Review doi: 10.5146/tjpath.2015.01320 An Update of Neuroendocrine Tumors of the Female Reproductive System Mehmet KEFelİ1, Alp USUBÜTÜN2 Department of Pathology, 1Ondokuz Mayıs University Faculty of Medicine, SAMSUN, TURKEY, 2Hacettepe University Faculty of Medicine, ANKARA, TURKEY ABSTRACT Endocrine disease related tumors of female reproductive system mostly seen in ovary. Hormone producing ovarian tumors, ovarian tumor with functioning stroma, tumor related paraneoplastic and paraendocrine syndromes, paraganglioma and neuroendocrine tumors may include in this category. These tumors or its stroma can produce some hormones, which are led to endocrine manifestations. Rarely tumors associated with paraneoplastic and endocrine syndromes. Among these lesions, primary neuroendocrine tumors are rarely seen in the gynecologic tract, comprising 2% of gynecologic cancers. They have specific cytological and histopathological features that are usually helpful in differentiating them from epithelial tumors. Nevertheless, they still provide a diagnostic and clinical challenge, given their rarity. Accurate diagnosis of neuroendocrine tumor is essential for both therapeutic and prognostic purposes. In this review, we focused on neuroendocrine tumors of the gynecological tract and their morphological, immunohistochemical and molecular findings. In addition, we will briefly discuss paraganglioma and other endocrine diseases related tumors in the gynecological tract. Key Words: Neuroendocrine tumors, Female genital neoplasms, Paraganglioma, Neuroendocrine cells, Immunohistochemistry INTRODUCTION and vulva (4-9). Among these locations, ovarian tumor has a different clinical significance. Two out of 6 reported Endocrine disease related tumors of female reproductive cases of ovarian paraganglioma behaved aggressively, one system are mostly seen in the ovary and typically include exhibiting lymph node metastasis and the other infiltrating hormone producing ovarian tumors, ovarian tumor the uterus. Both malignant cases were large, measuring with functioning stroma, tumor related paraneoplastic 9 and 8 cm, respectively. Moreover, one case was positive and paraendocrine syndromes, paraganglioma and with inhibin and other case positive with inhibin and neuroendocrine tumors (NETs). Primary NETs rarely seen calretinin. This staining result could be diagnostic pitfall for in the female reproductive system and create a clinical and sex cord- stromal and steroid cell neoplasms, which would diagnostic challenges because of their rarity. In this review, be expected to be positive with both markers (9). we are focusing on NETs of the female reproductive system along with their morphological, immunohistochemical Clinically, because of paragangliomas can be secreted and molecular findings. In addition, we will briefly discuss catecholamine, some cases had hypertension or other paraganglioma and other endocrine diseases related tumors manifestations related to catecholamine hypersecretion. in the gynecological tract. Morphologically, tumors generally show classical pattern; small nests (‘zellballen’) of neuroendocrine cells with PARAGANGLIOMA interspersed small blood vessels. Syncytial-like growth, Paragangliomas are tumors arising from paraganglia, which diffuse pattern, spindle cells and extreme cytological atypia composed of neural-crest derived neuroendocrine cells may also be observed. Immunohistochemically, tumors associated with symphathetic and parasympathetic nerves. are usually positive with general neuroendocrine markers Symphatetic paraganglioma arise sympathetic chains along and tyrosine hydroxylase (except of some parasymphatetic the paravertebral axis and sympathetic nerve branches paraganglioma), and negative with cytokeratins (except in pelvic organs and retroperitoneum. Parasympathetic of some cauda equine paraganglioma). S100 protein paraganglioma arise mainly from branches vagus and demonstrates the sustentacular cells network. It is of glossopharyngeal nerves in head and neck region (1-3). note that loss of SDHB expression is important to triage Paragangliomas rarely seen outside the usual location and a patient with familial paraganglioma syndromes caused few cases has been reported from the ovaries, uterus, vagina by SDHx mutations. Additionally, use of SDHB antibody (Turk Patoloji Derg 2015, 31(Suppl):128-144) Correspondence: Mehmet Kefeli Ondokuz Mayıs Üniversitesi Tıp Fakültesi, Patoloji Anabilim Dalı Received : 01.06.2015 Accepted : 02.06.2015 SAMSUN, TURKEY E-mail: [email protected] Phone: +90 362 312 19 19 128 KEFelİ M and USUBÜTÜN A: NETs of Female Reproductive System Turkish Journal of Pathology also provides prognostic information of tumor, because of hormone secretion, others cause mechanically progressive the high rate of malignancy associated with SDHB related compression of graafian follicule leading to mechanical paragangliomas (1-3). There has not been reported SDHx pressure of stroma and result in release of hormones. related familial paraganglioma in female reproductive Tumors with synctiotrophoblast cells (e.g. dysgerminoma system yet. with syncytiotrophoblast giant cells) have been considered in this category owing to chorionic gonadotropin secretion. HORMONE PRODUCING OVARIAN TUMORS Microscopically, a functional stroma of the tumor may be Hormones producing ovarian tumors are generally arising adjacent to the ovarian stroma or its own stroma derived from ovarian cortical and hilar cells, and classified as sex from the ovarian stroma, or combination of both. Stromal cord-stromal tumors. These cells as condensations of cells may resemble theca externa cells, theca lutein cells or subcoelomic mesenchyme during the embryogenesis, combination. Stromal luteinization or stromal Leydig cell and then differentiated into the supporting stroma of the differentiation may also occur (11,13). cortex and granulosa-theca cells of the developing follicle PARANEOPLASTIC AND PARAENDOCRINE in the adult ovary. Granulosa-stromal cell tumors, Sertoli- SYNDROMES ASSOCIATED WITH OVARIAN stromal cell tumors and steroid cell tumors compromise this group. Hyperestrinizm or hyperandrogenism rela- TUMORS ted symptoms are relatively common in this group of Paraneoplastic or paraendocrine syndromes may be the neoplasms due to excess estrogen or androgen production. first sign of epithelial or other types of ovarian tumors. The Other less common ovarian neoplasms that may have underlying mechanisms of most paraneoplastic syndromes endocrine manifestations include germ cell tumors (e.g. are not well elucidated; however, ectopic hormone secretion choriocarcinoma, dysgerminoma) producing of chorionic was typically linked to paraendocrine syndromes (Table I). gonadotropin, and monodermal teratoma (struma ovarii) While the most common paraneoplastic syndrome is sub- that can sometimes present with hyperthyroidism (10). acute cerebellar degeneration that is found in up to 37% of all patients with ovarian cancer, hypercalcemia due to inap- TUMORS WITH FUNCTIONING STROMA propriate secretion of parathyroid related peptide (PTHrp) Ovarian tumor with functional stroma (OTFS) firstly highlighted by Dr. Scully and described as tumors exhibiting a specialized stroma, which are morphologically compatible Table I: Paraneoplastic and paraendocrine syndromes related with steroid hormone secretion. They are different than with ovarian tumors sex cord-stromal and steroid cell tumors. These tumors Paraneoplastic syndromes have also clinical, biochemical or pathological findings Subacute cerebellar degeneration of endocrine function (11-13). Functioning stroma could Limbic encephalitis be found in primary benign or malignant tumor, and Polyneuritis also metastatic tumors of the ovary such as Krukenberg tumor as well (11,14). Among epithelial tumors, mucinous Dermatomyositis tumors frequently contain a functioning stroma (15,16). Autoimmune hemolytic anemia Most patients with OTFS are asymptomatic and have Thrombotic disorders only laboratory evidence of increased steroid hormone Nephrotic syndromes secretion. However, in the absence of exogenous hormone Cutaneous disorders replacement postmenauposal patients with OTFS may Palmar fasciitis present with proliferative or hyperplastic endometrium, Rheumatoid arthritis abnormal vaginal bleeding, or estrogenic effect in the Scleroderma vaginal cytology. In such cases, subsequent biochemical Systemic lupus Erythematosus workup often reveals an excess serum estrogen level. Some Paraendocrine syndromes and responsible hormones patients may be associated with endocrine manifestation Hypercalcemia – Parathyroid hormone-related peptide of estrogenic, androgenic, progestagenic, or a mixed Cushing’s syndrome – Corticotropin-releasing factor profile. It is of note that neoplastic cells may have also Zollinger-Ellison syndrome – Gastrin aromatase activities that have capacity to convert androgen to estrogens (15,17). While some tumors secret chorionic Hypoglycemia – Insulin or proinsulin gonadotropin to luteinize stromal cells and promote Hypertension –Renin or aldosterone Vol. 31, Suppl, 2015; Page 128-144 129 Turkish Journal of Pathology KEFelİ M and USUBÜTÜN A: NETs of Female Reproductive System is the most common paraendocrine syndromes associated Many NETs typically express wide spectrum cytokeratin with ovarian tumors. Hypercalcemia has been typically de- (CK), especially low molecular weight CKs (CK8 and scribed in two-thirds of patients with small cell carcinoma, CK18). CK immunoreactivity is usually seen as dot-like