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.     

Renal epithelioid angiomyolipoma: Histopathologic review,immunohistochemical evaluation and prognostic significance

Epithelioid angiomyolipoma (EAML) is considered to be a potentially malignant tumor and requires a differential diagnosis from renal cell carcinoma. In this study, we assessed the clinicopathologic features of renal EAML and evaluated the prognostic significance. Among 78 angiomyolipoma (AML) patients, a total of 5 EAMLs were identified, accounting for 6.4% of the total AML cases. The mean age was 41.4 years, and the average tumor size was 12.7 cm in diameter. Association of tuberous sclerosis complex was identified in two cases. One EAML case showed malignant behavior with local recurrence and distant metastasis. The malignant EAML had a larger tumor size, a higher percentage of epithelioid component and atypical epithelioid cells, ≥2 mitoses per 10 high power fields with atypical mitosis, necrosis, extrarenal extension, and carcinoma‐like growth pattern. Furthermore, the malignant case revealed p53 immunoreactivity and decreased membranous E‐cadherin expression. Pathologic evaluation of adverse prognostic factors will be helpful for risk stratification and prognosis estimation of EAML patients.     

Immunohistochemical study of hepatic angiomyolipoma

An immunohistochemical study was performed on nine hepatic angiomyolipomas (AML) found in eight patients. Histologically, the tumors were fundamentally composed of the three heterogeneous tissue components of blood vessels, smooth muscle cells (SMC), and fat cells, although the proportions and distributions were quite variable from tumor to tumor and from area to area in the same tumor. Additionally, cellular pleomorphism and atypia with occasional bizarre giant cells were found in the SMC component. This histologic feature might lead to a mistaken diagnosis of malignant neoplasm, and pathologists should therefore be aware of the broad histologic spectrum of hepatic AML. However, the immunostaining patterns were basically the same in all nine tumors. All tumor components were negative for epithelial membrane antigen (EMA) and for cytokeratin. The spindle-shaped SMC component of the tumor was occasionally positive for vimentin, desmin and alpha-smooth muscle actin, whereas epithelioid SMC were negative for all three. Both the epithelioid and spindle-shaped SMC were occasionally positive for S-100 and neuron-specific enolase. All types of SMC in the tumor, whether spindle, epithelioid, intermediate or pleomorphic SMC, were strongly positive for HMB-45, a melanoma-specific monoclonal antibody. Fat cells were occasionally positive for S-100. Endothelial cells were positive for factor VIII-associated antigen. Among hepatic tumors HMB-45 reactivity is, so far as we know, found exclusively in the SMC of AML, and the HMB-45 reactivity of a hepatic tumor is thus clearly an important piece of information in the diagnosis of AML.     

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.     

Renal epithelioid angiomyolipoma with epithelial cysts: demonstration of Melan A and HMB45 positivity in the cystic epithelial lining

Renal angiomyolipoma (AML) may present as rare variants such as epithelioid and AML with epithelial cysts posing difficulties for the diagnosis to the surgical pathologist. We report a case of a 46-year-old male patient presenting a 5-cm solid tumor in the lower pole of the left kidney, with cystic changes at cut surface. The tumor exhibited 95% of epithelioid cells with atypical nuclei. A small focus of typical AML was observed. The immunoprofile of tumor cells was classical of AML including expression of melanocytic markers such as HMB45 and Melan A. We report the immunohistochemical study of the cystic component in an epithelioid AML. In contrast to the immunoreactivity reported in typical AML, the present case shows obvious expression of melanocytic markers in the cystic epithelial lining. This is strong evidence that these cysts are neoplastic and derived from AML, rather than entrapped native collecting duct epithelium.     

Monotypic epithelioid angiomyolipoma of the adrenal gland: an unusual site for a rare extrarenal tumor

Epithelioid angiomyolipoma (AML) is an uncommon renal mesenchymal tumor with malignant potential and is frequently associated with tuberous sclerosis. Extrarenal AMLs are rare, and to the best of our knowledge, this is the first reported case of a primary monotypic epithelioid AML of adrenal gland in a patient without evidence of tuberous sclerosis. The patient is a 42-year old man who presented with retroperitoneal hemorrhage resulting from spontaneous rupture of adrenal mass. Histologically, the tumor showed a prominent component of epithelioid smooth muscle cells with slightly pleomorphic nuclei, sometimes with prominent nucleoli and eosinophilic cytoplasm resembling oncocytic tumors. Epithelioid cells were positive for melanoma (HMB45 and positive MelanA) and smooth muscle markers (α-smooth muscle–specific actin), but not for epithelial markers (cytokeratin, EMA). Differential diagnosis from renal cell carcinoma, adrenal gland carcinoma, and metastatic carcinoma is often challenging because of its epithelioid morphology. Because primary and secondary malignant tumors are much more common and aggressive neoplasms, establishing the correct diagnosis has important therapeutic and prognostic implications.     

Malignant pleomorphic adenoma (malignant mixed tumor) of the trachea. Report of a case

Malignant pleomorphic adenoma arising in the trachea has not been reported in the literature. We report here a case of malignant pleomorphic adenoma (malignant mixed tumor) occurring in the trachea of a 65-year-old woman. The tumor metastasized to the lung and the chest wall 11 years after complete resection of the primary tumor, which was a polypoid submucosal tumor, 1.3 cm in diameter. Light microscopic examination of the primary and metastatic tumors showed the presence of epithelial and stromal elements, consisting of grandular structures, foci of squamous metaplasia and a myxochondroid stroma. Many tumor cells showed myoepithelial cell features by electron microscopy, and immunoreactivity for S-100 protein and GFAP was also seen in many of them. These findings were consistent with those of pleomorphic adenoma. However, the epithelial elements were cytologically atypical with prominent mitotic figures. Infiltration of the tumor cells into the surrounding soft tissue was also seen. No foci of benign pleomorphic adenoma were found in the primary tumor. These findings indicate that this tumor was not a carcinoma ex pleomorphic adenoma, but a true malignant pleomorphic adenoma (true malignant mixed tumor) of the trachea.     

肝血管平滑肌脂肪瘤的形态学变异和免疫组织化学特征

目的探讨肝血管平滑肌脂肪瘤(AML)的临床病理学和免疫组织化学特征、诊断和鉴别诊断要点。方法对44例手术切除肝AML的临床病理学特征进行详细分析,并对10种免疫组织化学标志物的表达状况进行检测。结果肿瘤由平滑肌细胞、厚壁血管及脂肪3种成分混合组成,根据瘤组织成分的比例可分为经典型(13例)、肌细胞为主型(25例)、脂肪细胞为主型(4例)、血管瘤型(2例);肌细胞可呈多种形态变异,主要有上皮样细胞型、中间细胞型、梭形细胞型、嗜酸细胞型和多形细胞型5种;8例可见髓外造血。免疫组织化学染色显示,瘤细胞呈HMB45(44／44,100％)、SMA(38／38,100％)和CD117(30／38,78．9％)阳性。结论肝AML形态学变异较大,容易造成误诊,HMB45阳性瘤细胞具有重要的诊断意义,CD117可作为诊断AML的一个有用的辅助标记物。     

MALIGNANT PLEOMORPHIC ADENOMA (MALIGNANT MIXED TUMOR) OF THE TRACHEA. Report of a Case

Malignant pleomorphic adenoma arising in the trachea has not been reported in the literature. We report here a case of malignant pleomorphic adenoma (malignant mixed tumor) occurring in the trachea of a 65-year-old woman. The tumor metastasized to the lung and the chest wall 11 years after complete resection of the primary tumor, which was a polypoid submucosal tumor, 1.3 cm in diameter. Light microscopic examination of the primary and metastatic tumors showed the presence of epithelial and stromal elements, consisting of grandular structures, foci of squamous metaplasia and a myxochondroid stroma. Many tumor cells showed myoepithelial cell features by electron microscopy, and immunoreactivity for S-100 protein and GFAP was also seen in many of them. These findings were consistent with those of pleomorphic adenoma. However, the epithelial elements were cytologically atypical with prominent mitotic figures. Infiltration of the tumor cells into the surrounding soft tissue was also seen. No foci of benign pleomorphic adenoma were found in the primary tumor. These findings indicate that this tumor was not a carcinoma ex pleomorphic adenoma, but a true malignant pleomorphic adenoma (true malignant mixed tumor) of the trachea. ACTA PATHOL JPN 38: 1215∼1226, 1988.     

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.     

Estrogen receptor is significantly associated with the epithelioid variants of renal angiomyolipoma: a clinicopathological and immunohistochemical study of 67 cases

Perivascular epithelioid cells (PEC) in angiomyolipoma (AML) were recently proposed to be its most common progenitor cells. Histologically, triphasic components were present in various proportions, but were overwhelmingly myogenic in epithelioid variants of AML. Despite histological discrimination, the immunophenotypic profiles between triphasic and epithelioid AML have never been compared. The aim of the present study was to clarify the identity of PEC by using immunoreactivity to estrogen receptor (ER), progesterone receptor (PR), bcl-2 and placenta alkaline phosphatase (PLAP), and to use this information to compare triphasic and epithelioid AML. A total of 33 out of 67 cases of renal angiomyolipoma that underwent surgery were reviewed over the period 1998-2003. Two cases were associated with tuberous sclerosis. Ten patients had other malignant tumors, and three patients had a nodal extension. Immunohistochemistry showed that bcl-2 (59.4%), PLAP (46.9%), HMB-45 (100%) was predominantly localized around vessels. The stem cell markers were absolutely negative in all AML types. The estrogen receptors were positive in 14 cases (42.4%) and the progesterone receptors were positive in five cases. Bcl-2 and both female sex hormone receptors were significantly more frequent in the epithelioid variant of AML than in the triphasic type. Perivascular epithelioid cells express bcl-2, ER, PR and PLAP, and ER could be partly associated with myogenic proliferation.     

Hepatic epithelioid angiomyolipoma with an unusual pathologic appearance: expanding the morphologic spectrum

Hepatic epithelioid angiomyolipoma (AML) is a rare lesion that is characteristically composed of a predominant or exclusive population of epithelioid cells coexpressing melanocytic and myogenic markers. The cystic variant of epithelioid AML is exceedingly uncommon. In this study, we present the clinicopathological features of a case of hepatic epithelioid AML with remarkable cystic degeneration in a 34-year-old female as well as with a literature review. A magnetic resonance imaging scan revealed a well-defined 30 cm × 25 cm hepatic mass. Sectioning of the well-defined mass revealed a non-encapsulated tumor that was multiloculated with amorphous necrotic tissue and hemorrhagic fluid. The inner cystic wall was rough and brownish-black in color. Microscopically, the tumor largely consisted of epithelioid cells that comprised approximately 95% of the total neoplastic components but also contained some spindle myoid cells, mature fat, and a thick-walled vasculature. Both intracellular and extracellular hyaline globules were frequently identified. Necrosis and invasive growth patterns were also present. By immunohistochemistry, spindle-epithelioid neoplastic cells were variably positive for Melan-A, HMB45, and SMA but were uniformly negative for epithelial and hepatocytic markers. This is the third report of a cystic AML in liver. The patient was followed for 71 months without any evidence of metastasis or recurrence.     

Epithelioid variant of pleomorphic liposarcoma: a study of 12 cases of a distinctive variant of high-grade liposarcoma.

We describe 12 patients with a distinctive variant of pleomorphic liposarcoma that histologically shows epithelioid features and focally resembles a solid carcinoma. The tumors occurred in nine men and three women (median age, 63 yr; range, 40-78 yr). Five tumors were in the thigh, two in the chest wall, two in the axilla, and one each in the retroperitoneum, groin, and calf. Most were 15 to 20 cm in maximal diameter. They consisted of sheets of epithelioid-appearing cells with ample, variably eosinophilic cytoplasm, often showing a honeycomb-like pattern of cell borders and little if any collagenous extracellular matrix. Their histologic features often resembled those of renal clear cell carcinoma or adrenal cortical carcinoma, but all showed evidence of adipocytic differentiation, and five also showed focal spindle cell components. One patient whose tumor in the thigh had been originally diagnosed as metastatic renal carcinoma had undergone nephrectomy without a finding of a kidney tumor. All of the cases were positive for vimentin; 6 of 11 cases were positive for S-100 protein, usually focally; 5 of 11 were focally positive for keratins; and all were negative for epithelial membrane antigen, muscle actins, desmin, and CD34. High mitotic activity (mean, 42 mitotic figures per 10 high power fields) and high MIB-1-positive proliferative fraction (>30%) were seen in all of the cases, and nuclear p53 immunoreactivity was detected in five of seven cases. Of the eight patients with complete follow-up, five died of disease (median survival, 6 mo), two died of unrelated causes 10 and 18 years later, and 1 was alive and well 24 years later. The epithelioid variant of pleomorphic liposarcoma is a high-grade tumor that must be distinguished from malignant epithelial tumors, especially in view of the keratin immunoreactivity of some of these neoplasms.     

Localized malignant mesothelioma of the epithelial type occurring as a primary hepatic neoplasm: a case report with review of the literature

We report a localized malignant mesothelioma of the epithelial type, occurring as a primary hepatic neoplasm in a 64-year-old male. He was found to have a mass located in the right lobe of the liver. Surgery was carried out with resection of the mass from the right hepatic lobe, with partial resection of the diaphragm. Grossly, an ill-defined tumor was present in the hepatic parenchyma. Histologically, the tumor displayed a predominant tubular pattern of growth with a desmoplastic stroma. The tubules were lined by a single layer of cuboidal or flattened cells with pleomorphic vesicular nuclei. A hyaluronidase-digestible, mucin-like substance was demonstrated in the lumen and tumor cytoplasm. The tumor cells were immunohistochemically positive for calretinin, HBME-1, cytokeratin, i.e. AE1/AE3 and CAM 5.2, but negative for carcinoembryonic antigen, CD 34 and Leu M1. Moreover, the tumor cells showed nuclear accumulation of the p53 oncopotein and reacted frequently with Ki-67 antibody. These findings support the concept that malignant mesothelioma of the epithelial type may occur at extrapleural sites. To the best of our knowledge, this is the first reported case of localized malignant primary mesothelioma arising in the liver.     

Epithelioid angiomyolipoma of kidney with atypical nuclear features and intranuclear inclusions on cytology

Described herein are the cytological findings of epithelioid angiomyolipoma (EAML) of the kidney with atypical nuclear features mistaken for renal cell carcinoma (RCC) in a 61‐year‐old male patient. Aspirates from this large renal mass were cellular and showed epithelioid cell clusters with focally crowded nuclei showing moderate anisonucleosis, small nucleoli, and prominent eosinophilic intranuclear inclusions. Failure to recognize the scanty adipose tissue component and preponderance of epithelioid cells with nuclear pleomorphism lead to a diagnosis of RCC on cytology. On histology, the tumor was essentially composed of epithelioid and spindle cells that showed the typical immunoprofile of an angiomyolipoma and only occasional foci of typical AML were seen. The hilar lymph node was involved in contiguity. However, in view of lack of obvious features of malignancy, the tumor was labeled as EAML with atypical features. Immunocytochemistry on the destained cytology aspirates revealed strong smooth muscle actin staining of all cells. To conclude, EAML can mimic a RCC. In such instances, lack of arborizing vasculature, absence of cytoplasmic fatty vacoulation, crowded nuclei with intranuclear inclusions, and lack of prominent nucleoli along with typical immunophenotype of EAML may assist in the cytology diagnosis. Diagn. Cytopathol. 2011;39:278–282. © 2010 Wiley‐Liss, Inc.     

Malignant hepatic epithelioid hemangioendothelioma with abdominal pain due to rapid progression

Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor. We report on a patient who underwent hepatectomy for malignant HEH associated with abdominal pain due to rapid progression. An 83-year-old man was admitted to Nippon Medical School Hospital because of acute, severe upper abdominal pain. Seven months before admission, a hepatic tumor, 3 cm in diameter, had been detected in the left lateral sector. The diagnosis was hepatic cavernous hemangioma. Abdominal ultrasonography revealed a heterogeneous hyperechoic tumor with a smooth border, 6 cm in diameter, in the left lateral sector (segment 3). Contrast-enhanced computed tomography of the abdomen showed that the tumor was enhanced from the early to the late phase. Abdominal angiography revealed a cotton wool-like appearance of the tumor. The diagnosis was hepatic cavernous hemangioma. A malignancy could not be ruled out because of the tumor's rapid growth, which had caused abdominal pain. Left hepatectomy was performed. Histopathological examination showed necrosis throughout the tumor. Slightly pleomorphic neoplastic cells with rounded, spindle-like nuclei and scant cytoplasm were sporadically found in vascular channels. Intracytoplasmic lumina occasionally contained red cells. Neoplastic cells were positive for factor VIII-related antigen, CD31, and CD34. The Mib-1 index was high. The tumor was diagnosed as malignant HEH. The postsurgical course was uneventful, and the patient was discharged on postoperative day 11. After 3 months, multiple metastatic tumors appeared in right hepatic lobe. Transcatheter arterial chemoembolization was performed.     

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.     

Biomarker analysis in carcinoma ex pleomorphic adenoma at an early phase of carcinomatous transformation

Diagnostic criteria for intracapsular carcinoma ex pleomorphic adenoma (CXPA) are subjective and vary among authors. Biomarker analysis, which could provide more objective evaluation of these tumors, has rarely been studied in intracapsular CXPA. Immunohistochemical evaluation of c-erbB-2, p53 protein, bcl-2, and Ki-67 was performed in 8 cases of CXPA at an early phase of malignant transformation (4 intracapsular and 4 minimally invasive) and in 17 pleomorphic adenomas (PA). In all cases of CXPA, p53 and Ki-67 were demonstrated predominantly in luminal cells of benign and malignant areas, significantly more in the latter. Few benign myoepithelial cells were p53 positive. c-erbB-2 reactivity was strongly associated with atypical luminal cells. Bcl-2 expression was weak and focal in malignant areas from 2 cases. In conclusion, both p53 and c-erbB-2 proteins appear to be involved at an early stage of malignization of PA. In PA with atypical cells, evaluation of the expression of these 2 markers provides more objective criteria for the diagnosis of intracapsular CXPA.     

Malignant peripheral nerve sheath tumor arising in benign ancient schwannoma: a case report with an immunohistochemical study

A rare example of malignant transformation in an ancient schwannoma arising in the right side of the neck of a 51-year-old man without any clinical manifestations suggesting neurofibromatosis is described. The tumor, approximately 4 cm at its largest dimension, was well circumscribed and had a direct connection with the sympathetic nerve. Microscopically, the central portion of the tumor showed features of ancient schwannoma characterized by extensive hyalinization with cystic degeneration, scattered spindle cells with hyperchromatic and tapered nuclei, and some symplastic changes. However, predominantly in the outer portion, a proliferation of spindle-shaped cells with enlarged nuclei was present. The nuclei of these cells showed irregular contours, coarse granular chromatin texture, and conspicuous nucleoli. Mitotic figures and small necrotic foci with scattered apoptotic bodies were also seen. Immunohistochemically, S-100 protein was almost negative in areas consisting of overtly atypical cells where the mitotic index evaluated with MIB-1 antibody was 30.5%. In contrast, S-100-positive bland spindle cells were scattered in an extensively hyalinized area with a labeling index less than 3%. P53 protein was strongly positive in atypical spindle cells. Although it is a very uncommon event, definite nuclear atypia, frequent mitotic figures, and the existence of small necrotic foci should be recognized as indicating a diagnosis of malignant degeneration of benign schwannoma. Immunohistochemistry would be useful as an ancillary technique in such a setting.