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Gynaecology Case Reports

Diagnostic and therapeutic dilemma in the management of primary small-cell neuroendocrine tumour of the cervix N. Singh, P. Varshney, R. Tripathi & Y. M. Mala Department of Obstetrics and Gynaecology, Maulana Azad Medical College and associated LokNayak Hospital, New Delhi, India DOI: 10.3109/01443615.2014.930424

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Figure 1. A gestational sac of 9 ⫻ 6 mm is visualised in the scar area of a previous caesarean delivery; in its interior, a small yolk sac and embryo with no heartbeat.

Correspondence: N. Singh, Department of Obstetrics and Gynaecology, Maulana Azad Medical College and associated LokNayak Hospital, Bahadur Shah ZafarMarg, Delhi Gate, New Delhi 110002, India. E-mail: nilanchalisingh@ gmail.com

Introduction 7; then 447 mU/ml, 98 mU/ml and ⬍ 1 mU/ml in weeks 2, 3 and 4, respectively. The patient remained asymptomatic at all times and was discharged from care after 4 weeks.

Discussion As far as we are aware, this is the first case of CSEP successfully treated with methotrexate i.m. and oral mifepristone as a single dose. This treatment has already been used by our research group, as well as by others for non-tubal ectopic (cornual and cervical) pregnancies with a poor prognosis. The mechanism of action of the combination of the two drugs in the resolution of ectopic pregnancy is uncertain. It has been speculated that the antitrophoblastic effect of methotrexate is potentiated with the antidecidual action of mifepristone, which could cause the destruction of ectopic trophoblasts (Gómez García et al. 2012). In 2006, Storgaard et al. reported a CSEP treated with methotrexate and mifepristone, but the combination was not effective, and a transvaginal intrathoracic injection of potassium chloride was required for resolution. The literature describes various therapeutic strategies with good outcomes. Recently, the American Society for Reproductive Medicine (Pfeifer et al. 2013) highlighted the role of systemic and/ or local methotrexate with and without subsequent dilation and curettage. It also mentions surgical options (dilation and curettage and trophoblastic excision via either laparotomy or laparoscopy) (Pfeifer et al. 2013). Other options include a wait-and-see attitude, local administration of embryocides, hysteroscopic coagulation and embolisation of uterine arteries, either isolated or combined (Litwicka and Greco 2011). Early diagnosis is essential, and treatment should be conservative and individualised. Methotrexate plus mifepristone is a therapeutic option that could be effective. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References Gómez García MT, Aguarón Benitez G, Barberá Belda B et al. 2012. Medical therapy (methotrexate and mifepristone) alone or in combination with another type of therapy for the management of cervical or interstitial ectopic pregnancy. European Journal of Obstetrics, Gynecology, and Reproductive Biology 165:77–81. Litwicka K, Greco E. 2011. Caesarean scar pregnancy: a review of management options. Current Opinion in Obstetrics and Gynecology 23:415–421. Pfeifer S, Goldberg J, Lobo R et al. 2013. Practice Committee of the American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy: a committee opinion. Fertility and Sterility 100:638–644. Storgaard T, Frandsen KH, Lauszus FF. 2006. Caesarean section scar pregnancy – various treatment alternatives. Ugeskrift for Laeger 168:2820–2821. Uysal F, Uysal A, Adam G. 2013. Cesarean scar pregnancy: diagnosis, management, and follow-up. Journal of Ultrasound in Medicine 32:1295–1300.

Neuroendocrine tumour of the cervix is a rare tumour accounting for 3% of all cervical malignancies (Abeler et al. 1994). It is associated with HPV 18 or 16 and develops from either neuroendocrine cells occurring in the normal endocervix or from stimulated multipotential reserve cells of the endocervical epithelium (Siriaunkgul et al. 2012). This tumour has been documented to be resistant to all forms of treatment and therefore, has a poor prognosis (Bifulco et al. 2009). Due to the paucity of literature, with only a few reported cases, no consensus exists regarding the treatment modality of choice. We report a 30-year-old woman, diagnosed with neuroendocrine tumour of the cervix, with lung metastasis.

Case report A 30-year-old, female non-smoker presented to our cancer clinic with complaints of inter-menstrual bleeding for 3 months. General and abdominal examinations were normal. Speculum visualisation showed an exophytic growth of 2 ⫻ 2 cm size on the cervix. Vaginal examination revealed friable growth felt on cervix, which bled on touch. Bilateral parametria had no tumoral involvement. Cervical biopsy from the growth was suggestive of small-cell neuroendocrine carcinoma. Cells were small-cell in type with condensed nuclear chromatin, arranged in nests and strands. Chromogranin, a prognostic marker of neuroendocrine tumour, was positive. A chest X-ray showed homogenous well-defined rounded opacity in the right paracardiac region Figure 1(a). Contrast enhanced computed tomography (CECT) of the thorax revealed a well-defined, round, hypodense lesion in right middle lobe of the lung, likely to be metastatic in nature. CECT head and abdomen showed no abnormality. CECT-scan of the pelvis revealed a bulky cervix without parametrial invasion. No lymphadenopathy was noted. The patient refused to undergo any diagnostic or therapeutic procedure for the chest lesion. Due to the rare nature of the malignancy, no treatment guidelines exist. In view of suspicion of metastatic chest lesion (Stage IV disease), the initial treatment modality considered was chemo-radiation, but, as there was no local spread clinically or radiologically, we opted for neoadjuvant chemotherapy and radical surgery. The patient received four cycles of neoadjuvant chemotherapy (etoposide, carboplatin, ifosfamide). Modified radical hysterectomy with bilateral pelvic lymphadenectomy was performed Figure 1(b). The histopathology of the specimen confirmed the diagnosis of neuroendocrine carcinoma Figure 1(c,d). Parametrium, lymph nodes and margins were free of tumour. Post-surgery chest X-ray showed the same lesion as before. A PET scan was performed, which showed low activity in the chest lesion but there were high activity areas noted in the pelvis. In view of these findings, the decision for radiation therapy was taken. The woman received 200 cGy daily, in 25 fractions, up to a total of 5,000 cGy external beam radiation therapy. The patient remained asymptomatic during 18 months follow-up. The chest X-ray performed 10 months after treatment showed no change in the size of the lesion.

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Figure 1. (a) CT chest image showing well defined round hypodense nodular lesion (arrow) in medial segment of right middle lobe. (b) Gross photograph of the surgically removed specimen. (c) Tumour comprised of nest and strands of small cells. Cells showing marked nuclear moulding, nuclear hyperchromasia and condensed nuclear chromatin (Inset). (d) Tumour cells immune-reactivity for chromogranin white (i) and immune-negativity for p63 (ii).

Discussion Neuroendocrine carcinoma of the cervix is a rare malignancy, with only a few cases being reported. It is a highly malignant tumour, with lower survival rates compared with other histological variants (Wentz and Reagan 1959). The College of American Pathologists have categorised neuroendocrine tumours of the cervix as small-cell carcinoma; large-cell neuroendocrine carcinomas; typical carcinoid tumours; and atypical carcinoid tumours (Gardner et al. 2011). Clinical outcome is driven by the neuroendocrine component, hence it should be considered the primary diagnosis until there are only a few scattered neuroendocrine cells. The poor prognostic factors are: smoking status; polypoid pattern; presence of positive lymph nodes or lymphovascular space invasion; extrapelvic recurrence; pure histology; treatment with surgery; margin status and advanced FIGO stage (Bifulco et al. 2009). Immunohistochemical prognostic factors have been studied and neurone-specific enolase, chromogranin and synaptophysin have been associated with poor outcomes, according to one case series (Straughn et al. 2001). A low viral load of HPV 18 has also been related to shortened diseasefree survival in these patients (Siriaunkgul et al. 2012). The patients usually present in a similar way to squamous cell carcinomas, unlike lung counterparts who usually have carcinoid manifestations. Extrapelvic disease spread is common and the common sites are bone, lymph nodes, lung and, infrequently, pancreas. Staging is similar to traditional cervical cancer. Diagnosis is made by histopathology. The role of a PET scan in the early stages of cancer to detect distant metastasis, is controversial. The unpredictable nature with, at times, aggressive behaviour of this malignancy, leads to the dilemmas of management. No definite treatment guidelines exist and the approach to this disease has been described in the Society of Gynaecologic Oncology Clinical document (Gardner et al. 2011). The therapies are mainly derived from some retrospective studies and experience with lung neuroendocrine carcinomas. A multi-modality approach is usually adopted. Triple modality and multiple modality treatment in early stage lead to complete resolution in most cases (McCann et al. 2013). Radical

surgery in Stage Ib and II neuroendocrine carcinoma is associated with recurrence in 10–15% of cases, unlike in squamous cell carcinomas; a difference attributed to the differences in biological behaviour (Samlal et al. 1998). Advanced stage malignancies are treated by chemoradiation with limited success (Lan-Fang et al. 2012). Newer potential therapies targeting multiple biomolecules are evolving and under clinical trials. The prognosis is usually poor due to the aggressive nature of the disease. Even in early stages, the chances of distant metastasis are high; hence local pelvic control is not sufficient for these cancers. The prognosis is generally graded poorer than equally staged poorlydifferentiated squamous cell carcinoma.

Conclusion Neuroendocrine cancer of the cervix is a rare and aggressive malignancy, with early distant metastasis. A PET scan may be useful for the diagnosis of distant metastasis. A multi-modal treatment approach is recommended. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References Abeler VM, Holm R, Nesland JM et al. 1994. Small cell carcinoma of the cervix. A clinicopathologic study of 26 patients. Cancer 73:672–677. Bifulco G, Mandato VD, Giampaolino P et al. 2009. Small cell neuroendocrine cervical carcinoma with 1-year follow-up: case report and review. Anticancer Research 29:477–484. Gardner GJ, Reidy-Lagunes D, Gehrig PA. 2011. Neuroendocrine tumors of the gynecologic tract. A Society of Gynecologic Oncology (SGO) clinical document. Gynecologic Oncology 122:190–198. Lan-Fang L, Hai-Yan S, Zuo-Ming Y et al. 2012. Small cell neuroendocrine carcinoma of the cervix: analysis of the prognosis and role of radiation therapy for 43 cases. European Journal of Gynaecological Oncology 33:68–73.

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McCann GA, Boutsicaris CE, Preston MM et al. 2013. Neuroendocrine carcinoma of the uterine cervix: the role of multimodality therapy in earlystage disease. Gynecologic Oncology 129:135–139. Samlal RA, Van Der Velden J, Van Eerden T et al. 1998. Recurrent cervical carcinoma after radical hysterectomy: An analysis of clinical aspects and prognosis. International Journal of Gynecological Cancer 8:78–84. Siriaunkgul S, Utaipat U, Suwiwat S et al. 2012. Prognostic value of HPV18 DNA viral load in patients with early-stage neuroendocrine carcinoma of the uterine cervix. Asian Pacific Journal of Cancer Prevention 13:3281–3285. Straughn JM Jr, Richter HE, Conner MG et al. 2001. Predictors of outcome in small cell carcinoma of the cervix – a case series. Gynecologic Oncology 83:216–220. Wentz WB, Reagan JW. 1959. Survival in cervical cancer with respect to cell type. Cancer 12:384–388.

(Doi et al. 1997), with a prevalence of approximately 1–3% among all cervical adenocarcinomas (Kaminski and Norris 1983). AM exhibits an endophytic growth pattern, and ultrasound findigs mimic multiple nabothian cysts (Chang Jie et al. 2008; Lim et al. 2012). The most common presenting symptom is abnormal vaginal bleeding and watery discharge. AM is unlikely to be diagnosed by a Pap smear or small cervical biopsies. The final diagnosis of AM is often made by histological examination. Because of its rarity, the nature and clinical course of the disease and its standard treatment have not been clarified completely. Here, we present a case report of adenoma malignum.

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Case report

Adenoma malignum of the cervix diagnosed after surgery based on a prediagnosis of ovarian cancer U. Solmaz1, L. Dereli1, E. Mat1, N. Peker2, M. Adiyeke1 & U. Kücük3 Department of Obstetrics and Gynecology, 1Tepecik Training and Research Hospital, Izmir, 2Elazıg Training and Research Hospital, Elazıg and 3Department of Pathology, Tepecik Training and Research Hospital, Izmir, Turkey DOI: 10.3109/01443615.2014.931363 Correspondence: N. Peker, Department of Gynecology and Obstetrics, Elazıg Training and Research Hospital, 23000, Elazıg, Turkey. E-mail: [email protected]

Introduction Adenoma malignum (AM), also called ‘minimal-deviation adenocarcinoma’, is a rare variant of mucinous adenocarcinoma of the cervix

A 59-year-old woman diagnosed with a right adnexal mass was referred to our clinic. Physical examination revealed normal findings. Her uterus was normal in size, shape and consistency. The cervix was grossly normal, yet slightly enlarged, with the exception of profuse mucoid discharge. Examination of the parametrium on both sides revealed normal findings. Transvaginal Doppler sonography showed a 70 ⫻ 80 mm, multiseptated cystic mass on the right adnexa, with a small number of ascites. Her Pap smear was normal. Her serum cancer antigen (CA)125 level was slighly elevated (49 U/ml) and her serum CA19-9 level was ⬎ 1,000 U/ml. Abdominal computed tomography (CT) showed a 78 ⫻ 81 mm, multiloculated cystic lesion on the right adnexa and a small amount of pelvic ascites (Figure 1a). Endometrial biopsy revealed chronic cervicitis and a proliferative endometrium. A low median-line incisional laparotomy was performed. Approximately 250 ml of mucinous fluid was drained from the pouch of Douglas and cytology was reported as ‘benign’. The uterus was measured at 10 gestational weeks in size, and the cervix was slightly more enlarged than usual. An 8 ⫻ 8 cm right ovarian cyst was observed. The left adnexa seemed to be normal. A right salpingo-oophorectomy was performed, sent for a frozen section and was reported as benign. Total abdominal hysterectomy and left salpingo-oophorectomy was performed; frozen sections were prepared and sent for diagnosis

Figure 1. (a) Lower abdominal CT scan showed a 78 ⫻ 81 mm, multiloculated cystic lesion on the right adnexa (∗) and a small amount of pelvic ascites. The cervix is slightly more enlarged than usual and there are multiple cystic structures within the cervix (arrow). (b) A histological section of the cervix demonstrates numerous irregularly-shaped dilated glands marked throughout the full thickness of the epithelium; dilated glandular structures composed of columnar cells with clear cytoplasms and basal located nuclei. (c) Polymorphonuclear leucocytes (arrow) are observed in the glandular lumens (H&E, ⫻ 100). (d) The section from the right ovary demonstrates mucinous columnar cells of the glandulae that are positively stained with Alcian blue, revealing the presence of intracytoplasmatic mucin (PAS staining with Alcian blue, ⫻ 100).

Diagnostic and therapeutic dilemma in the management of primary small-cell neuroendocrine tumour of the cervix.

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