and in the enlarged lymph nodes.
The case was classified as a pulmonary NET, metastasizing to regional lymph nodes and bilateral ovaries. The patient refused further operative therapy and was managed medically by somatostatin therapy. There was a poor response to somatostatin, with increase in the size of mediastinal mass and increasing respiratory distress. Due to the aggressiveness of the neoplasm, cisplatin- and etoposide-based chemotherapy was initiated. There was limited clinical and subjective improvement after four cycles, but the patient succumbed to an acute myocardial infarction during the course of treatment.
| Discussion|| |
Tumors of the diffuse neuroendocrine cell system/NETs develop in several sites of the body, the most common being the gastrointestinal tract (GIT) and the lung. Around 10%–25% of primary NETs are located in the bronchopulmonary tract. Pulmonary NETs can be high-grade small cell lung carcinomas (SCLCs), large cell neuroendocrine carcinomas (LCNECs), or lower grade well-differentiated NETs termed “carcinoids”. PCs affect a wide range of ages, mean being 46 years, and there is an equal gender distribution. PC accounts for only 1%–2% of primary lung cancers, and 80%–90% of these are the least aggressive typical subtype. Nearly 10%–20% of PCs are atypical carcinoids, with more aggressive course and increased rate of metastasis.,,, The typical carcinoid has distinctive histopathological features, while atypical carcinoids have similar morphology, but can be distinguished by the presence of central punctate necrosis and 2–10 mitoses/10 hpf. IHC is essential, with neuroendocrine markers such as chromogranin, synaptophysin, and CD56 establishing the diagnosis, while epithelial markers such as pan-CK, CK7, CK20, CDX-2, and TTF-1 aid in identifying primaries for metastatic lesions. Most carcinoids express cytokeratin, while about 50% of lung carcinoids are TTF-1 positive. Atypical carcinoids do not express neuroendocrine markers consistently. Ki-67 labeling is used to differentiate typical carcinoid (0%–2.3%) and atypical carcinoid (0%–17%) from LCNEC (20%–90%) or SCLC (25%–96%). SCLC is also characterized by extensive necrosis.,,
Multiple metachronous metastases can arise in patients with high-grade NETs and are consistent with advanced disease. Bronchopulmonary NETs commonly metastasize to the brain, liver, bones, or adrenal glands. Neuroendocrine metastasis from PC to ovaries is extremely rare.,,
Approximately 5%–10% of malignant ovarian tumors are metastases, commonly arising from female genital tract, GIT, or breast. Lung primaries account for sporadic cases of metastases to ovary.
Metastatic carcinoid tumor in the ovary predominantly arises from GIT primaries. If a patient presents solely with the clinical manifestation of ovarian disease, as in the current report, IHC is crucial in identifying the site of origin.,,, In the largest reported series of carcinoid tumors metastatic to the ovary, all the patients were of adult age and had a poor prognosis, with one-third of patients dying within a year and 75% within 5 years. These tumors are usually solid, and metastasis is suggested by multinodularity and bilateral ovarian involvement.
Morphology of well-differentiated metastatic NETs in the ovary is similar to that of primary ovarian carcinoids, but with no associated teratomatous components as found in the latter. Synaptophysin and chromogranin are expressed by ovarian carcinoids, and epithelial membrane antigen, estrogen receptor, progesterone receptor, inhibin, or calretinin are negative. Other markers are used to identify the primary site for metastatic tumors, such as TTF1 for pulmonary primaries, PAX8 and CDX2 for intestinal and pancreatic primaries, respectively, and PDX1 exclusively for pancreatic NETS. Vascular and perineural invasion, lymph node involvement, and Ki-67 antigen IHC (MIB-1 index) indicate the biological aggressiveness of tumors.,,
When there is clinical suspicion of an asymptomatic pulmonary NET with no respiratory complaint, further investigations are required. The diagnosis of pulmonary NETs relies on histologic evaluation of tissue, and biopsy of suspected metastases can expedite both diagnosis and staging.,,,
Radiological diagnosis by high-resolution CT scan is the initial examination of choice. CT scan images can be nonspecific, and appearances overlap with that of adenocarcinoma. PCs are usually seen as hilar or perihilar soft-tissue nodules with variable degree of contrast enhancement due to vascularity of the lesions. Whole body somatostatin receptor scintigraphy (SRS) with thorax single photon emission CT can visualize 80% of primary tumors.68 Ga-DOTANOC-PET has emerged as a more sensitive and preferable method to SRS.,
Treatment of carcinoids is primarily based on surgical resection and use of long-acting somatostatin analogs (SSAs) such as octreotide and lanreotide. SSAs are considered the first-line systemic treatment for advanced PCs of low proliferation index. Pulmonary surgery should be considered only for patients with limited sites of disease and clear possibility of radical treatment for all sites. Other approaches have been tried in metastatic and unresectable tumors, such as hepatic artery embolization, chemotherapy, interferon therapy, and radiolabeled SSAs. Conventional chemotherapy has shown disappointing results in several studies. New agents such as everolimus targeting PI3K signaling pathway of lung NETs, or antiangiogenic agents such as sunitinib and bevacizumab, have also been evaluated in PC management.,
The current report adds to the limited number of cases documenting ovarian metastases in PCs and also illustrates the poor response to somatostatin and conventional chemotherapy in PCs with distant metastases.
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Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, Advanced Medicare and Research Institute Hospital, Kolkata - 700 029, West Bengal
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]