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

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Abstract

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.

Introduction

Epithelioid angiomyolipoma (AML) is a subtype of AML in which epithelioid cells are mainly involved, while in the classic type of AML, matured adipose tissue smooth muscle-like cells and thick-walled blood vessels are involved. More than half of the patients with epithelioid AML present with stigmata of tuberous sclerosis [3].

Epithelioid AML frequently presents with necrosis, hemorrhage, nuclear atypia, and mitotic activity, and is thought to be a potentially malignant tumor. However, there are no histological criteria for malignant epithelioid AML, and only distant metastases are accepted as a definite sign of malignancy [15]. In classic AML, involvement of lymph nodes [5] or the spleen [12] has been reported, and it is considered multicentric because it follows a more benign course [1].

The p53 gene is the most significant tumor-suppressor gene, and loss of function of the p53 protein because of a mutation in the gene is associated with malignant progression of various tumors [14]. Although a case of renal epithelioid AML with a p53 missense mutation has been reported [13], the pathogenesis and mechanisms of the malignant transformation of AML remain unclear. To the best of our knowledge, only 20 cases of renal epithelioid AML with distant metastases have been reported in English language [2], [4], [7], [8], [10], [11], [15], [16], [19], [21], [22], [23], [24], [27], [29], [30]. In the current study, we performed mutation analysis of exons 5–8 of the p53 gene of malignant (metastatic) epithelioid AML in a patient with tuberous sclerosis.

A 36-year-old man presented with marked abdominal fullness. He had been diagnosed to have tuberous sclerosis at the age of 6 after presenting with mental retardation and epilepsy. Bilateral renal tumors were detected at the age of 16, and after imaging studies the patient was diagnosed to have AML. Angiofibroma on the face and subungal fibroma of the toes were also present. A brain tumor was excised at the age of 26 with a pathological diagnosis of subependymal giant cell astrocytoma. At the age of 34, he underwent a left nephrectomy for angiomyolipoma with repeated intratumoral hemorrhage. The surgically resected left kidney weighed 3900 g and contained a 20 cm tumor with classic AML. A hemorrhagic epithelioid AML component accounted for approximately 20% of the entire tumor, and epithelioid AML cells infiltrated the renal arterial wall of the resected kidney. Repeated blood transfusions were needed after 1 year to treat intractable hypochromatic microcytic anemia. Abdominal CT scans demonstrated a rapidly growing tumor of the right kidney compressing the surrounding organs, along with splenomegaly. Right nephrectomy and maintenance hemodialysis were scheduled, but the patient suddenly died of cardiac arrest, and an autopsy was performed 1.5 h after death.

Section snippets

Materials and methods

Autopsy specimens were fixed in 10% neutral-buffered formalin, cut into 5 mm thick tissue blocks, and embedded in paraffin. Sections of 4 μm thickness were cut for hematoxylin and eosin staining and for immunohistochemical examination. Immunohistochemical studies were performed on deparaffinized sections using an automated immunostainer (Ventana Medical System, Tucson, AZ, USA). Primary antibodies used were anti-melanosome (HMB-45, Dako, Glostrup, Denmark, 1/75), Melan-A (A103, Dako, 1/50),

Results

At autopsy, the right kidney, containing the tumor in the upper pole, weighed 7120 g and measured 28×20×17 cm3. Macroscopically, the tumor had grown within the renal capsule, but infiltrated into the renal parenchyma, the right renal vein, and the inferior vena cava, resulting in tumor thrombus (Fig. 1A). The cut surface demonstrated a yellow–brown solid tumor with massive central necrosis, but no evidence of hemorrhage (Fig. 1B). Renal parenchyma was identified in the lower pole (Fig. 1C). The

Discussion

Epithelioid AML is considered to be a potentially malignant neoplasm because approximately one-third of cases have been reported to develop metastatic lesions [8]. To the best of our knowledge, there are 20 cases of epithelioid AML reported as presenting with distant metastases [2], [4], [7], [8], [10], [11], [15], [16], [19], [21], [22], [23], [24], [27], [29], [30]. The clinicopathological features of these cases are summarized in Table 1. Ages at diagnosis ranged from 21 to 78 years (median

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