Leiomyomatosis peritonealis disseminata: Three case reports.

RATIONALE: Leiomyomatosis peritonealis disseminata (LPD) is a rare benign lesion primarily consisting of smooth muscle cells, which mostly affects premenopausal females. Here, we reported 3 females with LPD (age, 40-48 years) admitted for pelvic masses. PATIENT CONCERNS: All 3 LPD cases received laparoscopic uterine fibroid morcellation at 3, 8, and 14 years ago, respectively. Two cases were admitted for pelvic masses. One case was admitted for recurrent fibroids with pollakiuria. DIAGNOSES: LPD was considered in 2 cases preoperation according to imaging examination, and one of them received ultrasound-guided biopsy of the lesion in the right lobe of the liver. One case was considered as recurrent fibroids preoperation. After surgery, all cases were pathologically diagnosed as LPD consisting of benign smooth muscle cells. INTERVENTIONS: A total abdominal hysterectomy, salpingo-oophorectomy, and debulking was performed for all 3 cases. Intraoperative exploration revealed that the fibroids distributed in the mesentery (3 cases), broad ligament (1 case), omentum (1 case), liver (1 case), and rectus abdominis (1 case). OUTCOMES: No recurrence was found during postoperative following-up (5-12 months). LESIONS: Preoperative diagnosis of LPD is presented as a challenge due to unspecific clinical manifestations. Its diagnosis mainly depends on histopathologic evaluation. Surgery still is the primary treatment for LPD. For patients without reproductive desire, total abdominal hysterectomy, salpingo-oophorectomy, and debulking can be performed, and the affected tissue should be removed as much as possible based on the risk assessment.

A clinicopathological and molecular analysis in uterine leiomyomas and concurrent/metachronous peritoneal nodules: New insights into disseminated peritoneal leiomyomatosis.

Disseminated peritoneal leiomyomatosis (DPL) is a rare, benign entity, but DPL following morcellation has become a major concern recently. This study aimed to investigate the molecular relationship between uterine leiomyoma and DPL. We analyzed the clinicopathological and molecular features of 8 DPL patients including 6 (#3-8) with and 2 (#1 and 2) without antecedent morcellation. Patients 1 and 2 were characterized by numerous, small peritoneal nodules whereas patients 4-8 harbored less but larger peritoneal nodules. Patient 3 had a peritoneal carcinomatosis-like dissemination, but she has been alive with disease for 68 months. Histological examination confirmed the diagnosis of leiomyomas in the uterus and extra-uterine sites. Immunohistochemistry demonstrated that both uterine and extra-uterine tumors were invariably positive for HMGA2 and MED12. MED12 mutation (c.130 G > A, p.G44S) was found in original uterine (n = 3) and peritoneal (n = 11) tumors from patients 3, 6, 7 and 8. Microsatellite instability at TPOX and D19S433 was observed in the uterine leiomyoma (patient 2) whereas LOH at CSF1PO was found in the peritoneal tumors (patient 1). D13S317 LOH was present in both uterine and peritoneal tumors detected (patient 8). However, D3S1358 LOH and D19S433 LOH was only found in the peritoneal tumors (patient 8) and recurrent tumors (patient 3), respectively. We suggested that DPLs following morcellation might be closely associated with original uterine leiomyomas. DPLs with and without prior morcellation may harbor different pathogenetic pathways. These findings are critical for the clinical intervention and prevention of DPL patients.

Advances in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) research.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant hereditary cancer syndrome with incomplete penetrance. It is caused by a germline amorphic allele of the FH gene, which encodes the TCA cycle enzyme, fumarate hydratase (FH). HLRCC patients are genetically predisposed to develop skin leiomyomas, uterine fibroids, and the aggressive kidney cancer of type 2 papillary morphology. Loss-of-heterozygocity at the FH locus that cause a complete loss of FH enzymatic function is always detected in these tumor tissues. Molecular pathway elucidation, genomic studies, and systematic genetics screens reported over the last two decades have identified several FH-inactivation driven pathways alterations, as well as rationally conceived treatment strategies that specifically target FH-/- tumor cells. These treatment strategies include ferroptosis induction, oxidative stress promotion, and metabolic alteration. As the fundamental biology of HLRCC continues to be uncovered, these treatment strategies continue to be refined and may one day lead to a strategy to prevent disease onset among HLRCC patients. With a more complete picture of HLRCC biology, the safe translation of experimental treatment strategies into clinical practice is achievable in the foreseeable future.

Pathologic Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma.

: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited cancer syndrome associated with a highly aggressive form of type 2 papillary renal cell carcinoma (PRCC). Germline inactivating alterations in fumarate hydratase (FH) cause HLRCC and result in elevated levels of reactive oxygen species (ROS). Recent work indicates that FH-/- PRCC cells have increased activation of ABL1, which promotes tumor growth, but how ABL1 is activated remains unclear. Given that oxidation can regulate protein-tyrosine phosphatase (PTP) catalytic activity, inactivation of an ABL-directed PTP by ROS might account for ABL1 activation in this malignancy. Our group previously developed "q-oxPTPome," a method that globally monitors the oxidation of classical PTPs. In this study, we present a refined q-oxPTPome, increasing its sensitivity by >10×. Applying q-oxPTPome to FH-deficient cell models showed that multiple PTPs were either highly oxidized (including PTPN12) or overexpressed. Highly oxidized PTPs were those with relatively high sensitivity to exogenous H2O2. Most PTP oxidation in FH-deficient cells was reversible, although nearly 40% of PTPN13 was irreversibly oxidized to the sulfonic acid state. Using substrate-trapping mutants, we mapped PTPs to their putative substrates and found that only PTPN12 could target ABL1. Furthermore, knockdown experiments identified PTPN12 as the major ABL1 phosphatase, and overexpression of PTPN12 inhibited ABL1 phosphorylation and HLRCC cell growth. These results show that ROS-induced oxidation of PTPN12 accounts for ABL1 phosphorylation in HLRCC-associated PRCC, revealing a novel mechanism for inactivating a tumor suppressor gene product and establishing a direct link between pathologic PTP oxidation and neoplastic disease. SIGNIFICANCE: This work identifies a novel mechanism of activation of the oncogenic kinase ABL1 via ROS-induced, oxidation-mediated inactivation of cognate protein tyrosine phosphatases.

The association between ultrasound-estimated visceral fat deposition and uterine fibroids: an observational study.

Uterine fibroids are the most common neoplasm of the genital tract in reproductive women. Obesity holds a role as risk factor for uterine fibroids, through hormonal and inflammatory mechanisms. Visceral fat is a hormonally active tissue, so an increase in visceral fat may be considered as a risk factor, through the increased production of inflammatory mediators. The aim of the study was, therefore, to evaluate the association between the presence of uterine fibroids and fat tissue distribution, and to assess the efficacy of both anthropometric and instrumental indicators, in particular the sonographic measurement of preperitoneal fat thickness (PFT) and subcutaneous fat thickness (SFT). Study group consisted of childbearing-age women with at least one uterine fibroid with a diameter ≥10 mm (n = 71), all the childbearing-age women who access to the outpatient service of our institution in the same period, without evidence of uterine fibroids, constituted the control group (n = 145). A significantly difference in BMI (p = 0.0034), PFT (p < 0.0001), and SFT (p = 0.0003) emerged. At the multivariate analysis, only PFT showed an independent significant association with the presence of uterine fibroids (p < 0.0001). The ROC curve analysis identified a cut-off value of 6.7 mm of PFT as discriminator for the presence of uterine fibroids.

Hereditary leiomyomatosis and renal cell cancer syndrome: identification and clinical characterization of a novel mutation in the FH gene in a Colombian family.

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome (HLRCC) is a rare disease and since the first report, it has been found in just over 200 families approximately, around the world (Smit et al. in Clin Genet 79:49-59, 2009). Patients in Colombia or in Latin America have not been described, as far as we know. HLRCC is inherited in an autosomal dominant manner, and it is caused by heterozygous germline mutations in the FH gene, which encodes the fumarate hydratase enzyme. It is characterized mainly by the appearance of cutaneous and uterine leiomyomas, and an early-onset, aggressive form of type 2- papillary renal cell carcinoma (Smit et al. in Clin Genet 79:49-59, 2009; Schmidt and Linehan in Int J Nephrol Renovasc Dis 7:253-260, 2014]. We report a Colombian family with HLRCC syndrome, with a novel mutation in FH gene (c.1349_1352delATGA) in which cutaneous leiomyomas have not been found, but other clinical manifestations such as type 2- papillary renal cell carcinoma, uterine leiomyomas and rare tumors were present. This investigation constitutes the first report of HLRCC syndrome in Colombia, and probably in Latin America.

[DISSEMINATED PERITONEAL LEYOMYOMATOSIS--PRACTICAL APPROACH TO DIAGNOSIS].

Disseminated peritoneal leiomyomatosis (DPL) is a rare condition characterized by the presence of multiple histologically benign smooth muscle nodules on the surface subperitoneal tissue simulating macroscopic peritoneal carcinomatosis. This disease is rare, but in recent years, in connection with the widespread introduction of laparoscopic surgery, the reports of disseminated peritoneal leiomyomatosis occurring after laparoscopic morcellation, were frequent. The knowledge of DPL is necessary to develop methods of prevention, and individualized treatment depending on the pathogenesis and clinical manifestations in each patient.

Surgical removal of multiple mesenteric fibroids (Kg 4,500) by abdominal spread of previous laparoscopic uterine myomectomy.

INTRODUCTION: Huge and multiple mesenteric fibroids (4,500 Kg weight) are very unusual. In many cases they are mistaken for subserosal fibroids of the womb due to the proximity with uterine walls. When they have a rapid growth, the risk of becoming malignant (sarcoma) has not to be underestimated. Surgery is challenging to remove abdominal nodes. CASE REPORT: A case of a 40-year old woman, admitted to the hospital with abdominal masses occupying the entire cavity was reported. Both computerized tomography (CT) and ultrasounds (US) were not diriment for belonging of tumours. Clinical history of patient reports a laparoscopic removal of uterine fibroids, using the morcellator. Laparoscopy was performed four years before. Open surgery by means of a large transversal suprapubic laparotomy according to Pfannestiel was carried out. Multiple and huge mesenteric, peritoneal and intestinal tumours spread in the whole abdominal cavity were found, removed and examined by frozen section histology; in addition a series of small conglomerated myomas in the site of previous laparoscopic transumbilical route was taken away as well (the largest fibroid weighed Kg 3.500 and the all tumors removed 4,500 Kg); the result was benign (fibroids) and genital apparatus was preserved. Operation was challenging. Postoperative course was uneventful; after five days patient was discharged. CONCLUSIONS: This case is very interesting for many factors: A) many extra-uterine fibroids spread throughout abdominal cavity; B) considerable weight of the masses C) intraoperative and postoperative danger. Finally, due to involvement of previous laparoscopic transumbilical incision together with other findings, the hypothesis of post laparoscopic dissemination has to be considered. A case of so large extragenital abdominal fibroids following laparoscopic uterine myomectomy has never been published so far.

Leiomyomatosis peritonealis disseminata: pregnancy, contraception and myomectomy of its pathogenesis.

Leiomyomatosis peritonealis disseminata (LPD) is a rare smooth muscle tumour characterized by multiple small nodules on the omentum and peritoneal surface, composed of benign smooth muscle cells with minimal mitotic activity, frequently admixed with decidual cells. The possible pathogenetic mechanisms include hormonal dysfunction, differentiation of subperitoneal mesenchymal stem cells, myofibroblastic metaplasia and genetic and iatrogenic causes (resection of myomas during laparoscopic surgery). Diagnosis is easily made on biopsy specimens. Reduction of oestrogen exposure, surgical castration or gonadotrophin releasing hormone agonists are generally sufficient to cause regression of LPD. We report a case of an asymptomatic 36-year-old pregnant woman with long-term use of oral contraceptives, and previous myomectomy, who had a mass of uncertain origin which was, histopathologically, diagnosed as leiomyomatosis peritonealis diffusa with foci of ectopic decidua. Ectopic decidua was also present in a pelvic lymph node. To the best of our knowledge, this is the first case of LPD containing foci of ectopic decidua in a pregnant woman with a past history of myomectomy and use of oral contraception for three years; ectopic decidua was also detected in a pelvic lymph node.

Racial and ethnic differences in the pathogenesis and clinical manifestations of uterine leiomyoma.

Uterine leiomyomas are the most common benign gynecologic condition. The prevalence is three times more common among women of African ethnicity. Disparity in this disease is evidenced by earlier age of onset, greater severity of symptoms, and different response to treatment. Although the pathogenesis of disease development is not completely known, growing evidence focuses on investigating the molecular mechanisms in disease development and the influence of ethnicity. Variation in the expression levels or function of estrogen and progesterone receptors, polymorphism of genes involved in estrogen synthesis and/or metabolism (COMT, CYP17), retinoic acid nuclear receptors (retinoid acid receptor-α, retinoid X receptor-α), and aberrant expression of micro-RNAs (miRNAs) are some of the molecular mechanisms that may be involved. Nutritional factors, such as vitamin D deficiency, might also contribute to the higher incidence in dark skinned populations who are also commonly suffer from hypovitaminosis D. Culture and environmental difference might have a role in disease development. Further analysis and better understanding of these mechanisms will provide insight into the molecular basis of racial disparities in leiomyoma formation and will help to develop new innovations in leiomyoma treatment.

An unusual cause of pseudoachalasia: the Alport syndrome-diffuse leiomyomatosis association.

Alport syndrome (AS) is a hereditary disease characterized by glomerular nephropathy progressing to end-stage renal disease, frequently associated with sensorineural deafness and ocular abnormalities. Rarely, AS coexists with diffuse leiomyomatosis, a benign proliferation of smooth muscle in the gastrointestinal tract, mostly of the oesophagus, but also of the tracheobronchial tree and the female genital tract. Patients with this association have been shown to have contiguous gene deletion involving both COL4A5 and COL4A6 genes. The authors report the case of a 25-year-old man with AS and long-standing dysphagia. The patient received a renal transplant at the age of 23 because of end-stage renal disease. Clinical assessment as well as endoscopic, manometric and radiologic studies suggested the diagnosis of achalasia, which was treated by Heller's myotomy with Dor fundoplication. Postprocedure dysphagia led to an endoscopic ultrasound that showed diffuse thickening of the second layer, resulting in the hypothesis of oesophageal leiomyomatosis. The diagnosis was confirmed through histological study of endoscopic biopsies and genetic analysis.

Leiomyomatosis peritonealis disseminata with formation of endometrial cysts within tumors arising after supracervical laparoscopic hysterectomy.

BACKGROUND: Use of morcellation during laparoscopic hysterectomy may result in seeding of uterine tissue throughout the abdominal cavity and development of 'iatrogenic' leiomyomatosis peritonealis disseminata. CASE: Two years after a supracervical laparoscopic hysterectomy a 42-year-old parous women presented with abdominal pain and bloating. CT scans and subsequent surgical exploration reveled multiple solid tumors containing cysts filled with altered blood. Histologically the tumors had characteristic features of a benign leiomyoma with smooth muscle cells infiltrated by endometrial glands. CONCLUSION: Pieces of smooth muscle cell and endometrial uterine tissue lost in the abdominal cavity during morcellation may progress to leiomyomatosis peritonealis disseminata with unusual appearance.

[Uterine myoma in remnant cervix]. / Miomatosis uterina en cérvix residual.

Parasitic myomas are rare and their ethiopathogenesis is uncertain. They may develop from a detached fibroid adhering to an extrauterine surface in order to obtain new blood supply. It has been stated that they form from uterine or myoma fragments left behind after morcellation in the abdominopelvic cavity and thus are called "iatrogenic". Surgeons must be aware of this recently reported complication related to the increasing number of laparoscopic procedures. Thorough inspection and washing of the abdominal cavity are recommended. A case of a patient with iatrogenic parasitic myomas, which appeared six years after a laparoscopic supracervical hysterectomy involving a morcellator, is reported.

Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata.

BACKGROUND: US black women have higher rates of uterine leiomyomata (UL) and lower intakes of fruit and vegetables than do white women. Whether fruit and vegetable intake is associated with UL in black women has not been studied. OBJECTIVE: We assessed the association of dietary intake of fruit, vegetables, carotenoids, folate, fiber, and vitamins A, C, and E with UL in the Black Women's Health Study. DESIGN: In this prospective cohort study, we followed 22,583 premenopausal women for incident UL (1997-2009). Diet was estimated by using food-frequency questionnaires in 1995 and 2001. Cox regression was used to derive incidence rate ratios (IRRs) and 95% CIs for the association between each dietary variable (in quintiles) and UL. RESULTS: There were 6627 incident cases of UL diagnosed by ultrasonography (n = 4346) or surgery (n = 2281). Fruit and vegetable intake was inversely associated with UL (≥4 compared with <1 serving/d; IRR: 0.90; 95% CI: 0.82, 0.98; P-trend = 0.03). The association was stronger for fruit (≥2 servings/d compared with <2 servings/wk; IRR: 0.89; 95% CI: 0.81, 0.98; P-trend = 0.07) than for vegetables (≥2 servings/d compared with <4 servings/wk: IRR: 0.97; 95% CI: 0.89, 1.05; P-trend = 0.51). Citrus fruit intake was inversely associated with UL (≥3 servings/wk compared with <1 serving/mo: IRR: 0.92; 95% CI: 0.86, 1.00; P-trend = 0.01). The inverse association for dietary vitamin A (upper compared with lower quintiles: IRR: 0.89; 95% CI: 0.83, 0.97; P-trend = 0.01) appeared to be driven by preformed vitamin A (animal sources), not provitamin A (fruit and vegetable sources). UL was not materially associated with dietary intake of vitamins C and E, folate, fiber, or any of the carotenoids, including lycopene. CONCLUSION: These data suggest a reduced risk of UL among women with a greater dietary intake of fruit and preformed vitamin A.