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A 45-year-old woman presented with vague abdominal pain. Ultrasound revealed a predominately solid right ovarian mass and mild ascites. A hysterectomy and bilateral salpingooophorectomy were performed. The uterus and left adnexa were unremarkable. The right ovary was replaced by a 10.0 x 4.0 x 4.0 cm, 850 g, predominately solid, red-brown, focally necrotic tumor that demonstrated scattered small hemorrhagic cysts. Immunohistochemical studies revealed focal areas that were thyroglobulin positive and other areas that were synaptophysin positive. Rare areas were positive for both markers. Stains for mucin were negative.
Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2005, Case 04 and is a strumal carcinoid.
Criteria for Diagnosis and Comments:
The histological features of the tumor vary from slide to slide, but the predominate pattern is that of follicular structures lined by cuboidal to low columnar cells with lightly eosinophilic flocculent cytoplasm and round to ovoid fairly uniform nuclei with evenly dispersed chromatin. Only an occasional small nucleolus is seen and mitotic figures are rare. A rare cell is oxyphilic. The lumen contains scalloped PAS positive eosinophilic colloid-like material. Birefringent calcium oxalate, not common in our index case, may be found in the colloid-like material. The follicles vary in size with both macrofollicular and microfollicular patterns present. Solid areas (embryonal pattern) are also present. In areas the follicular pattern transforms subtly into anastomosing solid thin cords of cells (trabecular pattern). Scattered larger cysts lined by the same cells, but lacking colloid-like foci are also seen. The epithelial elements are surrounded by and enmeshed in a loose fibroblastic stroma. Rare slides of our index case may contain elements of mature teratomas, such as pilosebaceous follicles, respiratory epithelium and squamous epithelium. The luminal surface of the cells lining the follicles, as well as the colloid material, stain positive for thyroglobulin. The cells with the trabecular pattern stain positive for synaptophysin. Rarely, in some of the transformation areas, cells stain positive for both markers. The histological features and immunohistochemical pattern are diagnostic of strumal carcinoid.
Strumal carcinoid is an uncommon ovarian tumor that is composed of varying proportions of intimately admixed thyroid elements and carcinoid tumor. Some investigators consider it to be a type of primary ovarian carcinoid while others consider it to be a separate entity. Patients range in age from 21 to 77 years. Although most patients are asymptomatic, virilization, hyperinsulinemia, hypoglycemia, constipation due to tumor producing peptide YY, carcinoid heart disease, and type IIA multiple endocrine neoplasia (Sipple syndrome) have been reported in rare patients. The thyroid elements may show macrofollicular, microfollicular and solid patterns with colloid that merge into the cord-like pattern of carcinoid. Although usually intermixed, occasionally the elements are separate and demonstrate a distinct interface. The trabecular pattern of carcinoid is by far the most common, but insular, mucinous and mixed patterns have also been reported. The thyroid areas show luminal and colloid staining for thyroglobulin and the carcinoid areas stain for neuropeptides and occasionally calcitonin. Ultrastructural and immunohistochemical studies have shown a crossover between the two cell types with some cells lining follicles containing neurosecretory granules and cells in classical carcinoid areas staining for thyroglobulin. Some investigators have identified an intermediate cell that shows both thyroid and neuroendocrine markers and resembles the C cell of the thyroid. Mucinous carcinoid elements will stain for mucin and may have signet ring cells. The stroma of the tumor is variable and may contain amyloid or show stromal luteinization.
Struma ovarii is the lesion to be most likely confused with strumal carcinoid. Although thyroid tissue can be found in up to 13% of mature teratomas, by definition a germ cell tumor must be composed of greater then 50% thyroid tissue or have functional active thyroid tissue to be a struma ovarii. Up to 50% are pure and the rest are associated with mature teratomas. Struma ovarii is found in the same age group as strumal carcinoid, but are three times more common. They account for approximately 1.4% of ovarian germ cell tumors. Patients have developed ascites or even a Meig's like syndrome with pleural effusions that should not be interpreted as a sign of malignancy. Likewise, extraovarian extension with peritoneal implants of benign thyroid tissue (strumosis) is not an unequivocal indication of malignancy, although, it may recur. Both follicular and papillary carcinomas have been reported, but at least in the case of follicular carcinoma the presence of an extraovarian metastasis may be needed before a diagnosis of malignancy can be made. Only a very rare case has metastasized. The presence of the carcinoid element in our case excludes struma ovarii.
Primary carcinoid tumors of the ovary are rare (constituting less than 5% of ovarian teratomas), but are still four times more common than metastatic carcinoid. They are classified as a monodermal germ cell tumor. Four architectural patterns are recognized: (1) insular or islet, (2) trabecular, (3) mucinous and (4) mixed. Although there are varied types reported in the literature (pure or combined with other teratomatous elements), the insular or islet (midgut derivation) architectural pattern is the most common. Approximately 40% of insular carcinoid tumors appear as pure forms and 60% are combined with other teratomatous elements, most commonly gastrointestinal or respiratory epithelium. The tumor has also been associated with solid teratomas, mucinous tumors, and Sertoli-Leydig cell tumors. Architecturally the tumor is composed of small acini and solid nests of cells. The cytological features are similar to that described in our index case, but the cytoplasm may be amphophilic or basophilic. The cytoplasm contains argentaffin or argyrophil granules that ultrastructurally appear as numerous neurosecretory granules. The trabecular (hindgut) pattern consists of long wavy bands, one to two cells thick, with scant loose connective tissue, but similar cytological features. Mucinous carcinoid has the same architectural and cytological features of insular and trabecular carcinoid, but contains mucin containing goblet cells that may rupture and form mucinous pools and acini containing mucin. Mucinous carcinoid tumors tend to be more aggressive than the other forms of carcinoid tumors. Mixed forms, as the name implies, consists of mixtures of the three types. The presence of the thyroid elements rules out primary and metastatic carcinoid tumor.
Mature teratomas are predominately cystic; the solid form is rare. By definition they contain only mature (adult) tissue and less than 50% inactive thyroid tissue or carcinoid; greater than 50% thyroid tissue or carcinoid would result in classification as struma ovarii or strumal carcinoid, respectively. They should be thoroughly sampled to rule out immature areas or malignant components. Both mature and immature teratomas may be excluded from our differential diagnosis.
Androblastomas (Sertoli-Leydig cell tumors) account for less than 0.5% of ovarian tumors and fall under the classification of sex cord-stromal tumors of the ovary. They are usually found in the second or third decade of life and are predominately (98%) unilateral. The tumors may be endocrinologically active and patients may demonstrate androgenic or feminizing signs or symptoms; but most tumors are inactive. The histology of the tumors varies with the degree of differentiation. Well differentiated tumors are composed of tubules with lumina, but the cells may be distended with lipid, which can obscure the lumina, mimicking a mucinous carcinoid. In addition, well and moderated differentiated tumors may contain cysts suggestive of thyroid tissue. Poorly differentiated tumors may also contain solid cords, but in addition may have heterologous elements, such as gastrointestinal epithelium, skeletal muscle, smooth muscle, cartilage, bone, fat and even carcinoid tumors. The clinical presentation, age of the patient, finding of areas with more classical histological features of androblastoma, lack of colloid and lack of immunohistochemical staining for thyroglobulin distinguish this tumor from strumal carcinoid.
Granulosa cell tumor falls under the classification of sex cord-stromal tumors and occurs in both premenopausal as well as postmenopausal women. Patients usually present with abdominal symptoms (pain, swelling, backache, dysuria or dyspareunia), but may also have endocrine abnormalities (irregular menstruation or menorrhagia). The tumor cells may be round, polygonal or spindle. The tumor nuclei are bland with round, oval or angulated shapes. Like androblastoma, granulosa cell tumors may have a varied histological pattern (microfollicular, macrofollicular, trabecular, insular or mixed). The microfollicular pattern shows multiple small spaces (Call-Exner bodies) surrounded by granulosa cells and containing PAS positive chondroitin 6-sulfate secondary to degeneration of tumor cells. The macrofollicular pattern is caused by degeneration of granulosa cells in solid tumors leading to large cysts lined by multilayered granulosa cells that may have an external layer of theca-like cells. These patterns may be confused with struma ovarii, strumal carcinoid, as well as an ovarian carcinoid tumor. The trabecular pattern consists of anastomosing ribbons or cords that on occasion may form tubules. The insular pattern consists of solid nests of cells embedded in a fibrous stroma. Moderately differentiated tumors have a more complex anastomosing pattern and poorly differentiated tumors have a spindle or sarcomatoid appearance. Although, well differentiated tumors may be confused with struma ovarii, strumal carcinoid or carcinoid tumors they lack immunoreactivity for thyroglobulin and chromogranin.
Metastatic disease to the ovary is not uncommon. It can be found in up to 12% of autopsies in patients dying from nonovarian carcinoma, but represents only 6% of ovarian carcinomas found at laparotomy. Gastric carcinoma has the highest propensity to metastasize to the ovary. Metastatic thyroid carcinoma to the ovaries on the other hand is extremely rare. Our present case shows both thyroid differentiation as well as neuroendocrine differentiation effectively ruling out both metastatic thyroid carcinoma as well as metastatic adenocarcinoma.