Arch Gynecol Obstet (2013) 287:12631266 DOI 10.

1007/s00404-012-2644-4

LETTER TO THE EDITOR

A rare case of low grade and metastatic appendiceal neuroendocrine tumor co-existing with severe endometriosis
Gurkan Arikan F. Tokat U. Ince

Received: 11 May 2012 / Accepted: 12 November 2012 / Published online: 24 November 2012 Springer-Verlag Berlin Heidelberg 2012

Introduction Appendiceal neuroendocrine tumor (NET) is usually an incidental nding after a laparotomy for appendectomy, with a frequency of 25 cases per 1,000 appendectomies. Most appendiceal NETs are less than 2 cm in size and nonmetastasizing [1]. We report an unusual case of an appendiceal NET coexisting with severe endometriosis. The NET did not show any changes on the appendiceal surface and was palpated via laparoscopic graspers. It was small and of low histological grade; however, it showed, in contrast to previous reports, local and multiple regional lymph node metastases. Based on a search between 1966 and 2012, we conclude that this co-existence is so far unique in the literature. Case presentation A 33-year-old nulliparous Caucasian woman with a history of primary infertility, secondary dysmenorrhea and with physical and sonograc examination ndings of posterior cul-de-sac tenderness, thickening of uterosacral ligaments and a right-sided ovarian cyst was treated with an operative laparoscopy.

G. Arikan (&) Department of Obstetrics and Gynecology, Fulya Hospital, Acibadem University, Dikilitas Mah. Hakki Yeten cad. Yes ilc imen sok. No:23, Fulya, Besiktas, 34349 Istanbul, Turkey e-mail: grarikan@yahoo.com F. Tokat U. Ince Department of Pathology Altunizade Mah, Acibadem University, Fahrettin Kerim Gokay Cad. No:49 Uskudar, Istanbul, Turkey

The intra-operative ndings revealed scattered small endometriotic lesions on the peritoneum of the lower abdomen. The cul-de-sac was completely obliterated. The right ovary contained a 4-cm large cystic mass. The primary surgical therapy consisted of a cystectomy on the right ovary, lysis of adhesions, coagulation or resection of peritoneal implants, partial resection of uterosacral ligaments, and debulking in rectovaginal septum. The further abdominal exploration and the palpation of normal looking appendix via graspers revealed a small nodular structure on its tip (Fig. 1). An appendectomy was performed by the gynecologic surgeon. The patient was discharged on post-operative day 1. The histo-pathological study conrmed endometriosis in the right ovary and in resected specimens. The nodular structure on the tip of the appendix emerged as a low grade neuroendocrine tumor (NET): a gray or yellow, welldemarcated, rm, intramural tumor, which was 9 mm at its greatest dimension, narrowed the lumen. The hematoxylinand eosin-stained sections showed the typical features of a classic carcinoid of uniform polygonal cells with minimal pleomorphism. Tumor arose in mucosa but the bulk was within the muscularis propria, and penetrated the mesoappendix with associated brosis and smooth muscle hypertrophy (Fig. 2). There was no necrosis, no vascular invasion. The immunohistochemistry showed a strong positivity for chromogranin [Scytek (5H7)] (Fig. 3) and synaptophysin [Biocare (27612)]. The Ki-67 expression was 1 %. One lymph node in the mesoappendix, 1 cm away from the NET, showed micrometastases (Fig. 4). Due to the inltration into the mesoappendix and the lymph node micrometastasis of the NET, right hemicolectomy was justied which was performed 3 weeks later by laparoscopy. The post-operative course was uneventful after both interventions.

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Fig. 1 Appendix epiploica Fig. 4 Lymph node in mesoappendix with micrometastases of neuroendocrine tumor. Strong positivity of chromogranin (hematoxylin and eosin stain, magnication 9100)

Fig. 2 Neuroendocrine tumor with ribbons and strands of cells growing on the wall of the appendix. MI tumor inltration into mesoappendix (hematoxylin and eosin stain, magnication 9100)

The histo-pathologic study of the right hemicolon revealed no foci of NET. However, 2 of the 37 mesocolic lymph nodes had micrometastases of NET. The chromogranin A (CgA) level was 26 ug/L (normal range 1998 ug/L) at the time of the diagnosis and remained within normal ranges as the case was being reported. The abdominal magnetic resonance imaging (MRI) showed no signs of further metastases. The patient was not given any adjuvant therapy and is being followed-up regularly for the detection of any possible recurrence of NET by measurements of CgA, and MRI of abdomen twice a year. The follow-up has so far remained uneventful for the 1-year period after the surgery. We counseled our patient concerning recurrence risk and available data on pregnant patients with NET. She uses no contraception at present and will not be offered asissted reproductive therapy within the rst 2 years of follow-up.

Discussion Co-existence of carcinoid tumors in patients with endometriosis has been previously reported: Azordegan et al. [2] reported the co-existence of a non-metastatic appendiceal carcinoid and an ileal endometriosis in a 37-year-old nulliparous woman, who had to be operated because of symptoms mimicking acute appendicitis. Therefore, the detection of the entity was facilitated by the leading symptoms. Rodriguez et al. [3] reported another symptomatic patient with an inside-out appendix, where a mucinous goblet cell carcinoid and endometriosis coexisted. Robbins et al. found a metastatic carcinoid in a 35-year-old woman who underwent laparoscopic excision of pelvic endometriosis. The primary tumor was clearly

Fig. 3 Immunohistochemistry showed a strong positivity for synaptophysin (magnication 9400)

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visible and the metastases of carcinoid co-existed with endometriosis in both pelvic sidewall specimens [4]. In our patient, the clinical symptoms and intra-operative ndings were dominated by severe endometriosis in the cul-de-sac and by an endometrioma of the right ovary. The NET has not yet caused visible changes on the appendix, and the small nodular structure on the tip of the appendix was only detectable by the surgeons sense of touch through laparoscopic instruments. Although the tactile information via laparoscopic instruments is strongly diminished, it is still helpful in present laparoscopic practice for exploring abdominal pathologies. Carcinoids (neuroendocrine tumors) are the most commonly occurring gut endocrine tumors. The incidence is estimated to be approximately 1.5 cases per 100,000 of the general population [5]. NET of the appendix is usually found incidentally after appendectomy. The prevalence of neuroendocrine tumor (carcinoid) is very low; Tchama-Sato et al. [6] reported 5 out of 1,237 cases (0.4 %), where the mean diameter of the lesion was 0.6 mm and the tumors were usually found on the tip of the appendix. Marudayanagam et al. [7] reported a prevalence of NETs (carcinoids) as 0.5 % in 2,660 appendectomies. Blair et al. [8] reported 6 cases of carcinoids in 2,154 appendectomy specimens (0.2 %). The risk of lymph node and distant metastasis of NET depends on the size and site of the primary tumor. Several authors observed that the risk of lymph node and distant metastasis increases when the carcinoid (NET) is larger than 2 cm [9, 10] and stated that a carcinoid \1 cm usually does not entail metastasis. An uneventful long-term follow-up has been reported in patients with appendiceal carcinoid tumors \2 cm at its largest dimension, who were treated with simple appendectomy; in 122 patients for 26 years [11], in 9 patients for 24214 months [1] and in 5 patients for 33 months [12]. Thus, it is well accepted that simple appendectomy seems to be adequate in patients with apparently localized tumors \2 cm in the largest dimension. Our case represents an exception, because the small NET (9 mm at its largest dimension) showed a local invasion and local and regional lymph node metastasis. Thus, it shows that a right hemicolectomy can be justied also in patients with small tumors. Non-metastatic appendiceal NETs have an excellent overall prognosis. Experience of NETs in pregnancy is very limited and restricted to isolated case reports or case series only [13]. Most of the patients with metastatic NET had uneventful gestations following surgery or during adjuvant therapy [14, 15]. There are no reports revealing gestation related worsening of prognosis in patients with NET. Therefore, fertility sparing interventions are justied in surgical therapy of low grade NET. Also assisted reproductive technologies (ART) may be discussed after a certain period of uneventful follow-up. The appropriate duration of follow-up prior to ART should be planned individually.

Laparoscopy may be considered as a gold standard for the diagnosis of abdominal endometriosis. Furthermore, laparoscopic surgery is superior to diagnostic laparoscopy alone, concerning pelvic pain therapy [16]. The surgery may enhance fecundity in infertile patients with stage I or II endometriosis [17]. There are no randomized studies revealing the benet of extensive surgery in the treatment of infertile patients with deep inltrative endometriosis: Douay-Hauser et al. [18] found retrospectively that extensive surgery for intraperitoneal and deep endometriosis in infertile women did not modify global fertility. A prospective non-randomized study of patients with deep inltrative endometriosis showed that conservative surgery was not superior to expectant management concerning spontaneous pregnancy rates (45 vs. 47 %, respectively) [19]. Bianchi et al. reported a signicant improvement of IVF pregnancy rates in patients who had extensive surgery due to deep inltrative endometriosis prior to IVF therapy compared to those who had IVF therapy only (41 vs. 24 %, respectively, p = 0.004, OR: 2.45) [20]. However, the allocation of the patients was not randomized; the patients chose between two intervention options after comprehensive counseling regarding potential benets and risks associated with the procedures. In this case, an appendiceal NET co-existing with severe endometriosis is extraordinary, because the NET did not show any changes on the appendiceal surface and was palpated on abdominal exploration via laparoscopic graspers. Furthermore, the NET was small (9 mm at its largest dimension) and of low histological grade; however, it showed local and regional lymph node metastases. All surgical interventions, comprising the debulking of endometriotic nodules, appendectomy, and, nally, right hemicolectomy were performed laparoscopically, which is an effective tool for the detection and treatment of such coexisting neoplastic conditions. This case also highlights the importance of careful inspection of the abdomen including the appendix before focusing on the genital tract, and shows that gynecologic surgeons should retain appendectomy in their armamentarium (as the rst laparoscopic appendectomy was done by a gynecologist) [21].
Acknowledgment We thank Mr. Dursun Bugra, M.D. Professor of Surgery for making the data on fnal surgery available. Conict of interest peting interests. The authors declare that they have no com-

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