[Hereditary leiomyomatosis syndrome associated with renal cell carcinoma. A case report]. / Síndrome de leiomiomatosis hereditaria asociado a carcinoma de células renales. Presentación de un caso.

Hereditary leiomyomatosis (HL) is a rare autosomal dominant syndrome resulting from a mutation in the germline of the fumarate hydratase (FH) gene. Patients with this syndrome have an increased risk of cutaneous and uterine smooth muscle tumors as well as renal cancer. Renal carcinoma associated with hereditary leiomyomatosis (HLRCC) was recognized as a subtype of independent renal tumor in the 2016 WHO classification. We present a case of HLRCC occurring in a 39-year-old man with no family history or specific skin manifestations at the time of diagnosis.

MED12 exon 2 mutation is uncommon in intravenous leiomyomatosis: clinicopathologic features and molecular study.

Intravenous leiomyomatosis (IVL) is a rare neoplasm that is characterized by smooth muscle cell proliferation within venous vessels. The aim of this study is to investigate the clinicopathological features, immunophenotypes, and MED12 gene mutations in IVL. Nine cases of IVL from the Affiliated Hospital of Qingdao University were collected, and the clinicopathological features were reviewed. The immunohistochemical expressions of p16, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alpha thalassemia/mental retardation syndrome X-linked (ATRX), retinoblastoma 1 (RB1), fumarate hydratase (FH), and p53, were evaluated. The mutation status of MED12 gene exon 2 was detected by Sanger sequencing. All the 9 patients were women ranging from 32 to 58 years, and uterine leiomyomas were identified in 5 patients. Immunohistochemical staining showed that all IVL and leiomyoma samples were positive for estrogen receptor and progesterone receptor, but negative for CD34. IVL displayed similar immunostaining patterns with their uterine counterparts with focal p16 immunostaining. FH, PTEN, ATRX, and RB1 were variably positive, and p53 and Ki-67 positive rates were less than 5% in all cases. Two novel genetic variations at MED12 exon 2, a synonymous mutation c.141C>T (p.Asn47=), and an in-frame deletion mutation c.133_147del15 (p.Phe45_Pro49del) were identified in two IVL cases. One missense mutation c.131G>A (p.Gly44Asp) was identified in one uterine leiomyoma. The remaining 11 tumor samples (7 IVL cases and 4 uterine leiomyomas) showed no mutations at MED12 exon 2. Our results showed two novel MED12 mutations in IVL. The MED12 mutations are different between IVL and uterine leiomyoma. These findings indicate that IVL is a unique entity and different from uterine leiomyoma.

Review of hereditary leiomyomatosis renal cell carcinoma with focus on clinical and pathobiological aspects of renal tumors.

The entity of hereditary leiomyomatosis renal cell carcinoma (HLRCC)-associated RCC has been proposed and integrated into the recent International Society of Urologic Pathology (ISUP) of renal tumors. This tumor is characterized by presence of cutaneous and/or uterine leiomyomas and RCC and autosomal dominant hereditary form. Grossly, HLRCC arising in the kidney show the solid tumor with frequent partial cystic area. Microscopically, the tumor typically shows papillary RCC, type 2, with eosinophilic large nucleoli reminiscent of cytomegaloviral inclusion and perinuclear clearing/haloes. Immunohistochemically, tumor cells show the overexpression for 2SC and reduced expression of FH. Germline mutation of fumarate hydratase (FH) gene, the HLRCC responsible gene mapped to chromosome 1q43, has been identified in patients with HLRCC. As the renal cancer in patients with HLRCC generally behave aggressively even in a small size, complete surgical resection and retroperitoneal lymph node resection should be performed promptly when the tumor is discovered. The surveillance of renal tumor in FH gene germline mutation-positive patients should be started from the early age using ultrasound sonography or magnetic resonance imaging.

Atypical uterine leiomyoma: a case report and review of the literature.

BACKGROUND: Atypical uterine leiomyomas show benign behavior. However, the distinction between leiomyomas and leiomyosarcomas may at times be problematic. We report a rare case of atypical uterine leiomyoma. We try to investigate potential immunohistochemical parameters that could be essential to distinguish cases of malignant smooth muscle tumors and those of uncertain or borderline histology. CASE PRESENTATION: A 56-year-old white ethnic Albanian woman from Kosovo presented with uterine bleeding because of uterine multiple leiomyomas. A hysterectomy with unilateral adnexectomy was performed. Her hysterectomy specimen contained multiple leiomyomas in submucosal, intramural and subserosal locations. The leiomyomas were well demarcated, firm and white with a whorled cut surface and one had foci of hemorrhage. Histology of most of the leiomyomas showed a whorled (fascicular) pattern of smooth muscle bundles separated by well-vascularized connective tissue. Smooth muscle cells were elongated with eosinophilic or occasional fibrillar cytoplasm and distinct cell membranes. Some of them developed areas of degeneration including hyaline change, with less than five mitotic figures per ten high power fields in most mitotically active areas, and no significant atypia. One leiomyoma was characterized by moderately to severely pleomorphic atypical tumor cells with low mitotic counts and no coagulative tumor cell necrosis. Immunohistochemistry showed strong immunoreactivity for vimentin, smooth muscle actin and desmin, while cyclin-dependent kinase inhibitor 2A (p16), and B-cell lymphoma 2 (bcl-2) showed focal immunoreactivity, estrogen and progesterone were positive, Ki-67 expressed a low proliferation index, whereas p21 and tumor suppressor gene p53 were negative. CONCLUSIONS: The combination of evaluation of conventional morphologic criteria with cyclin-dependent kinase inhibitor 2A (p16), p21, progesterone, B-cell lymphoma 2, tumor suppressor gene p53 and Ki-67 expression may be of great value in the assessment of uterine smooth muscle tumors of uncertain or borderline histology.

Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas From Young Patients.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant syndrome that results from mutations in the fumarate hydratase (FH) gene. Patients with HLRCC are at risk for smooth muscle tumors of the uterus and skin as well as renal tumors. The renal cell carcinomas associated with HLRCC are usually high stage at presentation, aggressive, and have poor clinical outcomes. Therefore these patients and family members would benefit from early identification and appropriate surveillance. In small studies, HLRCC-associated uterine leiomyomas have been noted to display characteristic morphologic features including eosinophilic cytoplasmic inclusions, prominent eosinophilic nucleoli, and perinucleolar halos. Limited data suggest that positive staining for 2-succinocysteine (2SC) and loss of staining for FH by immunohistochemistry (IHC) can help with identification of HLRCC. The aim of this study was to evaluate the ability of morphology and IHC for FH and 2SC to help identify HLRCC in young patients with uterine smooth muscle tumors. We identified 194 evaluable uterine leiomyomas from women less than 40 years of age. We found FH gene aberrations by mutation analysis in 5 cases, a 2.6% incidence. Of these 5 cases, 4 displayed the characteristic morphologic features outlined above, whereas 1 did not. All 5 tumors with FH gene abnormalities showed positive staining for 2SC, whereas no FH gene aberrations were found in the 2SC-negative cases. Loss of FH staining was seen in 2 of the 5 cases, 1 with frameshift mutation and the other with homozygous deletion, whereas the remaining 3 cases with missense FH gene mutations were FH positive. Our study shows that morphologic features can be helpful for detection of HLRCC in uterine leiomyomas, although they may not be present in every case. IHC for 2SC and FH can be helpful: presence of positive staining for 2SC is sensitive and specific for detection of FH gene aberrations, whereas loss of staining for FH is specific but not sufficiently sensitive, as cases with missense mutations in the FH gene can show retained staining.

Pulmonary benign metastasizing leiomyoma: a case report.

Pulmonary benign metastasizing leiomyoma (PBML) is a rare entity usually occurring in females with history of uterine leiomyoma, and it is preferential to metastasize to the lung and appears as a histopathologic benign tumor of smooth muscle origin. In this article, the clinical and pathological data from 1 patient with PBML were analyzed. Chest CT scan showed that multiple well-defined nodules in the both lobes of the lungs. The tumor cells in the lung were well differentiated, and the pattern of tumor was similar to the original tumor. IHC identified it originated from smooth muscle cells, consistent with the diagnosis of PBML. Positive staining of estrogen and progestogen receptors was detected in both the leiomyoma and the metastasizing lesions. During two years of observation, pulmonary function parameters were within normal limits and there was no evidence of tumor recurrence.

Leiomyomatosis peritonealis disseminata coexisting with endometriosis within the same lesions: a case report with review of the literature.

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 LPD with endometriosis 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.

Intravascular adenomyomatosis: expanding the morphologic spectrum of intravascular leiomyomatosis.

Intravascular leiomyomatosis (IVL) is characterized by the presence of smooth muscle in venous and lymphatic spaces within the myometrium. Although the intravascular component usually consists solely of typical smooth muscle or variants of smooth muscle differentiation, we report 5 cases in which the intravascular component also included endometrioid glandular and stromal elements. We propose the term "intravenous adenomyomatosis" to describe this unusual variant of IVL. The mean age of the patients in this series was 50.2 years, slightly older than that of patients with conventional IVL. In addition to intravenous adenomyomatosis, both adenomyosis and leiomyomas were identified in all of our cases, supporting the hypothesis that the intravascular smooth muscle component in IVL is derived from associated myometrial pathology rather than from vessel walls. In our series, intravenous adenomyomatosis had a similar benign clinical behavior to most cases of IVL with no metastatic or recurrent disease identified at follow-up in 4 cases for which follow-up information was available. The main differential diagnoses are adenomyosis with vascular involvement, low-grade endometrial stromal sarcoma (ESS), including ESS with smooth muscle and glandular differentiation, and adenosarcoma with lymphovascular invasion. The possibility of intravenous adenomyomatosis should be borne in mind when considering these diagnoses, particularly ESS and adenosarcoma, which have different implications for patient management and prognosis.

Successful one-stage surgical removal of intravenous leiomyomatosis with cardiac extension in an elderly patient.

Intravenous leiomyomatosis is a benign smooth muscle tumor that sometimes spreads to the right heart via the inferior vena cava. A complete surgical resection is necessary to ensure its successful treatment. Surgical removal has been performed safely in middle-aged patients. Here we report a case of successful surgical removal in an elderly woman (age 81 years). The woman was admitted with palpitation and diagnosed as having an intravenous leiomyomatosis with cardiac extension. She underwent a one-stage surgical removal with cardiopulmonary bypass and circulatory arrest. We therefore recommend a one-stage operation, if possible, even in elderly patients.

A case of intravenous leiomyomatosis with high levels of hyaluronan.

Intravenous leiomyomatosis (IVL) is a rare benign tumor. The clinical behavior can be life-threatening due to extension through the pelvic veins. A 70-year-old woman was referred to our hospital with IVL originating from a uterine leiomyoma and extending to the inferior vena cava. The patient was diagnosed on the basis of the results of various studies, and the tumor was resected completely through a single-stage approach. The intravascular tumor was 20 cm long, multinodular and rubbery. Microscopic findings showed benign smooth muscle that was partly hyalinized and fibrous. Immunohistochemical studies revealed that hyaluronan was expressed more prominently in IVL than in uterine leiomyomas. IVL has viscoelastic properties and contains a large amount of hyaluronan, which may promote invasion during pathogenesis.

Leiomyomatosis peritonealis disseminata with malignant change in a man.

Leiomyomatosis peritonealis disseminata (LPD) is a rare clinicopathological entity typically observed in women of reproductive age. We report a case of LPD with malignant change in a man. A 77-year-old man presented with a mass measuring 10 cm in diameter at the terminal ileum and numerous peritoneal small nodules that were revealed by abdominal computed tomography. Right hemicolectomy with lymph node dissection was performed. Macroscopically, a tumor of the terminal ileum consisted of aggregates of small nodular lesions with calcification and necrosis. The wall of the ileum and colon was intact. Microscopically, some of the nodular lesions consisted of neoplastic growths of atypical spindle cells with cellular atypism and abnormal mitoses. A few of these lesions were completely surrounded by smooth muscle bundles. Hemorrhages and necroses were found within the tumor nodules. Immunohistochemically, the tumor cells were positive for vimentin, desmin, muscle actin, alpha-smooth muscle actin, cytokeratin and p53. The remaining nodular lesions, including small peritoneal lesions, were composed of hypocellular hyalinizing nodules. This case was thought to be LPD with malignant change, although the pathogenesis was uncertain because the tumor cells were negative for estrogen and progesterone receptors.

[Benign metastasizing pulmonary leiomyoma: description of a case and review of the literature]. / Leiomioma metastatizzante benigno nel polmone: descrizione di un caso e revisione della letteratura.

We report the case of a 48-year-old woman with multiple benign metastasizing leiomyomas in both lungs and a single retroperitoneal leiomyoma. The patient underwent surgical resection of the lesions 15 years after total hysterectomy for uterine myomas. Immunohistochemical studies performed on the retroperitoneal and pulmonary neoplasms showed them to be of mesenchymal derivation with smooth muscle differentiation; the samples were negative for HMB-45. Some histogenetic hypotheses for the multiple leiomyomas are presented.

Intravenous leiomyomatosis of the uterus with multiple pulmonary metastases associated with large bullae-like cyst formation.

We present a case of uterine intravenous leiomyomatosis associated with multiple pulmonary metastases with bullae-like cystic change. A 53-year-old woman who had undergone hysterectomy 5 years previously underwent an operation for multiple pulmonary nodules with bullae formation. After resection of several large bullae, a subsequent extirpation of the pulmonary nodules was performed, and a pathological examination showed multiple leiomyomatous nodules with occasional cystic change. A review of the previous slides of the uterus and immunohistochemical analysis of the proliferating ability using anti-Ki-67 and anti-proliferating cell nuclear antigen (PCNA) antibodies were performed. Proliferating cells of the uterus had very few mitotic figures for their high cellularity, and the labeling indices of Ki-67 and PCNA indicated very low levels in both uterine neoplasm and pulmonary nodules. From these findings, an intravenous leiomyomatosis associated with multiple pulmonary metastases was diagnosed.

Benign metastasizing leiomyoma of the lung: a case report.

Benign metastasizing leiomyoma (BML) refers to benign pulmonary neoplasm associated with a previous or coincident history of uterine leiomyomata. We report the case of a 56-year-old postmenopausal woman with a 4-year history of multiple benign leiomyomatous lesions in bilateral lungs and the uterus. The tumor cells from the lungs and uterus were focally immunoreactive for HMB-45 antibody and progesterone receptor. Immunoreactivity to HMB-45 is well known in smooth muscle cells of hamartomatous neoplasms, such as angiomyolipoma and lymphangioleiomyomatosis, but has not been reported in BML previously. These features suggest a multifocal hamartomatous histogenesis rather than metastasis in the present case.

Progesterone receptor activity in leiomyomatosis peritonealis disseminata.

Leiomyomatosis peritonealis disseminata (LPD) is a rare condition that primarily affects women of reproductive age. Immunohistochemical studies were performed in four cases: LPD from a premenopausal woman on oral contraceptives (one case); LPD associated with postpartum massive ectopic decidual reaction (one case); and LPD from a perimenopausal and a postmenopausal woman. Progesterone receptor activity was present in nine of nine cases, and eight of eight cases were strongly positive for vimentin; reactivity for cytokeratin was uniformly negative. Most cases had a pattern of staining typical of smooth muscle tumors with expression of desmin, smooth muscle actin, and muscle-specific actin. Although estrogen receptor was detected in most cases, reactivity was notably absent (one case) or weak (one case) in nodules with a prominent decidual reaction. Expression of CD 34, a marker for which LPD staining characteristics have not been previously reported, varied from absent to weak. Peritoneal nodules from the postmenopausal woman lacked staining for both estrogen receptor and desmin, smooth muscle actin and muscle-specific actin were only focally expressed, whereas staining for CD 34 was focally intense. Uterine myometrium and leiomyomata were positive for progesterone and estrogen receptor, vimentin, desmin, smooth muscle actin, and muscle-specific actin. Cytokeratin expression was absent. CD 34 exhibited weak staining in leiomyomata, but was absent from myometrium. Progesterone receptor appears to be uniformly expressed in LPD nodules from premenopausal and postmenopausal women, a finding supporting the contention that hormones influence the development of LPD in all cases, regardless of menopausal status.

Diffuse leiomyomatosis of the esophagus: disorder of cell-matrix interaction?

Diffuse leiomyomatosis (DL) is rare condition characterized by proliferation of smooth muscle in the upper gastrointestinal tract. Most cases are associated with X-linked Alport syndrome and have partial deletions in the genes encoding both the alpha5 and alpha6 chains of collagen type IV. We studied aspects of cell-matrix interaction of myocytes in an esophagogastrectomy specimen from a 12-year-old patient with DL. Myocytes had central areas of cytoplasmic rarefaction, which were actin positive and desmin poor, with the reverse pattern of staining at the cell periphery. Electron microscopy (EM) showed that the areas of rarefaction consisted of disorganized aggregates of filaments. The basement membranes ranged from thickened to thinned or absent. Immunohistochemical staining for the alpha1-alpha4 chains of collagen type IV, the alpha1, alpha2, beta2, and gamma1 chains of laminin, nidogen, type VI collagen, and fibronectin was normal. There was loss of the alpha5 and alpha6 chains of collagen type IV and the beta1 chain of laminin. Normal staining for alpha1, alpha2, alpha3, alpha4, alpha6, alpha8, and beta1 integrins was noted. Staining for alpha5 integrin varied from normal to reduced or negative in different cells. In DL, a primary abnormality of basement membrane may be associated with disorganization of the contractile apparatus and alterations of certain integrins. This may reflect a disturbance of cell-matrix interactions that play a role in cell differentiation and internal organization.