Equal contributors. Received October 1, 2013; Accepted October 29, 2013; Epub November 15, 2013; Published December 1, 2013

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1 Int J Clin Exp Pathol 2013;6(12): /ISSN: /IJCEP Original Article Leiomyomatosis peritonealis disseminata coexisting with endometriosis within the same lesions: a case report with review of the literature Ayano Toriyama 1*, Mitsuaki Ishida 1*, Tsukuru Amano 2, Tetsuya Nakagawa 2, Shouji Kaku 2, Muneo Iwai 1, Keiko Yoshida 1, Akiko Kagotani 1, Kentarou Takahashi 3, Takashi Murakami 2, Hidetoshi Okabe 1 1 Department of Clinical Laboratory Medicine and Division of Diagnostic Pathology, 2 Department of Obstetrics and Gynecology, 3 Department of Community Perinatal Medicine, Shiga University of Medical Science, Shiga, Japan. * Equal contributors. Received October 1, 2013; Accepted October 29, 2013; Epub November 15, 2013; Published December 1, 2013 Abstract: Leiomyomatosis peritonealis disseminata (LPD) is an extremely rare condition, which is characterized by the presence of multiple peritoneal and subperitoneal nodules composed of bland smooth muscle cells. Albeit extremely rare, coexistence of endometriosis within LPD lesions has also reported. Herein, we report the seventh documented case of LPD coexisting with endometriosis within the same lesions and review the pathogenesis of this lesion. A 42-year-old Japanese female presented with an abdominal tumor. Computed tomography revealed a tumorous lesion in the right ovary and multiple small nodules in the abdominal cavity. Under a clinical diagnosis of ovarian cancer with peritoneal dissemination, resection of these lesions was performed. Histopathological study of the disseminated peritoneal nodules revealed proliferation of interlacing bundles of spindle cells with eosinophilic cytoplasm and bland cigar-shaped nuclei. Mitotic figures were hardly seen. The peritoneal nodules of the rectum had cystic cavities within the spindle cell bundles, and endometrial glands and stroma were present around the cystic cavities and spindle cells. The resected tissues of the ovary and cecum showed the same histopathological features. Accordingly, a diagnosis of within the same lesions was made. A possible origin of LPD is thought to be the submesothelial multipotential stem cells, also referred to as the secondary müllerian system. The presence of endometrial tissues within LPD lesions, as seen in the present case, also support this hypothesis because endometrial tissues are also derived from the müllerian system. Keywords: Leiomyomatosis peritonealis disseminata, endometriosis, peritoneum, ovary Introduction Leiomyomatosis peritonealis disseminata (LPD), also referred to as disseminated peritoneal leiomyomatosis, is an extremely rare condition, which is characterized by the presence of multiple peritoneal and subperitoneal nodules composed of bland smooth muscle cells occurring mainly in the reproductive-aged females [1]. This disease was first described by Willson and Peale in 1952 [2], and later designated as LPD by Taubert et al. in 1965 [3]. Since then, less than 150 cases have been reported in the English literature [1]. Albeit extremely rare, coexistence of endometriosis within LPD lesions has also been reported, and only 6 cases have been documented in the English literature [4-8]. Herein, we report the seventh documented case of LPD coexisting with endometriosis within the same lesions, and review the clinicopathological features and pathogenesis of this extremely rare lesion. Case report A 42-year-old Japanese female (2 gravida and 2 partus), who was not taking oral contraceptives, presented with an abdominal tumor at an outpatient clinic. Physical examination revealed an immovable tumor in her abdominal cavity. Laboratory tests demonstrated elevated serum CA125 (567 U/mL; range <34) and CA19-9 (193 U/mL; range <36) levels. Contrastenhanced computed tomography showed a cystic lesion containing solid area with enhance-

2 Figure 1. Histopathological features of the peritoneal nodules and cecum. A: Multiple nodules composed of spindle cells are present in the peritoneal surface, HE, x 40. B: These nodules are composed of interlacing bundles of spindle cells with eosinophilic cytoplasm and bland cigar-shaped nuclei, HE, x 200. C: The nodule in the rectum has a cavity with hemorrhage and endometrial tissue among the spindle cells, HE, x 40. D: Within the spindle cell bundles, endometrial glands and stroma are observed, HE, x 40. E: Endometrial glands and stromal cells are without atypia, HE, x 200. F: Multiple nodules are present in the muscularis propria (upper half) of the cecum, HE, x 40. ment in the right ovary and multiple small nodules with enhancement in her abdominal cavity. According to these results, ovarian cancer with peritoneal dissemination was suspected clinically, and subsequently, she was referred to our hospital for surgery. Intraoperative examination revealed that the right ovarian tumor, measuring 12 cm in diameter, was strongly adhered to the cecum, and innumerable small nodular lesions, measuring 1 to 30 mm in diameter, were present in the mesentery, omentum, peritoneum, Douglas s 2950 Int J Clin Exp Pathol 2013;6(12):

3 Figure 2. Immunohistochemical features of the peritoneal nodules. A: Desmin is expressed in the spindle cells, x 40. B: CD10 is expressed in the endometrial stroma, x 40. pouch, and serosal surface of the small intestine, large intestine, and rectum. Total hysterectomy and bilateral salpingo-oophorectomy with resection of the ascending colon and some of the disseminated nodules were performed. Histopathological examination of the resected disseminated nodules revealed well-circumscribed multiple nodular lesions, measuring 1 to 25 mm in diameter, in the peritoneum (Figure 1A). These nodules were composed of proliferation of interlacing bundles of spindle cells with eosinophilic cytoplasm and bland cigar-shaped nuclei without conspicuous nucleoli (Figure 1A, 1B). Mitotic figures were hardly seen (<1/10 high-power fields). Most of these lesions were comprised of smooth muscle component, however, two nodules from the rectum, measuring 25 x 25 mm and 25 x 15 mm in diameter, had cystic cavities with hemorrhage within the smooth muscle nodules (Figure 1C). Endometrial tissues were present around the cystic cavities and within the bundles of smooth muscle cells in these two lesions (Figure 1C, 1D). Endometrial tissues were composed of endometrial gland as well as endometrial stroma (Figure 1D, 1E). The nuclei of the endometrial glandular cells were pseudostratified, however, no nuclear enlargement was noted (Figure 1E). Moreover, the nuclei of the endometrial stroma were also bland (Figure 1E). The resected specimens of the ovary also demonstrated multiple nodules composed of proliferation of interlacing bundles of spindle cells with eosinophilic cytoplasm and bland cigarshaped nuclei. Mitotic figures were hardly seen (<1/10 high-power fields). Some of these nodules had endometrial tissues within the spindle cell bundles and cystic cavities with hemorrhage. Endometrial tissues were composed of endometrial glands without atypia and endometrial stroma. The cecum had multiple nodular lesions composed of bland interlacing bundles of spindle cells from the serosa to the muscularis propria (Figure 1F). Some nodules of the cecum also had endometrial glands and stroma. Multiple leiomyomas were observed in the uterine corpus, and no endometrial tissues were present within these leiomyomas. The uterine cervix had no neoplastic lesions. Immunohistochemical studies were performed using an autostainer (Ventana) by the same method as previously reported [9-12]. Desmin and alpha-smooth muscle actin were diffusely positive for spindle cells of the disseminated nodules of the peritoneum, ovary, and cecum, but negative in the endometrial glands and stroma (Figure 2A). Estrogen and progesterone receptors were diffusely expressed in the spindle cells and endometrial glands and stroma. CD10 was expressed in the endometrial stroma, but not in the endometrial glands and spindle cells (Figure 2B). Ki-67 labeling index was 1.5% in the spindle cell component. According to these results, an ultimate diagnosis of LPD coexisting with endometriosis within the same lesions was made Int J Clin Exp Pathol 2013;6(12):

4 Table 1. Clinicopathological features of leiomyomatosis peritonealis disseminata with endometriosis within the same lesions Case No. Age Location Reference 1 32 Pelvic and abdominal peritoneal surfaces, omentum, and left ovary [4] 2 41 Peritoneal surfaces and omentum [4] 3 41 Peritoneal surfaces, and serosal surface of the bowel and the uterus [5] 4 32 Peritoneal surfaces, omentum, and serosal surface of the intestine [6] 5 33 Omentum [7] 6 30 Peritoneum, mesentery, and small and large intestines [8] Present Case 42 Peritoneum, mesentery, the serosal surface of the small and large intestines, and ovary Discussion LPD is an extremely rare benign condition of unknown etiology. A possible origin of the smooth muscle cells in LPD is thought to be the submesothelial multipotential cells, however, it has not been clear whether the stimuli to induce smooth muscle differentiation is hormonal, genetic, or both [1]. The submesothelial multipotential cells have also been referred to as the secondary müllerian system, which lacks organization of the fallopian tubes, uterus, and upper vagina, although it seems to maintain its ability to differentiate into specialized epithelia or stroma of the müllerian system in the adult life [4-6]. Tavassoli and Noris reported the largest case series of LPD [7]. They studied 20 cases of LPD, and speculated that LPD occurs due to an unusual predisposition, or selective sensitivity of subperitoneal mesenchymal stem cells undergoing smooth muscle metaplasia [7]. This hypothesis is persuasive because LPD occurs exclusively in the reproductive-aged females [1], and some cases of this disorder are found after prolonged use of oral contraceptives [7, 13], hormonal replacement therapy [14], or tamoxifen use [15], during pregnancy [7, 16], and in the presence of an estrogensecreting tumor [2, 17]. Moreover, the results of positive immunoreactivity for estrogen and progesterone receptors in the smooth muscle cells of LPD, as also seen in the present case, and the cases of spontaneous regression of LPD after discontinuation of hormonal agents or after pregnancy further support this hypothesis [1, 18, 19]. These results suggested that an increased sensitivity to estrogen in susceptible patients predisposes them to the development of LPD [1]. The peculiar histopathological finding of the present case was the presence of endometrial tissue within LPD. Most of the LPD lesions of the present case lacked endometrial tissues, however, nodules in the rectum, ovary, and cecum had endometrial tissues within the smooth muscle cell bundles, and moreover, the lesions in the rectum and ovary had cavities with hemorrhage and endometrial tissues within the smooth muscle cell bundles. To the best of our knowledge, only six cases of LPD with endometriosis within the same lesions have been reported in the English literature [4-8], although some cases of LPD without endometrial tissues within the lesions but accompanied by endometriosis of the ovary have been documented [20, 21]. Table 1 summarizes the clinicopathological features of the previously reported cases of this condition as well as the present one. Kuo et al. reported the first case of this lesion in a 30-year-old female in 1980 [8]. In the series by Tavassoli and Norris, one of 20 patients with LPD had endometriosis within smooth muscle nodules [7]. All patients were of reproductive age (range from 32 to 42 years). No differences in the clinicopathological features of LPD with or without endometriosis were present. The concise mechanism of the presence of endometrial tissues within LPD lesions has been unresolved. However, the most persuasive hypothesis is that submesothelial multipotential stem cells can differentiate to not only smooth muscle cells but also endometrial glands and stroma [7]. In addition, an extremely rare case of LPD with endocervicosis has also been documented by Liu et al. [22]. Endocervicosis is a rare lesion characterized by the presence of mucinous endocervical-type glands, and is usually found in the urinary bladder. In their case, endocervical type glands were present within most areas (approximately 2952 Int J Clin Exp Pathol 2013;6(12):

5 80%) of the LPD lesions [22]. This case also supports the hypothesis that submesothelial multipotential cells (secondary müllerian system) are origins of LPD because endocervical tissues are derived from the müllerian system. Endometriosis is defined as the presence of endometrial tissue outside the endometrium. It usually consists of endometrial glands and stroma, however, smooth muscle is occasionally present in endometriotic lesions [23]. Extensive amounts of smooth muscle in endometriosis have been referred to as endomyometriosis or uterus-like masses, when they demonstrate a central cavity lined by endometrial tissue [23, 24]. The frequent locations of endomyometriosis are the ovary (42%), uterus (25%), and broad ligament (13%). The abdominal cavity is an exceptional location of this entity [23]. The ovarian lesion of the present case resembled uterus-like masses because abundant endometrial tissues were present within the smooth muscle bundles and had cavities with hemorrhage. In addition, although LPD is a benign condition, only a few cases of LPD with malignant transformation (leiomyosarcoma) have been reported [1, 25]. Therefore, extensive histopathological examination is needed to diagnose LPD. Address correspondence to: Dr. Mitsuaki Ishida, Department of Clinical Laboratory Medicine and Division of Diagnostic Pathology, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga, , Japan. Tel: ; Fax: ; mitsuaki@belle.shiga-med. ac.jp References [1] Al-Talib A, Tulandi T. Pathophysiology and possible iatrogenic cause of leiomyomatosis peritonealis disseminata. Gynecol Obstet Invest 2010; 69: [2] Willson JR, Peale AR. Multiple peritoneal leiomyomas associated with a granulosa-cell tumor of the ovary. Am J Obstet Gynecol 1952; 64: [3] Taubert HD, Wissner SE, Haskins AL. Leiomyomatosis peritonealis disseminata; an unusual complication of genital leiomyomata. Obstet Gynecol 1965; 25: [4] Carvalho FM, Carvalho JP, Pereira RM, Ceccato BP Jr, Lacordia R, Baracat EC. Leiomyomatosis peritonealis disseminata associated with endometriosis and multiple uterus-like mass: report of two cases. Clin Med Insights Case Rep 2012; 5: [5] Mueller F, Kuehn K, Neudeck H, Siedentopf N, Ulrich U. Disseminated peritoneal leiomyomatosis with endometriosis. J Minim Invasive Gynecol 2012; 19: [6] Zotalis G, Nayar R, Hicks DG. Leiomyomatosis peritonealis disseminata, endometriosis, and multicystic mesothelioma: an unusual association. Int J Gynecol Pathol 1998; 17: [7] Tavassoli FA, Norris HJ. Peritoneal leiomyomatosis (leiomyomatosis peritonealis disseminata): a clinicopathologic study of 20 cases with ultrastructural observations. Int J Gynecol Pathol 1982; 1: [8] Kuo T, London SN, Dinh TV. Endometriosis occurring in leiomyomatosis peritonealis disseminata: ultrastructural study and histogenetic consideration. Am J Surg Pathol 1980; 4: [9] Ishida M, Iwai M, Yoshida K, Kagotani A, Okabe H. Sarcomatoid carcinoma with small cell carcinoma component of the urinary bladder: A case report with review of the literature. Int J Clin Exp Pathol 2013; 6: [10] Ishida M, Mori T, Umeda T, Kawai Y, Kubota Y, Abe H, Iwai M, Yoshida K, Kagotani A, Tani T, Okabe H. Pleomorphic lobular carcinoma in a male breast: case report with review of the literature. Int J Clin Exp Pathol 2013; 6: [11] Nakanishi R, Ishida M, Hodohara K, Yoshida T, Yoshii M, Okuno H, Horinouchi A, Iwai M, Yoshida K, Kagotani A, Okabe H. Prominent gelatinous bone marrow transformation presenting prior to myelodysplastic syndrome: a case report with review of the literature. Int J Clin Exp Pathol 2013; 6: [12] Ishida M, Mochizuki Y, Iwai M, Yoshida K, Kagotani A, Okabe H. Pigmented squamous intraepithelial neoplasia of the esophagus. Int J Clin Exp Pathol 2013; 6: [13] Hoynck van Papendrecht HP, Gratama S. Leiomyomatosis peritonealis disseminata. Eur J Obstet Gynecol Reprod Biol 1983; 14: [14] Heining J, Neff A, Cirkel U, Klockenbusch W. Recurrent leiomyomatosis peritonealis disseminata after hysterectomy and bilateral salpingo-oophorectomy during combined hormone replacement therapy. Eur J Obstet Gynecol Reprod Biol 2003; 111: [15] Bristow RE, Montz FJ. Leiomyomatosis peritonealis disseminata and ovarian Brenner tumor associated with tamoxifen use. Int J Gynecol Cancer 2001; 11: [16] Lim OW, Segal A, Ziel HK. Leiomyomatosis peritonealis disseminata associated with pregnancy. Obstet Gynecol 1980; 55: Int J Clin Exp Pathol 2013;6(12):

6 [17] Drake A, Dhundee J, Buckley CH, Woolas R. Disseminated leiomyomatosis peritonealis in association with oestrogen secreting ovarian fibrothecoma. BJOG 2001; 108: [18] Düe W, Pickartz H. Immunohistologic detection of estrogen and progesterone receptors in disseminated peritoneal leiomyomatosis. Int J Gynecol Pathol 1989; 8: [19] Butnor KJ, Burchette JL, Robboy SJ. Progesterone receptor activity in leiomyomatosis peritonealis disseminata. Int J Gynecol Pathol 1999; 18: [20] Haberal A, Kayikcioglu F, Caglar GS, Cavusoglu D. Leiomyomatosis peritonealis disseminata presenting with intravascular extension and coexisting with endometriosis: a case report. J Reprod Med 2007; 52: [21] Herrero J, Kamali P, Kirschbaum M. Leiomyomatosis peritonealis disseminata associated with endometriosis: a case report and literature review. Eur J Obstet Gynecol Reprod Biol 1998; 76: [22] Liu JY, Zheng J, Liao SL. Leiomyomatosis peritonealis disseminata associated with endocervicosis. Chin Med J 2009; 122: [23] Seki A, Maeshima A, Nakagawa H, Shiraishi J, Murata Y, Arai H, Kubochi K, Kuramochi S. A subserosal uterus-like mass presenting after a sliding hernia of the ovary and endometriosis: a rare entity with a discussion of the histogenesis. Fertil Steril 2011; 95: 1788, e15-e19. [24] Cozzutto C. Uterus-like mass relapacing ovary: report of a new entity. Arch Pathol Lab Med 1981; 105: [25] Sharma P, Chaturvedi KU, Gupta R, Nigam S. Leiomyomatosis peritonealis disseminata with malignant change in a post-menopausal woman. Gynecol Oncol 2004; 95: Int J Clin Exp Pathol 2013;6(12):