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Aims: To determine the significance of the epithelioid type and the corresponding molecular alterations in hepatic angiomyolipoma (AML)., Methods and Results: We retrieved 24 samples of hepatic AML to delineate the clinicopathological features and the immunohistochemical expression of components in the mTOR pathway, and employed microsatellite markers to analyse allelic imbalances in the TSC1 and TSC2 regions. Myomatous AML was the most common type, and a predominantly epithelioid cell population was observed in 50% of the samples. Two-thirds of all samples contained <20% of fat tissue. Four cases of monotypic epithelioid AML were discovered without prognostic implications. Elevated phospho-p70S6 kinase expression was noted in 19 samples in the absence of phospho-AKT activity. Loss of heterogeneity (LOH) of TSC1/TSC2 was found in 15 samples. As compared wityh syndromic AML samples, sporadic AML samples showed LOH of microsatellite markers to a limited extent. Only four samples had increased β-catenin expression in the context of concurrent high expression of phospho-p70S6 kinase and phospho-S6 (P = 0.018)., Conclusions: The low fat content and epithelioid cytomorphology in hepatic AML potentially obstruct preoperative and pathological diagnosis. Alteration of the mTOR pathway and LOH of the tuberous sclerosis complex genes is a frequent pathogenesis in hepatic AMLs., (© 2014 John Wiley & Sons Ltd.)

Aims:   Mesenchymal neoplasms of the kidney are rare, and most represent sporadic angiomyolipomas. A few haemangiomas have been reported in end-stage renal disease (ESRD) but, to date, no study has focused on the frequency and morphological spectrum of mesenchymal lesions in ESRD., Methods and Results:   We evaluated retrospectively 90 nephrectomy specimens with ESRD. Haemangiomas were detected in eight cases (8.8%; six males and two females; mean age: 55 years); four were multifocal and four had concurrent renal epithelial neoplasms. Lesions involved the medulla (three), cortex (two) or both (three), and the size range was 1-25 mm (mean 4.8 mm). Histologically, all were capillary haemangiomas with an at least focally detectable spleen-like anastomosing pattern. All tumours stained positively for CD31 and FLI-1, but none expressed pankeratin (KL-1), podoplanin/D2-40, HHV8 or GLUT-1. Minute angiomyolipomas (mean size 2.3 mm) were detected in four patients (mean age 49.5 years). Tumour-like smooth muscle proliferations were seen surrounding muscular arteries (eight), occasionally admixed with fat extending from the renal sinus mimicking angiomyolipoma. No similar tumours were found in 105 control kidneys., Conclusions:   Benign haemangiomas are not uncommon in ESRD, but may be under-recognized. They display distinctive morphology and should be distinguished from angiosarcomas and capillary-rich renal cell carcinomas., (© 2012 Blackwell Publishing Limited.)

Aims: The aim of this study was to characterize and delineate the broad histological spectrum of hepatic angiomyolipoma (AML) and to obtain a better understanding of its clinicopathological diagnosis by reviewing a large series of AMLs., Methods and Results: According to the proportions of three histological components, AML could be classified into 10 types; 36 of 55 tumours (65%) were classified as myomatous, eight as myoangiomatous, six as mixed (conventional), two as lipomatous, two as myolipomatous, and one as lipomyomatous. The morphology of smooth muscle cells (SMCs) in AML was quite variable, giving a wide variety of growth patterns. Fourteen (25%) of 55 tumours showed severe cellular atypia, and invasive growth of tumour cells was found in 69% of the tumours. However, except for two autopsy cases, all of the patients were in good health at follow-up, without metastases. Immunostaining for HMB-45 was positive in all cases. We found frequent lymphocyte infiltration, and the occasional presence of abnormally large blood vessels around the tumour at the tumour-background liver interface, features which have not been reported previously., Conclusions: The majority of hepatic AMLs were myomatous in type, showing variable cellular morphology and growth patterns. Cellular atypia and invasive growth were frequent, indicating that hepatic AMLs often show malignancy-like histological features. Although the majority of cases behave as benign tumours, AML should be considered to have uncertain malignant potential, and careful follow-up of patients is recommended. Immunostaining for HMB-45 is specific for AML, and establishes the diagnosis. The occasional presence of abnormally large blood vessels around the tumour may give new insights into the evaluation of findings from imaging., (© 2012 Blackwell Publishing Limited.)

Aims: Renal epithelioid angiomyolipoma (EAML) is only described in case reports or in multi-institutional small series. The aim was to report cases seen at our institution and to perform a meta-analysis based on a literature review., Methods and Results: Six EAML cases seen at our institution were reviewed and a meta-analysis performed using cases retrieved from a literature review. There were a total of 69 cases for review. The male:female ratio was 1:3. In the absence of areas of typical AML, useful features in distinguishing EAML from epithelial renal neoplasms include: extreme degree of cytological atypia, histiocytoid appearance, presence of melanocytic pigments, solid architecture with the absence of frequent areas of alveolar pattern, tubulo-papillary formation and scarring. A fatal outcome, distant or lymph node metastasis, venous invasion and local recurrence were considered as adverse events and occurred in 40% of cases over a period of follow-up of 3-60 months (mean 22.5 +/- 18 months). Tumours with an unfavourable outcome showing marked cytological atypia and extensive tumour necrosis were larger (135 +/- 43 mm) than those with a favourable outcome (79 +/- 50 mm) (P < 0.002), and predominantly occurred in men., Conclusions: Renal neoplasms with certain unusual features should be investigated immunohistochemically to rule out the possibility of EAML. The frequency of adverse outcome is lower in EAML than in renal cell carcinoma.

Aims: Although histological features of hepatic angiomyolipoma (AML) are highly variable, true malignant change is extremely rare. The aim was to review the histological features of invasive growth and clinical outcomes in 39 cases of hepatic AML., Methods and Results: An invasive growth pattern into surrounding hepatic parenchyma, portal triads and/or around hepatic veins was found in 24 of 39 tumours (62%). One variant showed tumour cells replacing hepatocytes within the liver cell cords. The other consisted of portal or perivascular invasive growth along blood vessels. In the former pattern, small isolated tumour cell clusters were occasionally found in the vicinity of the main mass, showing a sprouting pattern. Although these histological features suggest malignancy, distant metastases were not found in any of the cases within a mean follow-up period of 6.8 years., Conclusions: A previously unrecognized histological feature of an invasive growth pattern, which suggests malignancy and might promote an erroneous diagnosis, was frequently found in hepatic AMLs. However, among about 180 reported hepatic AMLs, including the present cases, only one hepatic AML with distant metastasis has been reported to date and nearly all hepatic AMLs behave in a benign fashion. Therefore, pathologists should not overdiagnose malignancy based solely on the histological invasive growth patterns described in this paper.

PEComas (tumours showing perivascular epithelioid cell differentiation) are a family of related mesenchymal neoplasms that include angiomyolipoma, lymphangiomyomatosis, clear cell "sugar" tumour of the lung, and a group of rare, morphologically and immunophenotypically similar lesions arising at a variety of visceral and soft tissue sites. These tumours all share a distinctive cell type, the perivascular epithelioid cell or "PEC' (which has no known normal tissue counterpart). PEComas show a marked female predominance and are composed of nests and sheets of usually epithelioid but occasionally spindled cells with clear to granular eosinophilic cytoplasm and a focal association with blood vessel walls. PEComas appear to arise most commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, and abdominopelvic sites, with a subset occurring in somatic soft tissue and skin. Nearly all PEComas show immunoreactivity for both melanocytic (HMB-45 and/or melan-A) and smooth muscle (actin and/or desmin) markers. A subset of PEComas behave in a malignant fashion. This review examines the members of the PEComa family, with an emphasis on lesions arising outside of the kidney, lung and liver, and discusses preliminary evidence for pathological features that might predict malignant behaviour.

Aims: Angiomyolipoma is the most common mesenchymal tumour of the kidney. It has been reported in several other sites outside the kidney, mainly in the liver. We report the first case of atypical pleomorphic angiomyolipoma in a man, arising from the pouch of Douglas and extending to the entire abdominal cavity., Methods: A 17-year-old man underwent a complete resection of a giant abdominopelvic mass. The tissue was formalin fixed and paraffin embedded and 4 micro m thick histological sections were stained with haematoxylin-eosin. Immunohistochemical stains for HMB-45, smooth muscle actin, vimentin, calponin, S100 and desmin were performed. Sections for electron microscopy were also prepared., Results: Microscopic examination revealed a neoplasm composed of pleomorphic epithelioid cells with atypical features, immunoreactive for HMB-45, MART-1, actin, vimentin and calponin, while S100 protein and desmin stains were negative. Ultrastructurally, the tumour cells showed prominent nucleoli, vacuolated cytoplasm, and some premelanosomes. A diagnosis of atypical pleomorphic epithelioid angiomyolipoma was then made., Conclusions: To date five patients with abdominal epithelioid angiomyolipoma have been described in the literature. All were women. Three of the five patients reported developed metastasis, while our patient is still free of disease at 16 months of follow-up. Clear prognostic pathological features have not been identified.

Aims: Lymphangioleiomyomatosis is categorized by proliferation of abnormal smooth muscle cells (LAM cells) in the lungs and lymphatics and the presence of angiomyolipomas. Recently mutations in the tuberous sclerosis complex-2 gene (TSC-2) have been described in LAM cells and angiomyolipomas. The TSC-2 protein tuberin is a tumour suppressor and its loss may result in cellular proliferation. We used immunohistochemistry to test the hypothesis that uncontrolled cellular proliferation in lymphangioleiomyomatosis is the result of reduced tuberin protein expression., Methods and Results: Tissue from normal lung, normal kidney, lymphangioleiomyomatosis and angiomyolipomas was immunostained with three separate anti-tuberin antibodies. Tuberin staining in normal tissues was similar to that previously described. Surprisingly, tuberin was strongly expressed in the LAM cells of all cases of lymphangioleiomyomatosis and angiomyolipoma at a greater level than in normal smooth muscle cells. The perivascular cells of angiomyolipomas, however, did not stain for tuberin., Conclusions: Our results suggest that a loss of tuberin protein in LAM cells is not the cause of the cellular proliferation seen in lymphangioleiomyomatosis. Lymphangioleiomyomatosis may result either from the expression of a mutant tuberin with abnormal function, as a result of mutations in functionally related proteins, or from more than one mechanism.

Aims: Monotypic epithelioid angiomyolipoma is a distinct and definable variant of angiomyolipoma, composed of monomorphous epithelioid cells that show HMB45 immunoreactivity. Angiomyolipoma, including its morphological variants, belongs to the family of perivascular epithelioid cell tumour., Methods and Results: The tumour was examined using immunohistochemical staining and by transmission electron microscopy. Neoplastic cells showed a cytoplasmic granular positivity for HMB45., Conclusions: Extrarenal angiomyolipomas are rare and, to the best of our knowledge, this is the first reported case of a primary monotypic epithelioid angiomyolipoma of bone in a patient without evidence of tuberous sclerosis.

Aims: Five cases of angiomyolipoma (AML) composed exclusively or predominantly of smooth muscle cells (SMC) are presented to emphasize the histological diversity and to caution against errors in histological diagnosis., Methods and Results: Four tumours were located in the liver and one in the renal capsule. Three patients were female and two were male, ranging from 36 to 76 years of age with a mean age of 50 years. One patient with a renal capsular tumour was associated with tuberous sclerosis. Two tumours were composed predominantly of a spindle-shaped SMC component, whereas three others were composed predominantly of epithelioid SMC elements. AMLs composed exclusively or predominantly of spindle-shaped smooth muscle cells (SMCs) stimulated leiomyoma, whereas AMLs composed exclusively or predominantly of epithelioid SMCs resembled epithelioid leiomyoma or leiomyosarcoma or other sarcoma when cellular atypia was present. However, both spindle and epithelioid SMCs were characteristically positive for HMB-45 melanoma-specific antibody; no other tissue components in either the liver or kidney were reactive to HMB-45., Conclusions: AML is often composed predominantly of SMC elements, and morphological features of the SMC elements are quite variable. Therefore, careful attention must be given to histological assessment of AML. Whenever a pathologist encounters an unfamiliar hepatic or renal tumour, the possibility of AML should be considered. Reactivity for HMB-45, however, confirmed the diagnosis of AML.