Malignant angiomyolipoma of the liver: a hitherto unreported variant

AIMS: After their original recognition in the kidney, angiomyolipomas (AMLs) have been reported in the liver for more than 20 years. In the kidney, five cases of malignant AML have been reported. We report the first case of malignant hepatic AML. METHODS AND RESULTS: A 70-year-old female patient presented with abdominal discomfort. Clinical examination revealed a palpable liver. CT scan showed a polymorphous hypervascular lesion in the right liver lobe. A biopsy was taken and resulted initially in a differential diagnosis between a hepatocellular carcinoma, a metastatic tumour (possibly of renal origin) and angiomyolipoma (AML). After immunohistochemistry, a hepatic AML was suggested, given the immunoreactivity for HMB45/NKIC-3. The mass was resected 5 years later because of relapsing abscess formation. Gross examination of the resection specimen showed a focally encapsulated brown mass with focal necrosis. Microscopic examination showed a tumour growing in sheets, separated by sinusoidal-like vessels. Most of the tumour cells had a large, polygonal, clear cytoplasm, often with eosinophilic condensation around the nucleus. There was prominent vascular invasion. Immunohistochemistry (reactivity for HMB-45, NKIC-3, S100 and alpha smooth muscle actin, negativity for cytokeratin and vimentin) and electron microscopy confirmed the diagnosis of monomorphic epithelioid AML with prominent vascular invasion. Seven months after tumour resection, the patient died of recurrent disease. CONCLUSIONS: This case highlights the importance of immunohistochemistry and electron microscopy in diagnosing this type of tumour. Possibly, in the past, malignant AML of the liver has been misdiagnosed as HCC.     

Angiomyolipoma mimicking true lipoma of the liver: report of two cases

Hepatic angiomyolipoma (AML) is very rare and only about 80 cases have been reported. The tumor is fundamentally heterogeneously composed of the three tissue components of blood vessels, smooth muscle cells (SMC), and fat cells. Two cases of hepatic AML are reported here, both of which are histologically composed predominantly of a fat cell element and resembled true lipoma (lipomatous AML). However, careful examination of both tumors revealed the presence of a small amount of epithelioid SMC, especially around blood vessels. Immunohistochemical study using monoclonal antibody for melanoma (HMB-45) clearly revealed a small amount of HMB-45-positive SMC around the blood vessels and scattered in the diffuse fat cell growth in both tumors. Since no liver tissue components or primary liver tumors are reactive with HMB-45 except AML cells, the presence of HMB-45-positive cells within the tumor clearly established the diagnosis of hepatic AML. Any fatty tumor or focal fatty lesion of the liver that superficially resemble true lipomas should be tested for the presence of HMB-45-positive SMC in the tumor to differentiate it from AML.     

Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2

Tuberous sclerosis (TSC) is a rare, genetically determined disorder / familial tumor syndrome, currently diagnosed using specific clinical criteria proposed by Gomez, including the presence of multiorgan hamartomas. Pulmonary involvement in TSC is well known as pulmonary lymphangioleiomyomatosis (LAM), which has an incidence of 1-2.3% in TSC patients. LAM has immunohistochemical expression of both smooth-muscle actin and a monoclonal antibody specific for human melanoma, HMB-45. It has recently been reported that multifocal micronodular pneumocyte hyperplasia (MMPH) associated with TSC should be considered as a distinct type of lung lesion, whether it occurs with or without LAM. Two predisposing genes have been found in families affected by TSC; approximately half of the families show linkage to TSC1 at 9q34.3, and the other half show linkage to TSC2 at 16p13.3. TSC genes are considered to be tumor suppressor genes, and mutations in them may lead to abnormal differentiation and proliferation of cells. Tuberin, the TSC2 gene product, has recently been found to be expressed in LAM and MMPH. In this article we discuss the histogenesis and genetic abnormalities of neoplastic lesions associated with TSC, and we review the current understanding of the pathogenesis of pulmonary hamartomatous lesions such as LAM and MMPH in TSC.     

Melanocyte-marker-HMB-45 is regularly expressed in angiomyolipoma of the kidney.

HMB-45 (melanocytic cell-specific monoclonal antibody) immunoreactivity was investigated in 10 cases of angiomyolipoma (AML) (1 with massive regional lymph node involvement) of the kidney and detected in all of them. No HMB-45 immunoreactivity was found in other tumors of the region which can occasionally be confused with AML, such as renal cell carcinoma, Wilms' tumor, and retroperitoneal sarcoma (leiomyosarcoma and liposarcoma). These findings indicate that HMB-45 is not a melanocyte-restricted marker and suggest that its expression might be useful in distinguishing AML from other tumors of the kidney and retroperitoneum.     

Monotypic epithelioid angiomyolipoma of the liver

AIMS: Monotypic epithelioid angiomyolipoma is a recently recognized renal tumour, which is composed purely of epithelioid cells coexpressing markers of both smooth muscle differentiation and melanogenesis (HMB45). We report here the first case of monotypic epithelioid angiomyolipoma arising in the liver. CASE DETAILS: A 30-year-old woman without tuberous sclerosis complex (TSC) was incidentally found to have a hepatic mass by ultrasonography. Grossly, the resected tumour showed a nodule-in-nodule appearance, with large areas of haemorrhagic necrosis. Microscopically, the tumour was composed of pleomorphic epithelioid cells with clear, eosinophilic cytoplasm. Neither adipocytes nor abnormal vessels were recognized in the tumour. Immunohistochemically, the tumour cells were strongly positive for HMB45 and S100 protein, focally positive for desmin, vimentin and smooth muscle actin, and negative for epithelial markers (cytokeratins, EMA). Ultrastructural analysis showed numerous dense granules with some striated ones resembling melanosomes, myofilaments and pinocytic vesicles in the cytoplasm. Molecular analysis showed no allelic loss of the TSC2 region or 12 other chromosomal regions. The patient is free of disease over 1 year after the operation. CONCLUSION: We consider that this hepatic tumour is closely related to angiomyolipoma, and a counterpart of renal monotypic epithelioid angiomyolipoma.     

Leiomyomatosis-like lymphangioleiomyomatosis of the colon in a female with tuberous sclerosis.

Smooth muscle lesions of the large bowel, excluding the rectum, are generally rare, and diffuse smooth muscle lesions, termed leiomyomatosis, are even rarer. In this report, we document, for the first time, leiomyomatosis-like lymphangioleiomyomatosis (LAM) of the ascending, transverse, and descending colon in association with bilateral renal angiomyolipoma (AML) in a 30-year-old Chinese female with tuberous sclerosis complex (TSC). She presented with protracted constipation for which a colectomy was performed. Histology disclosed multiple confluent nodular CD34 and CD117 negative smooth muscle proliferation within the large bowel wall, whereas the renal biopsy revealed typical features of AML. Interestingly, the epithelioid smooth muscle cells of both the colonic and renal lesions were HMB45 positive, suggesting that leiomyomatosis-like LAM of the colon, pulmonary LAM and AML are closely related entities. The patient remained free of complications for the last five years after surgery. Leiomyomatosis-like LAM of the large bowel probably represents another manifestation of the tendency of TSC to be associated with proliferative lesions.     

Atypical angiomyolipoma of kidney in a patient with tuberous sclerosis: a case report with p53 gene mutation analysis

Angiomyolipoma (AML) is the most common benign mesenchymal tumor of the kidney. It belongs to the family of perivascular epithelioid cell tumors and is typically composed of blood vessels, adipose tissue, and smooth muscle- like cells, which are characteristically positive for HMB-45. Results of recent studies suggest that p53 mutation may play an important role in AML progression. Here, we describe a locally destructive renal AML in a patient with tuberous sclerosis. The tumor consisted of mostly epithelioid cells with marked nuclear pleomorphism and frequent mitoses and was positive for HMB-45. The diagnosis of atypical epithelioid AML was made. Codon alteration in the p53 gene was not detected, despite focal p53 immunoreactivity and single nucleotide polymorphism at exon 6. Our finding indicates no definite link between p53 abnormalities and the atypical appearance of AML. To the best of our knowledge, this is the second renal AML case investigated for p53 mutations.     

PEComa: what do we know so far?

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.     

Multiple giant angiomyolipomas with a polygonal epithelioid cell component in tuberous sclerosis: An autopsy case report

A recent case of angiomyolipoma (AML) with a prominent Component of polygonal epithelioid cells is described. A 27-yearoid Japanese male with tuberous sclerosis presented with massive abdominal tumors increasing progressively in size. The patient died of respiratory disturbance and the autopsy revealed massive tumors in the bilateral kidneys, liver and lymph nodes, subependymal giant cell glioma of the brain and lymphangiomyomatosis of the lungs. The giant tumors were an unusual type of AML with a component of polygonal epithelioid cells, which showed a hepatocel-lular carcinoma-like pattern in some areas. Smooth muscle components comprising spindle cells, short or plump spindle cells and polygonal epithelioid cells frequently exhibited positive staining for HMB-45 but negative staining for epithelial cell markers. The unusual AML presented in this case was thought to be of low-grade malignancy and slow growing. it has been suggested that angiomyollpomas with diffuse areas of epithelioid cell component are potentially malignant. Immunostalnings positive for HMB-45 but negative for epithelial cell markers are considered to be useful in differentiating AML with polygonal epithelioid cell component from other tumors, especially from renal cell carcinoma and hepatocellular carcinoma.     

Pulmonary angiomyolipoma and multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis.

A 36-year-old woman with a long-standing diagnosis of tuberous sclerosis was found dead. A yellow-tan 0.4 cm-diameter pulmonary tumor was identified at autopsy which had typical microscopic features of an angiomyolipoma (AML). Immunohistochemical stains showed reactivity for actin, but not HMB-45, Melan-A, and tyrosinase (despite reactivity of the patient's renal AML for HMB-45 and Melan-A), perhaps owing to the small size of the lesion and the sometimes focal nature of the reactivity for these markers. Additional lung nodules proved to be multifocal micronodular pneumocyte hyperplasia. This report highlights the first occurrence of a pulmonary angiomyolipoma in the setting of tuberous sclerosis.     

Malignant epithelioid angiomyolipoma of the kidney in a patient with tuberous sclerosis: an autopsy case report with p53 gene mutation analysis

We report an autopsy case of malignant epithelioid angiomyolipoma in a 36-year-old male tuberous sclerosis patient. He had been diagnosed to have a bilateral renal tumor 20 years previously. The left kidney had been surgically resected at the age of 34, and the left renal tumor was pathologically diagnosed as classic angiomyolipoma and epithelioid angiomyolipoma. He suddenly died of cardiac arrest, and at autopsy the right kidney weighed 7120 g. The tumor presented with massive necrosis invading the inferior vena cava, but was not hemorrhagic. Microscopic examination revealed tumor cells varying in size with a predominantly solid proliferation pattern and marked atypical large cells with vesicular nuclei and abundant eosinophilic cytoplasm. Mitotic figures were often encountered, and atypical forms were also present. Metastatic lesions were identified in the right lung, liver, diaphragm, and mesentery. Immunohistochemical examination showed epithelioid angiomyolipoma cells that were focally reactive for HMB-45 and showed diffuse positive staining for Melan-A. No mutation was detected in the p53 gene by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis despite diffuse immunoreactivity for p53. This case was proven to be malignant because of the occurrence of distant metastases, and showed that p53 mutations are not always associated with malignant transformation in epithelioid angiomyolipoma.     

Angiomyolipoma of the liver and lung: a case explained by the presence of perivascular epithelioid cells

We report a case of synchronous hepatic and pulmonary angiomyolipoma not associated with tuberous sclerosis or renal angiomyolipoma. The liver tumor contained tortuous vessels, smooth muscle tissue, and fat. It was partially necrotic and made up of pleomorphic epithelioid smooth muscle cells. Positivity for HMB-45 confirmed the diagnosis of angiomyolipoma. Lung biopsy showed multiple abnormal proliferation of smooth muscle cells exhibiting spindle-shaped or epithelioid morphology. The tumor grew around the vessels, and the cells were positive for HMB-45. The occurrence of this case could be explained by a simultaneous proliferation of perivascular epithelioid cells. To the best of our knowledge, this is the first case of hepatic angiomyolipoma associated with multiple pulmonary angiomyolipomas, mimicking hepatic tumor lung metastases on X-ray examination.     

Expression of gp100, MART-1, tyrosinase, and S100 in paraffin-embedded primary melanomas and locoregional, lymph node, and visceral metastases: implications for diagnosis and immunotherapy. A study conducted by the EORTC Melanoma Cooperative Group

With the recent availability of novel antibodies against melanoma antigens tyrosinase and MART-1, it is important to validate their usefulness in pathology practice and in screening patients for immunotherapy treatment. In the present study conducted by the Melanoma Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC-MCG), immunohistochemical staining for gp100 (antibodies NKI-beteb and HMB-45), MART-1 (A103), tyrosinase (T311), and S100 (S100) was compared on formalin-fixed and paraffin-embedded tumour lesions from 80 patients with 130 malignant melanoma lesions, comprising 44 primary tumours, 18 locoregional metastases, 41 lymph node metastases, and 27 visceral metastases from the lung, liver, and brain. A score between 0 and 5 was allocated to each immunohistochemically stained section. These scores were evaluated in a statistical analysis. S100 was by far the most sensitive marker in all four types of lesions tested. Apart from a significantly better performance for T311 in primary melanomas compared with HMB-45, no significant differences were observed between the four remaining antigens tested. Three settings were next investigated to determine whether the expression of melanoma antigens decreases with tumour progression. First, within the primary melanomas, only NKI-beteb and A103 staining showed a nearly significant negative correlation with Clark's level of invasion and a similar tendency was observed for these antibodies with Breslow thickness. Second, when comparing primary melanoma-metastasis pairs from the same patient, lymph node metastases showed less staining with NKI-beteb, HMB-45, A103, and T311, at a level near significance. This difference was not significant when comparing the primary tumour with visceral metastases, probably due to the lower numbers of pairs. Third, regarding tumour progression from primary melanoma to locoregional, to lymph node, to visceral metastasis, a significant decrease with progression was found only for T311. The apparently stable expression of most of the melanoma antigens, and the small contribution of decreased expression in melanoma tumour progression, supports the rationale for immunotherapy based on the melanoma immunogens gp100, MART-1, and tyrosinase.     

Angiomyolipoma with epithelial cysts of the kidney in a man

Angiomyolipoma (AML) is a well-characterized tumor composed of vascular, smooth muscle and adipose elements. Recently, AML with epithelial cysts (AMLEC) has been described as a cystic variant of AML. Herein is reported an AMLEC in a 55-year-old man, and to the authors' knowledge this is the first case report of AMLEC in Japan. He was referred to hospital because of microhematuria. A left renal tumor was noted and partial nephrectomy was performed. Histology indicated that the tumor was composed of epithelial cysts, compact subepithelial stroma and muscle-predominant AML. Immunohistochemically, the subepithelial compact stroma and muscle-predominant AML were positive for HMB-45, estrogen receptor (ER), progesterone receptor (PR), CD10, smooth-muscle actin and desmin. Epithelial cysts were positive for pancytokeratin but negative for HMB-45, ER and PR. This tumor was diagnosed as AMLEC, mainly based on the immunohistochemical result that subepithelial compact stroma and muscle-predominant AML were positive for HMB-45. The patient was alive with no evidence of recurrence at 2 years postoperatively. This case was very interesting because it suggests that AMLEC should enter into the differential diagnosis of adult renal neoplasms.     

Clear-cell proliferation of the lung with lymphangioleiomyomatosis-like change

AIMS: To describe two cases of a peculiar pulmonary lesion, which expand both the morphological and the immunophenotypic spectrum of perivascular epithelioid cell (PEC)-related disorders. METHODS AND RESULTS: One man and one female, with and without the tuberous sclerosis complex (TSC), respectively, showed pulmonary cysts and small nodules on computed tomography scan. In the former, lymphangioleiomyomatosis (LAM) was suspected. In both cases, an open lung biopsy was performed, whose cut surface displayed numerous cysts lined by thin/thick septa. Microscopically, the septa were associated with micronodular or interstitial proliferation of medium/large-sized elements with abundant clear (periodic acid-Schiff-positive/diastase-sensitive) cytoplasm and distinct cell borders, embedded in fibrous tissue. The elements were CD34+, vimentin-positive and, to a lesser extent, HMB-45+ and MART-1+. The stains for specific muscle actin, desmin, S100 protein, CD31, FVIIIRAg, cytokeratins, CD45, CD68, oestrogen and progesterone receptors were all negative. Ki67 labelling was <1%. Electron microscopy displayed cytoplasmic vacuoles containing glycogen particles. The TSC1 and TSC2 gene status could not be assessed because of poor DNA preservation. In the man with TSC, a focus of micronodular pneumocyte hyperplasia was also found. CONCLUSIONS: Because of the coexpression of CD34 and melanoma-associated antigens and the occurrence of TSC in one patient, the cases described here add a new piece to the puzzle of PEC lesions and contribute to the open discussion on the origin of LAM and LAM-like proliferations.     

Multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis with a TSC2 gene.

A 45-year-old woman with a long-standing diagnosis of tuberous sclerosis (TSC) is presented. She has multifocal micronodular pneumocyte hyperplasia (MMPH) and lymphangioleiomyomatosis (LAM) of the lung, together with the detection of TSC2 gene mutation. During surgery for spontaneous pneumothorax, an open-lung biopsy was performed. Micronodules were well defined, measuring approximately 4 mm in diameter. These MMPHs were histologically composed of papillary proliferation of Type II pneumocytes, with positive immunoreactivity of keratin and surfactant apoprotein. The cystlike spaces, with dilatation and destruction of air spaces, were diffusely formed, and the walls were composed of the spindle cells. Such LAM showed positive immunoreactivity for HMB-45 (a monoclonal antibody specific for human melanoma) and tuberin (the gene product of TSC2). On germline mutation analysis using leukocytes of the present patient, a TSC2 gene mutation was confirmed as a deletion of G (or g) on Exon 9 by polymerase chain reaction-single-strand conformational polymorphism. However, no mutation was detected in her son. With microdissection analysis using paraffin-embedding lung tissues, LOH of the TSC2 gene preliminarily was detected in a LAM lesion but not in MMPH. It is suggested that MMPH, in addition to LAM, could be another pulmonary lesion in TSC patients and that the detection of TSC2 and/or TSC1 gene could essentially be useful for the pathogenesis of MMPH and LAM in TSC patients.     

Atypical pleomorphic epithelioid angiomyolipoma localized to the pelvis: a case report and review of the literature

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.     

Clinicopathologic features of renal epithelioid angiomyolipoma: report of one case and review of literatures

Epithelioid angiomyolipoma (EAML) is a rare renal mesenchymal tumor with malignant potential and is frequently associated with tuberous sclerosis complex (TSC). As metastasis of the tumor cells occur early, EAML is considered a potentially malignant tumor type and intrigues further research on it. Under the microscope, we could find the tumor was composed of atypical polygonal cells sheet mixed with classic angiomyolipoma (AML) components such as blood vessels with notable thick vascular walls, smooth muscle-like cells and adipocytes. Immunohistochemical studies showed that epithelioid cells were focally positive for vimentin, melanocytic markers (HMB-45), myoid markers (α-smooth muscle actin), CD34 and CD68; negative for cytokeratin, epithelial membrane antigen, CD10, and S-100. And the Ki67 index showed approximately 3%. Here, we report the morphological and immunohistochemical features of clinically or histologically malignant renal EAML and discuss its diagnosis, differential diagnosis and the prognosis.     

Combination of pulmonary lymphangioleiomyomatosis (LAM) with angiomyolipoma (AML) of the kidney and multilocular cystic nephroma

A rare case of pulmonary LAM in combination with AML and multilocular cystic nephroma of the kidney in a 18-year-old female is described. Granules of the melanosomic type in AML, HMB-45 antigen and steroid receptors expression in LAM and AML were observed.