Variants of uterine leiomyomas (fibroids)
- Elizabeth A Stewart, MD
Elizabeth A Stewart, MD
- Consultant and Professor of Obstetrics and Gynecology
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology
- Mayo Clinic and Mayo Medical School
- Bradley J Quade, MD, PhD
Bradley J Quade, MD, PhD
- Associate Professor of Pathology
- Harvard Medical School
Benign uterine leiomyomas (fibroids) are the most common pelvic tumor in women [1-3]. Less commonly, women with a uterine mass presumed to be a leiomyoma are found to have a uterine sarcoma or a leiomyoma variant. The rates of such unanticipated entities have been estimated to be approximately 1:100 for leiomyoma variants and approximately 1:500 for leiomyosarcoma . There are a number of leiomyoma variants in which the smooth muscle tumor manifests one histologic facet of malignancy, yet lacks all others. Other variants are defined by their quasi-malignant capacity to metastasize while remaining histologically and clinically benign. Finally, some smooth muscle tumor variants cannot be definitely classified, and consequently are deemed to have an uncertain malignant potential. (See "Differentiating uterine leiomyomas (fibroids) from uterine sarcomas", section on 'Prevalence of sarcoma after surgery for presumed leiomyomas'.)
Histologically and biologically defined variants of uterine leiomyomas are reviewed here. The diagnosis and management of ordinary uterine leiomyomas, as well as approaches to differentiating leiomyomas from uterine sarcoma, are discussed separately. (See "Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas (fibroids)" and "Overview of treatment of uterine leiomyomas (fibroids)" and "Differentiating uterine leiomyomas (fibroids) from uterine sarcomas".)
There are several rare syndromes with leiomyomas or leiomyoma-like lesions that require differentiation from ordinary uterine leiomyomas. The classification of these variants continues to evolve as information about their pathophysiology is gained. The currently used categories are descriptive in nature and are only beginning to be characterized in molecular and genetic terms. Thus, there may be some overlap among some categories.
Definition of benign versus malignant lesions — Leiomyoma variants are classified as benign or malignant based upon histologic features. Gross characteristics may suggest that a lesion is benign or malignant, but do not confirm a diagnosis. While some variants include lesions having extrauterine extension or dissemination, this does not automatically confer a diagnosis of malignancy if the histology is benign. On the other hand, some of the variants have histologic findings that make it difficult to define them as benign or malignant (eg, smooth muscle tumors of uncertain malignant potential). (See 'Smooth muscle tumors of uncertain malignant potential' below.)
Benign smooth muscle tumors (ie, leiomyomas of the usual histologic type or “garden-variety” leiomyomas) are defined as follows :
- Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003; 188:100.
- Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 1981; 36:433.
- Serden SP, Brooks PG. Treatment of abnormal uterine bleeding with the gynecologic resectoscope. J Reprod Med 1991; 36:697.
- Seidman MA, Oduyebo T, Muto MG, et al. Peritoneal dissemination complicating morcellation of uterine mesenchymal neoplasms. PLoS One 2012; 7:e50058.
- Quade, BJ, Robboy, SJ. Uterine smooth muscle tumors. In: Robboy's Pathology of the Female Reproductive Tract, 2nd ed, Robboy, SJ, Mutter, GL, Prat, J, et al. (Eds), Churchill Livingstone Elsevier, Oxford 2009. p.474.
- Bell SW, Kempson RL, Hendrickson MR. Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases. Am J Surg Pathol 1994; 18:535.
- Evans HL, Chawla SP, Simpson C, Finn KP. Smooth muscle neoplasms of the uterus other than ordinary leiomyoma. A study of 46 cases, with emphasis on diagnostic criteria and prognostic factors. Cancer 1988; 62:2239.
- Giuntoli RL 2nd, Gostout BS, DiMarco CS, et al. Diagnostic criteria for uterine smooth muscle tumors: leiomyoma variants associated with malignant behavior. J Reprod Med 2007; 52:1001.
- Christacos NC, Quade BJ, Dal Cin P, Morton CC. Uterine leiomyomata with deletions of Ip represent a distinct cytogenetic subgroup associated with unusual histologic features. Genes Chromosomes Cancer 2006; 45:304.
- Perrone T, Dehner LP. Prognostically favorable "mitotically active" smooth-muscle tumors of the uterus. A clinicopathologic study of ten cases. Am J Surg Pathol 1988; 12:1.
- O'Connor DM, Norris HJ. Mitotically active leiomyomas of the uterus. Hum Pathol 1990; 21:223.
- Ip PP, Tse KY, Tam KF. Uterine smooth muscle tumors other than the ordinary leiomyomas and leiomyosarcomas: a review of selected variants with emphasis on recent advances and unusual morphology that may cause concern for malignancy. Adv Anat Pathol 2010; 17:91.
- Taran FA, Weaver AL, Gostout BS, Stewart EA. Understanding cellular leiomyomas: a case-control study. Am J Obstet Gynecol 2010; 203:109.e1.
- Hodge JC, Kim TM, Dreyfuss JM, et al. Expression profiling of uterine leiomyomata cytogenetic subgroups reveals distinct signatures in matched myometrium: transcriptional profilingof the t(12;14) and evidence in support of predisposing genetic heterogeneity. Hum Mol Genet 2012; 21:2312.
- Hodge JC, Pearce KE, Clayton AC, et al. Uterine cellular leiomyomata with chromosome 1p deletions represent a distinct entity. Am J Obstet Gynecol 2014; 210:572.e1.
- Seidman JD, Thomas RM. Multiple plexiform tumorlets of the uterus. Arch Pathol Lab Med 1993; 117:1255.
- Hodge JC, Quade BJ, Rubin MA, et al. Molecular and cytogenetic characterization of plexiform leiomyomata provide further evidence for genetic heterogeneity underlying uterine fibroids. Am J Pathol 2008; 172:1403.
- Moinfar F, Azodi M, Tavassoli FA. Uterine sarcomas. Pathology 2007; 39:55.
- Solomon LA, Schimp VL, Ali-Fehmi R, et al. Clinical update of smooth muscle tumors of the uterus. J Minim Invasive Gynecol 2005; 12:401.
- Hardman WJ 3rd, Majmudar B. Leiomyomatosis peritonealis disseminata: clinicopathologic analysis of five cases. South Med J 1996; 89:291.
- Quade BJ, McLachlin CM, Soto-Wright V, et al. Disseminated peritoneal leiomyomatosis. Clonality analysis by X chromosome inactivation and cytogenetics of a clinically benign smooth muscle proliferation. Am J Pathol 1997; 150:2153.
- Halama N, Grauling-Halama SA, Daboul I. Familial clustering of Leiomyomatosis peritonealis disseminata: an unknown genetic syndrome? BMC Gastroenterol 2005; 5:33.
- Vaquero ME, Magrina JF, Leslie KO. Uterine smooth-muscle tumors with unusual growth patterns. J Minim Invasive Gynecol 2009; 16:263.
- Ordulu Z, Dal Cin P, Chong WW, et al. Disseminated peritoneal leiomyomatosis after laparoscopic supracervical hysterectomy with characteristic molecular cytogenetic findings of uterine leiomyoma. Genes Chromosomes Cancer 2010; 49:1152.
- Park JY, Park SK, Kim DY, et al. The impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine leiomyosarcoma. Gynecol Oncol 2011; 122:255.
- Anupama R, Ahmad SZ, Kuriakose S, et al. Disseminated peritoneal leiomyosarcomas after laparoscopic "myomectomy" and morcellation. J Minim Invasive Gynecol 2011; 18:386.
- Worley MJ Jr, Aelion A, Caputo TA, et al. Intravenous leiomyomatosis with intracardiac extension: a single-institution experience. Am J Obstet Gynecol 2009; 201:574.e1.
- Fasih N, Prasad Shanbhogue AK, Macdonald DB, et al. Leiomyomas beyond the uterus: unusual locations, rare manifestations. Radiographics 2008; 28:1931.
- Andrade LA, Torresan RZ, Sales JF Jr, et al. Intravenous leiomyomatosis of the uterus. A report of three cases. Pathol Oncol Res 1998; 4:44.
- Sun C, Wang XM, Liu C, et al. Intravenous leiomyomatosis: diagnosis and follow-up with multislice computed tomography. Am J Surg 2010; 200:e41.
- Quade BJ, Dal Cin P, Neskey DM, et al. Intravenous leiomyomatosis: molecular and cytogenetic analysis of a case. Mod Pathol 2002; 15:351.
- Dal Cin P, Quade BJ, Neskey DM, et al. Intravenous leiomyomatosis is characterized by a der(14)t(12;14)(q15;q24). Genes Chromosomes Cancer 2003; 36:205.
- Castelli P, Caronno R, Piffaretti G, Tozzi M. Intravenous uterine leiomyomatosis with right heart extension: successful two-stage surgical removal. Ann Vasc Surg 2006; 20:405.
- García Rinaldi R, Pérez Hernández J, Corbalá AR, et al. Surgical treatment of multiple intracardiac and pulmonary artery tumor implants embolic from uterine intravascular leiomyomatosis. Bol Asoc Med P R 2007; 99:51.
- Wang J, Yang J, Huang H, et al. Management of intravenous leiomyomatosis with intracaval and intracardiac extension. Obstet Gynecol 2012; 120:1400.
- Bodner-Adler B, Bartl M, Wagner G. Intravenous leiomyomatosis of the uterus with pulmonary metastases or a case with benign metastasizing leiomyoma? Anticancer Res 2009; 29:495.
- Biri A, Korucuoglu U, Zumrutbas N, et al. Intravenous leiomyomatosis treated with aromatase inhibitor therapy. Int J Gynaecol Obstet 2008; 101:299.
- Grella L, Arnold TE, Kvilekval KH, Giron F. Intravenous leiomyomatosis. J Vasc Surg 1994; 20:987.
- Evans AT 3rd, Symmonds RE, Gaffey TA. Recurrent pelvic intravenous leiomyomatosis. Obstet Gynecol 1981; 57:260.
- Jautzke G, Müller-Ruchholtz E, Thalmann U. Immunohistological detection of estrogen and progesterone receptors in multiple and well differentiated leiomyomatous lung tumors in women with uterine leiomyomas (so-called benign metastasizing leiomyomas). A report on 5 cases. Pathol Res Pract 1996; 192:215.
- Awonuga AO, Shavell VI, Imudia AN, et al. Pathogenesis of benign metastasizing leiomyoma: a review. Obstet Gynecol Surv 2010; 65:189.
- Rivera JA, Christopoulos S, Small D, Trifiro M. Hormonal manipulation of benign metastasizing leiomyomas: report of two cases and review of the literature. J Clin Endocrinol Metab 2004; 89:3183.
- Patton KT, Cheng L, Papavero V, et al. Benign metastasizing leiomyoma: clonality, telomere length and clinicopathologic analysis. Mod Pathol 2006; 19:130.
- Motegi M, Takayanagi N, Sando Y, et al. [A case of so-called benign metastasizing leiomyoma responsive to progesterone]. Nihon Kyobu Shikkan Gakkai Zasshi 1993; 31:890.
- D'Armiento J, Imai K, Schiltz J, et al. Identification of the benign mesenchymal tumor gene HMGA2 in lymphangiomyomatosis. Cancer Res 2007; 67:1902.
- Walker CL, Hunter D, Everitt JI. Uterine leiomyoma in the Eker rat: a unique model for important diseases of women. Genes Chromosomes Cancer 2003; 38:349.
- Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358:140.
- Taveira-Dasilva AM, Rabel A, Gochuico BR, et al. Prevalence of uterine leiomyomas in lymphangioleiomyomatosis. Fertil Steril 2011; 96:711.
- Pollard P, Wortham N, Barclay E, et al. Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome. J Pathol 2005; 205:41.
- Pollard PJ, Brière JJ, Alam NA, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005; 14:2231.
- Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol 1973; 53:409.
- Alam NA, Bevan S, Churchman M, et al. Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43. Am J Hum Genet 2001; 68:1264.
- Stewart EA, Morton CC. The genetics of uterine leiomyomata: what clinicians need to know. Obstet Gynecol 2006; 107:917.
- Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002; 30:406.
- Alam NA, Rowan AJ, Wortham NC, et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 2003; 12:1241.
- Bayley JP, Launonen V, Tomlinson IP. The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC Med Genet 2008; 9:20.
- Sanz-Ortega J, Vocke C, Stratton P, et al. Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol 2013; 37:74.
- Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 2001; 98:3387.
- Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 2003; 73:95.
- Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK, et al. Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med Genet 2006; 43:523.
- Pilarski R, Stephens JA, Noss R, et al. Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet 2011; 48:505.
- Pilarski R. Cowden syndrome: a critical review of the clinical literature. J Genet Couns 2009; 18:13.
- Zhou J, Mochizuki T, Smeets H, et al. Deletion of the paired alpha 5(IV) and alpha 6(IV) collagen genes in inherited smooth muscle tumors. Science 1993; 261:1167.
- Segal Y, Peissel B, Renieri A, et al. LINE-1 elements at the sites of molecular rearrangements in Alport syndrome-diffuse leiomyomatosis. Am J Hum Genet 1999; 64:62.
- Quade BJ, Wang TY, Sornberger K, et al. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling. Genes Chromosomes Cancer 2004; 40:97.
- Definition of benign versus malignant lesions
- BENIGN HISTOLOGIC VARIANTS OF LEIOMYOMAS
- Atypical leiomyomas
- Mitotically active leiomyomas
- Cellular leiomyomas
- Myxoid leiomyomas
- Epithelioid leiomyomas
- - Plexiform leiomyomas
- Dissecting leiomyomas
- SMOOTH MUSCLE TUMORS OF UNCERTAIN MALIGNANT POTENTIAL
- Clinical features and management
- BENIGN UTERINE VARIANTS WITH EXTRAUTERINE DISEASE
- Leiomyomatosis peritonealis disseminata
- Intravenous leiomyomatosis
- Benign metastasizing leiomyomas
- MULTIORGAN OR EXTRAUTERINE VARIANTS
- Hereditary leiomyomatosis and renal cell carcinoma syndrome
- Cowden syndrome
- Vulvar and esophageal leiomyomatosis
- SUMMARY AND RECOMMENDATIONS