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Anorectal leiomyomatosis is exceedingly rare in children. Its association with the more common diffuse oesophageal leiomyomatosis has been documented in only two previous cases. This report describes the presentation, diagnosis and treatment of two further cases of diffuse oesophageal combined with anorectal leiomyomatosis.
Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.
A case of vulvar leiomyomatosis in a young adult with a history of esophagogastrectomy as a child for esophagogastric leiomyomatosis is presented. The steroid receptor profile of the tumor is described. Therapy with a combination of gonadotropin suppression and surgery was undertaken. The literature pertaining to this rare combination is discussed.
Three uterine leiomyomas with vascular invasion (LWVI), two of which were associated with pulmonary leiomyomatous nodules, and a case of intravenous leiomyomatosis (IVL) invading the vena cava and extending to the right atrium, are described. Despite their histological benignity, these lesions have a strong tendency to metastasize and are closely related to the so-called benign metastasizing leiomyoma (BML). From a clinical point of view, the pulmonary nodules of LWVI are stable or slowly-growing. The IVL was a "worm-like" tumour that presented as a cardiac mass. On the basis of their histological and immunohistological features, a unified histogenetic view of LWVI, IVL and BML of the uterus is proposed. LWVI and BML may be the same pathological entity and microscopic vascular invasion may represent the metastatic mechanism of BML. Alternatively, LWVI may be the initial stage of IVL. In rare instances, IVL may be associated with distant parenchymal (pulmonary) metastases. LWVI seems to be the precursor of both BML and IVL.
We present a unique case of metastatic leiomyomatosis to the skeleton. The very extensive involvement of the axial and peripheral skeleton with "ring" lesions and associated cyclical premenstrual pain eventually led to the correct diagnosis and total relief with hormonal therapy.
Peritoneal leiomyomatosis (PL) occurs in women of reproductive age. Of 20 women with PL in this study, 10 were pregnant or immediately postpartum, and 7 were taking oral contraceptive steroids. Only three of the 20 women were not pregnant or taking exogenous hormones. All PL nodules were composed mainly of spindle cells, but decidual cells were admixed with the spindle cells in some of the nodules in six of the 10 pregnant and postpartum women. Electron microscopy was applied to the nodules from six women representing the three different hormonal backgrounds. All contained smooth muscle cells. One was composed exclusively of smooth muscle cells, while four of the six contained smooth muscle cells predominantly but were admixed with myofibroblasts or altered smooth muscle cells and fibroblasts. Decidual cells were conspicuous in the nodules examined ultrastructurally from a pregnant woman. Despite incomplete excisions, none of the 14 women with follow-up had progressive disease. Complete or partial regression of PL was verified by "second-look" laparotomy in four women, but a repeat cesarian section in a fifth woman revealed persistence (or recurrence) of PL 1.5 years after the initial diagnosis. PL probably results from an unusual predisposition, or selective sensitivity, of subperitoneal mesenchymal stem cells in some women to undergo metaplasia and differentiation to smooth muscle, fibroblasts, myofibroblasts, and decidual cells. In the majority of women, hormonal stimulation is an initiator or promoter of the process.
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Diffuse esophageal leiomyomatosis is characterized by diffuse muscular hypertrophy chiefly marked in the lower end of the esophagus looks at a large tumor. It involves the entire length of the esophagus and down to the upper part of the stomach (esogastric leiomyomatosis). Diffuse leiomyomatosis is a extremely rare pathology encountered in children (13 previous report cases) and young adults. Il may be isolated or found in association with other intrathoracic and genital localisations or Alport syndrome (nephropathy, sensorineural deafness, ocular lesions). Extensive leiomyomatosis, engulfing the trachea and stem bronchi, may involve acute respiratory insufficiency. Genital localisations, exclusively in women (clitoral hypertrophy, vulvar leiomyomatosis), in association with esophageal leiomyomatosis, realize the esophago vulvar syndrome. Recently, familial diffuse leiomyomatosis cases were described with, in association, esophageal and extra-esophageal leiomyomatosis and Alport syndrome. The majority of the patients developed esophageal or respiratory symptoms. The radiological appearance is that of a mediastinal tumor or achalasia. CT Scans findings can give evidence diffuse muscular thickening of esophageal wall. Prognosis depends on the associated lesions. In that reports, two young adults (27 and 39 years old) died of inhabitual carcinomas (esophageal and gallbladder carcinoma). The only surgical treatment for symptomatic esogastric leiomyomatosis is subtotal esophagectomy with proximal gastrectomy and esocoloplasty. Myotomy is ineffective (2 cases). Five cases of esophageal leiomyomatosis are described (3 children, 2 young adults). Among these, two are familial leiomyomatosis cases. An esophageal resection was performed in four patients.
Diffuse leiomyomatosis is associated with the inherited kidney disease Alport syndrome, and characterized by visceral smooth muscle overgrowth within the respiratory, gastrointestinal and female reproductive tracts. Although partial deletions of the type IV collagen genes COL4A5 and COL4A6, paired head-to-head on chromosome Xq22, are known to cause diffuse leiomyomatosis, loss of function for type IV collagen does not explain smooth muscle overgrowth. To further clarify pathogenic mechanisms, we have characterized novel deletions in patients with Alport syndrome-diffuse leiomyomatosis or Alport syndrome alone. A 27.6-kb deletion, in a female with Alport syndrome-diffuse leiomyomatosis, is marked by the most proximal, i.e. most 5', COL4A5 breakpoint described to date. By comparing this deletion to others described here and previously, we have defined a minimal overlap region, only 4.2 kb in length and containing the COL4A5-COL4A6 proximal promoters, loss of which contributes to smooth muscle overgrowth. A novel deletion in a male with Alport syndrome alone is>1.4 Mb in length, encompassing COL4A5 and COL4A6 entirely, as well as neighboring genes. We postulate that loss of the 4.2-kb region in diffuse leiomyomatosis causes misregulation of neighboring genes, contributing to smooth muscle overgrowth. Deletion of the neighboring genes themselves may afford protection from this condition.
BACKGROUND: Intravenous leiomyomatosis is a rare variant of leiomyoma. CASE: The patient was a 49-year-old gravida 3, para 3 woman with menopause at age 46. She presented with a history of syncope. Vaginal examination revealed an enlarged and elastic-soft mass of the uterus. A pelvic ultrasound, computed tomography scan, and magnetic resonance imaging showed a heterogeneous, irregularly shaped 8- to 10-cm tumor. In addition, the inferior vena cava was almost completely occluded. Cardiac ultrasound demonstrated a mobile mass in the right atrium. The serum estradiol was 208 pg/mL (normal 0-59). Intravenous leiomyomatosis with cardiac extension was diagnosed preoperatively. A resection of the intracardiac and intracaval mass and a subtotal hysterectomy with bilateral salpingo-oophorectomy were performed. The uterine tumor weighed 600 g, and the cordlike intravascular tumor extending from the internal iliac vein into the right ventricle was 40 cm long and weighed 60 g. Pathologic examination confirmed intravenous leiomyomatosis with no evidence of atypia. The level of estrogen receptor in the tissue was 140 fmol/mg protein. The postoperative course was uneventful, and she has been in good health for 17 months after the operation. CONCLUSION: We report a case of intravenous leiomyomatosis extending into the right ventricle treated with a one-stage operation. It is possible that a high concentration of serum estradiol and high level of tissue estrogen receptor are related to the intravenous leiomyomatosis.
Multiple cutaneous and uterine leiomyomatosis (MCUL; OMIM 150800) is an autosomal dominantly inherited disease characterized by leiomyomas of the skin and uterine leiomyomas. Recently, association of MCUL with different forms of renal cancer has been described. This syndrome is referred to as hereditary leiomyomatosis and renal cell cancer (OMIM 605839). Both disorders result from heterozygous germline mutations in the fumarate hydratase (FH) gene that may function as a tumor suppressor. Interestingly, cutaneous leiomyomas do not only manifest in a diffuse and symmetric fashion. Rather frequently, a segmental or band-like manifestation pattern can be observed, usually following the lines of Blaschko. Here, we sought to elucidate the molecular basis of diffuse and segmental cutaneous leiomyomatosis in six unrelated Dutch and Spanish patients and their families. We identified six novel FH mutations, including one missense and one nonsense mutation, two deletions and two splice-site mutations. The segmental phenotype that was observed in various patients with FH mutations most likely reflects a type 2 segmental manifestation of cutaneous leiomyomatosis as previously also described for other autosomal dominantly inherited skin diseases. The results presented here extend the current data on the molecular basis of familial cutaneous leiomyomatosis and comprise, to the best of our knowledge, the first genetic study in Dutch and Spanish patients with this disorder. In addition, we review the clinical and molecular aspects of the disease.
BACKGROUND: In some families, X-linked Alport syndrome (AS) is associated with diffuse leiomyomatosis. We describe clinical, pathologic and molecular-genetic findings in a Japanese family with this inheritance mode of AS in association with leiomyomatosis. PATIENT: AS was diagnosed in a one-year-old boy with recurrent aspiration pneumonia caused by esophageal stenosis from leiomyomatosis. Diagnosis was confirmed by electron microscopy coupled with type IV collagen chain subtype staining in a renal biopsy specimen. His mother, who exhibited esophageal leiomyomatosis and is heterozygous for AS, showed a discontinuous staining pattern for collagen alpha5(IV) chain along the epidermal basement membrane in a skin biopsy specimen. Genetic analysis in the boy revealed the deletion of the first two exons of COL4A6 together with deletion of the 5' end of COL4A5. Despite administration of cyclosporin A, massive proteinuria has persisted in the boy, although renal function otherwise remains normal. CONCLUSION: Identification of an AS patient during infancy is extremely rare. Clinical manifestations, including macroscopic hematuria, cataracts and leiomyomatosis caused by the large deletion involving COL4A5 to COL4A6, led to early presentation with AS.
Fourteen examples of intravenous leiomyomatosis in the FIP files were studied. Growth beyond the uterus occurred in 10 of the 14 examples, largely in vessels in the broad ligament and in uterine and iliac veins. Metastasis to the heart occurred in 1 example. The study provides evidence that is consistent with both theories of origin of intravenous leiomyomatosis; namely, that it may arise either from the wall of veins within the myometrium or be a result of unusually extensive vascular invasion from a leiomyoma of the myometrium. Intravenous leiomyomatosis should be distinguished from a leiomyoma with vascular invasion by arbitrarily limiting the designation of leiomyoma with vascular invasion to neoplasms in which the vascular growth is a microscopic finding and confined within the leiomyoma. Criteria are given for distinguishing intravenous leiomyomatosis from endometrial stromal sarcoma, leiomyosarcoma, leiomyoma with vascular invasion, and leiomyomatosis peritonealis disseminata.
BACKGROUND: Intravascular leiomyomatosis is an uncommon uterine tumor characterized by grossly visible intravascular proliferation of benign smooth muscle. Based on its role in reducing the size of leiomyomas, leuprolide acetate was given as induction therapy for extensive inoperable intravascular leiomyomatosis. CASE: A 44-year-old woman, gravida 1, para 1-0-0-1, presented in July 1992 with abnormal uterine bleeding. Pelvic examination and ultrasonography revealed the presence of a large irregular pelvic mass. At laparotomy, uterine and bilateral adnexal masses were noted extending up to the pelvic inlet and into the broad and infundibulopelvic ligaments. This tumor was not resectable. Based on histologic and immunoperoxidase studies, the lesion was interpreted as a plexiform epithelioid smooth-muscle tumor of uncertain malignant potential. Leuprolide acetate depot therapy (7.5 mg every 4 weeks) was begun in September 1992 and continued for a total of 20 months. Maximal tumor regression was achieved after 9 months. Subsequent reexploration at 20 months revealed a resectable tumor. Resection was accomplished successfully, leaving no apparent residual disease. CONCLUSION: Leuprolide acetate induced tumor regression and rendered debulking surgery feasible in a patient with previously unresectable, widespread, retroperitoneal intravascular leiomyomatosis. Primary hormone therapy may provide alternative therapeutic options for certain cases of intravascular leiomyomatosis.
Little has been known about the molecular background of familial multiple cutaneous leiomyomatosis (MCL). We report here a clinical, histopathological, and molecular study of a multiple cutaneous leiomyomatosis kindred with seven affected members. This detailed study revealed strong features of a recently described cancer predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). The family was compatible with linkage to the HLRCC locus in 1q. Also, all seven cutaneous leiomyomas derived from the proband and analyzed for loss of heterozygosity displayed loss of the wild-type allele, confirming the association with a susceptibility gene in chromosome 1q. One individual had had renal cell cancer at the age of 35 years. This tumor displayed a rare papillary histopathology, which appears to be characteristic for HLRCC. The derived linkage, loss of heterozygosity, and clinical data suggest that MCL and HLRCC are a single disease with a variable phenotype. The possibility that members of leiomyomatosis families are predisposed to renal cell cancer should be taken into account.
BACKGROUND: Leiomyomatosis peritonealis disseminata has been attributed to estrogen stimulation and is seen only rarely in postmenopausal women. In such cases, pathogenesis is uncertain. CASE: Leiomyomatosis peritonealis disseminata tumors were resected from a postmenopausal woman. She was receiving tamoxifen therapy for breast cancer and had bilateral ovarian Brenner tumors. Estrogen and progesterone receptors were detected. Immunohistochemical analysis indicated that LH receptors were present. CONCLUSION: Luteinizing hormone receptors were identified in leiomyomatosis peritonealis disseminata in one woman. Levels of FSH and LH increase after menopause, and immunohistochemical analysis showed the presence of LH receptors, so gonadotropin rather than estrogen stimulation might have contributed to development of leiomyomatosis peritonealis disseminata in this uncommon case.