Malignant Glioma Arising at the Site of an Excised Cerebellar Hemangioblastoma after Irradiation in a von Hippel-Lindau Disease Patient

We describe herein a malignant glioma arising at the site of the resected hemangioblastoma after irradiation in a patient with von Hippel-Lindau disease (VHL). The patient was a 25 year-old male with multiple hemangioblastomas at the cerebellum and spinal cord, multiple pancreatic cysts and a renal cell carcinoma; he was diagnosed as having VHL disease. The largest hemangioblastoma at the right cerebellar hemisphere was completely removed, and he received high-dose irradiation postoperatively. The tumor recurred at the same site 7 years later, which was a malignant glioma with no evidence of hemangioblastoma. The malignant glioma showed molecular genetic profiles of radiation-induced tumors because of its diffuse p53 immunostaining and the loss of p16 immunoreactivity. The genetic study to find the loss of heterozygosity (LOH) of VHL gene revealed that only the cerebellar hemangioblastoma showed allelic losses for the gene. To the best of our knowledge, this report is the first to show a malignant glioma that developed in a patient with VHL disease after radiation therapy at the site of an excised hemangioblastoma. This report also suggests that radiation therapy should be performed very carefully in VHL patients with hemangioblastomas.     

Renal angiomyoadenomatous tumor: morphologic, immunohistochemical, and molecular genetic study of a distinct entity

We present a series of a distinct tumorous entity named renal angiomyoadenomatous tumor (RAT). Five cases were retrieved from the consultation files of the authors. Histologic and immunohistochemical features were evaluated. Sequencing analysis of coding region of the VHL gene was carried out in all cases. The tumors were composed of admixture of an epithelial clear cell component and prominent leiomyomatous stroma. Epithelial cells formed adenomatous tubular formations endowed with blister-like apical snouts. All tubular/glandular structures were lined by a fine capillary network. The epithelial component was positive for epithelial membrane antigen, CK7, CK20, AE1-AE3, CAM5.2, and vimentin in all cases. In all analyzed samples, no mutation of the VHL gene was found. RAT is a distinct morphologic entity, being different morphologically, immunohistochemically, and genetically from all renal tumors including conventional clear cell carcinoma and mixed epithelial and stromal tumor of kidney.     

Inverse regulation of vascular endothelial growth factor and VHL tumor suppressor gene in sporadic renal cell carcinomas is correlated with vascular growth: an in vivo study on 29 tumors

Tumors associated with the VHL (von Hippel-Lindau) disease, such as hemangioblastomas and renal carcinomas and their sporadic counterparts, are cystic and well vascularized. Mutations of the VHL tumor-suppressor gene and elevated levels of vascular endothelial growth factor (VEGF) have been described in these tumors. The upregulation of VEGF has been shown in vitro as a consequence of alteration of the VHL gene. No comprehensive in vivo analysis has yet been carried out of the factors affecting tumor growth, vascularization, VEGF, and VHL expression. We performed immunohistochemistry and mRNA studies on primary sporadic renal carcinomas and matching normal renal tissue. We semiquantitatively analyzed 29 renal carcinomas (22 clear cell, 5 chromophilic, 2 chromophobic tumors) for VHL mRNA, and VEGF expression for morphology and tumor size. Immunohistochemistry was carried out for VEGF protein expression, vascularization, and macrophage infiltration. Vascularization of the chromophilic renal carcinomas was lower than that of the clear cell type of renal carcinoma. Low VEGF protein expression was seen in four of the five chromophilic renal carcinomas. We found two groups of clear cell renal cell carcinoma: one with reduced VHL mRNA and increased VEGF mRNA, and the other without significantly altered VHL or VEGF mRNAs. Tumor vascularization was correlated with VEGF protein and seemed to be independent of macrophage infiltration. Our in vivo findings support the inverse relationship between the regulation of VHL and that of VEGF. Our data also indicate that there may be an VHL-independent pathway for the induction of tumor vascularization.     

Tumor-to-tumor metastasis to follicular variant of papillary carcinoma of thyroid.

OBJECTIVE: To describe and document tumor-to-tumor metastases in the thyroid gland. METHODS AND RESULTS: In this series we describe 3 cases of tumor-to-tumor metastasis in which the recipient tumor was a follicular variant of papillary thyroid carcinoma. The donor tumors and sites were small cell carcinoma of the lung, neuroendocrine carcinoma probably of pancreatic origin with initial presentation as liver metastasis, and clear cell carcinoma of the kidney with metastasis to liver and pancreas. The donor tumor cells infiltrated the substance of the follicular variant of papillary thyroid carcinoma, the nontumorous thyroid parenchyma, and the lymphovascular spaces. Small cell carcinoma and neuroendocrine carcinoma showed positive reactivity for neuroendocrine markers and were negative for thyroglobulin and calcitonin. The follicular variant of papillary thyroid carcinoma showed positivity with thyroglobulin and cytokeratin 19. CONCLUSIONS: Although tumor-to-tumor metastases in thyroid gland are exceedingly rare, one should be aware of this phenomenon as the metastatic lesion may simulate a thyroid primary. History of a previous tumor and immunohistochemical stains can be helpful in distinguishing between primary and metastatic thyroid neoplasms.     

Molecular analysis as a tool in the differential diagnosis of VHL disease-related tumors.

Von Hippel-Lindau (VHL) disease is an autosomal dominant tumor syndrome, in which hemangioblastomas (HBs), clear cell renal cell carcinomas (RCCs), and pheochromocytomas are the most frequently encountered tumors. The differential diagnosis of dedifferentiated tumors in general can be difficult, as standard histologic and immunohistochemical investigations do not always allow a definitive diagnosis. We used molecular genetic analysis to resolve the differential diagnosis of sarcomatoid RCC versus pheochromocytoma of a (peri)renal tumor in a VHL patient. Germline mutation analysis identified the C407T mutation, which has been related to a VHL phenotype in which pheochromocytomas are rare. Chromosomal imbalances detected in the tumor by CGH showed a pattern typical for RCCs and not for pheochromocytomas. CGH analysis of the multiple tumors of this VHL patient revealed a comparable karyotype in the metastatic tumors and the (peri)renal tumor. Concordantly, although the germline mutation was detected in all analyzed tumors, LOH 3p was only detected in the (peri)renal mass and most metastases. Overall, based on all genetic data, this tumor corroborated a diagnosis of metastatic sarcomatoid RCC. In line with these observations is the immunopositivity for the RCC-specific RC38 detected in the (peri)renal mass and the metastases that was not detected in pheochromocytomas. The RCC specific marker G250 was uninformative as it stains positive in all types of VHL tumors. This case report illustrates the promising role of genetic analysis in the differential diagnosis of histologically dedifferentiated tumors.     

Inhibin-expressing clear cell neuroendocrine tumor of the ampulla: an unusual presentation of von Hippel–Lindau disease

von Hippel–Lindau (VHL) disease is a hereditary autosomal dominant disorder associated with deletions or mutations in the VHL tumor suppressor gene. Characteristically, up to 60 % of neuroendocrine tumors (NETs) associated with VHL disease display a spectrum of clear cell morphology including multivacuolated lipid-rich cell change. Unlike neurofibromatosis type 1 and multiple endocrine neoplasia type 1 syndromes, ampullary NETs have not been described in association with VHL disease. In this report, we discuss the features of an incidental ampullary clear cell NET occurring in a patient with pancreatic VHL disease including multiple pancreatic NETs. The ampullary lesion consisted of epithelial cells resembling lipoblasts or signet ring cells. In our case, all NETs showing clear cell change were positive for inhibin. While the underlying mechanism of this finding is largely unknown, it is of note that positivity for inhibin has not been observed in clear cell NETs associated with multiple endocrine neoplasia type 1 syndrome. Our case proves that NETs can develop in the ampullary region in patients with VHL; clear cell change can occur in these lesions and can mimic signet ring cell carcinoma. This issue is of clinical significance especially in small biopsy samples; thus, positivity for keratin alone should not be taken as evidence of an adenocarcinoma. Moreover, demonstration of inhibin expression in a NET with clear cell change along with other clinical stigmata should alert the diagnostician to the possibility of VHL disease. However, further larger series examining inhibin expression in both syndrome-related and sporadic clear cell NETs are needed to confirm our findings.     

Glycogen-rich clear cell carcinoma arising from minor salivary glands of the uvula. A case report

Glycogen-rich clear cell carcinoma arising from minor salivary glands of the uvula in a 35-year-old woman is reported. This tumor was composed of nests and cords of clear cells containing cytoplasmic glycogen but no mucin. The epithelial nature of this lesion was obvious because of positive immunoreactivity for cytokeratin and epithelial membrane antigen, and the presence of immature lumina and intercellular spaces lined by many microvilli, associated with desmosomal junctions and basal lamina, as revealed by ultrastructural study. However, no myoepithelial cells could be detected. From these findings, it may be concluded that this tumor corresponds to glycogen-rich clear cell carcinoma (a variant of clear cell tumor), revealing glandular differentiation.     

GLYCOGEN-RICH CLEAR CELL CARCINOMA ARISING FROM MINOR SALIVARY GLANDS OF THE UVULA. A Case Report

Glycogen-rich clear cell carcinoma arising from minor salivary glands of the uvula in a 35-year-old woman is reported. This tumor was composed of nests and cords of clear cells containing cytoplasmic glycogen but no mucin. The epithelial nature of this lesion was obvious because of positive immunore-activity for cytokeratin and epithelial membrane antigen, and the presence of immature lumina and intercellular spaces lined by many microvilli, associated with desmosomal junctions and basal lamina, as revealed by ultrastructural study. However, no myoepithelial cells could be detected. From these findings, it may be concluded that this tumor corresponds to glycogen-rich clear cell carcinoma (a variant of clear cell tumor), revealing glandular differentiation. ACTA PATHOL JPN 38: 1227∼1234, 1988.     

Inhibition of bleomycin-induced pulmonary fibrosis by nordihydroguaiaretic acid. The role of alveolar macrophage activation and mediator production.

The diagnosis of adrenocortical carcinoma (ACC) is often difficult, because this tumor may present with direct extension into adjacent renal parenchyma or with metastatic disease. Renal cell carcinoma and other histologically similar tumors are potentially confused with ACC by conventional light microscopy, and their separation from the latter is often impossible without the aid of additional studies. Furthermore, the distinction between adrenal cortical adenoma and ACC may also be problematic. Because of these factors, the authors studied 10 cases each of ACC, adrenocortical adenoma, and renal cell carcinoma (RCC) immunohistochemically, in an attempt to develop objective parameters which may aid in this differential diagnostic dilemma. Nontrypsinized, formalin-fixed, paraffin-embedded specimens were used in all cases, and tissue from the adrenocortical tumors was also studied for intermediate filament content after protease digestion. All 20 nontrypsinized adrenocortical neoplasms were positive for vimentin, but not for cytokeratin, epithelial membrane antigen, or blood group isoantigens. Conversely, each of 10 cases of RCC expressed epithelial membrane antigen, cytokeratin, and blood group isoantigens, but none was immunoreactive for vimentin. Two adrenocortical carcinomas and three adenomas manifested cytokeratin positivity after trypsin digestion. There were no significant differences between the immunostaining profiles of ACC and adrenocortical adenoma, which suggest that this distinction must still rely upon clinical and morphologic criteria.     

Clear cell papillary renal cell carcinoma and clear cell renal cell carcinoma arising in acquired cystic disease of the kidney: an immunohistochemical and genetic study

Clear cell papillary renal cell carcinoma (RCC) is a recently established disease entity. However, there are few reports on genetic study of this entity. We report such a case with focus on genetic study. A 57-year-old Japanese man was found to have 3 renal tumors. Histologically, two tumors showed findings of clear cell RCC; and the other tumor showed findings of clear cell papillary RCC that was characterized by papillary growth pattern of neoplastic cells in cystic space with purely clear cell cytology. Immunohistochemically, tumor cells of clear cell papillary RCC were diffusely positive for PAX2 and cytokeratin 7, but negative for CD10, RCC Ma, and AMACR. In fluorescence in situ hybridization study for one clear cell papillary RCC, we detected polysomy for chromosome 7 and monosomy for chromosomes 17, 16, and 20. In addition, we detected mutation of VHL gene in clear cell RCC, but found no VHL gene mutation in clear cell papillary RCC. Finally, our results provide further evidence that clear cell papillary RCC may be both morphologically and genetically distinct entity from clear cell RCC and papillary RCC.     

Tumor-to-tumor metastasis of renal cell carcinoma into oncocytic carcinoma of the thyroid. Report of a case and review of the literature

A case of a multifocal oncocytic carcinoma of the thyroid with intratumoral metastases of renal cell carcinoma in a 52-year-old male is reported. Thirteen months before the presentation of the thyroid lesion, the patient underwent nephrectomy for a renal cell carcinoma. The thyroid tumor clinically presented as a palpable nodule. Preoperative fine-needle aspiration cytology showed two cell types: oncocytes and multivacuolated clear cells. The cytologic features were interpreted as a coincidence of an oncocytic tumor of the thyroid and metastasis of a clear cell renal carcinoma. The diagnosis was confirmed by histologic and immunohistochemical examinations. Interestingly, except for metastases within multiple foci of the oncocytic carcinoma, there were no metastatic deposits in nontumoral thyroid. Although the occurrence of tumor-to-tumor metastasis in thyroid gland is exceptionally rare, with only 12 such cases reported to date, one should be aware of this phenomenon to avoid an incorrect diagnosis. To the best of our knowledge, this is the first report of a metastasis into tumor of the thyroid gland, with oncocytic carcinoma being the recipient.     

Chromophobe renal cell carcinoma with neuroendocrine differentiation

Chromophobe renal cell carcinoma was described by Thoenes et al. in 1986, and associations with carcinoma of collecting ducts, conventional renal cell carcinoma and sarcomatoid renal cell carcinoma have been described. We report a case of chromophobe renal cell carcinoma which showed neuroendocrine differentiation. This is the first known case to be clearly identified as such. The patient was a 56‐year‐old man with constant right flank pain and hematuria; CT scan revealed an 8.5 cm non‐homogeneous mass involving the right kidney. Right radical nephrectomy was performed. The tumor showed a mixture of classical and eosinophilic patterns of chromophobe cell carcinoma. Additionally, it showed insular, glandular and rosetoid‐like formations embedded in a dense eosinophilic hyaline stroma. The cells were cuboid or cylindrical with well‐defined boundaries, finely stippled chromatin and a small nucleolus. The appearance of the cytoplasm varied from faintly eosinophilic to coarsely granular eosinophilic. Immunohistochemically, the neuroendocrine areas were reactive for C‐kit, epithelial membrane antigen, cytokeratin, cytokeratin 7, chromogranin A, neuron‐specific enolase, CD56 and S‐100 protein. Our case represents a typical chromophobe carcinoma with neuroendocrine differentiation. Additionally, the immunohistochemical profile in both types of lesion suggests a common origin from renal tubular cells.     

Cancer genes, multiple primary cancer, and von Hippel-Lindau disease

Von Hippel-Lindau disease is inherited by an autosomal dominant gene that may show marked expressive variability of cancer phenotype in certain patients/families. We describe a patient with a strongly positive family history of this disease who, at age 28, underwent craniotomy with removal of a cystic cerebellar hemangioblastoma; at age 48, he developed syringomyelia of the spinal cord, became quadriplegic, and had a progressive downhill course. At autopsy, hemangioblastomas of the cerebellum and spinal cord were found, as well as a left renal cell carcinoma, an oat cell carcinoma of the lung, a hepatocellular carcinoma, and an atypical thyroid adenoma. This tumor spectrum appears to be unique, although chance cannot be excluded. It is possible, however, that these findings might represent an expression of the deleterious genotype that became evident because of this patient's prolonged survival from his initial cerebellar hemangioblastoma.     

Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma.

Analysis of the age incidence curves for unilateral and bilateral retinoblastoma led Knudson to propose that hereditary tumours may arise by a single event and sporadic tumours by a two stage mutation process. It has been suggested recently that sporadic renal cell carcinoma may arise from a two stage mutation process. We analysed the age incidence curves for symptomatic renal cell carcinoma (n = 26) and cerebellar haemangioblastoma (n = 68) in 109 patients with von Hippel-Lindau (VHL) disease, and compared them to 104 patients with sporadic renal cell carcinoma and 43 patients with sporadic cerebellar haemangioblastoma. The age incidence curves for renal cell carcinoma and cerebellar haemangioblastoma in VHL disease were compatible with a single mutation model, whereas the age incidence curves for sporadic renal cell carcinoma and cerebellar haemangioblastoma suggested a two stage mutation process. These data are compatible with the VHL gene functioning as a recessive tumour suppressor gene. Sporadic cerebellar haemangioblastoma and some renal cell carcinoma may arise from somatic mutations inactivating both alleles at the VHL locus.     

Novel insights into the role of the tumor suppressor von Hippel Lindau in cellular differentiation, ciliary biology, and cyst repression

The growth and differentiation of renal tubular epithelial cells is normally tightly controlled. Disturbances can lead to the development of renal cysts or renal cell carcinomas, clinically relevant disease entities, which have so far been considered as being caused by entirely distinct mechanisms. Clear cell renal carcinoma, the most frequent type of renal cancer is associated with inactivation of the von Hippel Lindau (VHL) protein. Genetic defects leading to cystic kidney disease usually affect proteins that play a role in structure or function of primary cilia of renal epithelial cells. Accumulating evidence suggests that the VHL protein also controls cilia function and that its inactivation may result in both malignant or nonmalignant growth of epithelial cells and that this effect is in part mediated through the accumulation of hypoxia-inducible factors. Unraveling the complex role of VHL in renal epithelial cells is likely to shed further insight into mechanism of epithelial growth control, epithelial–mesenchymal transformation, and tumor development.     

Role of chromosome 3p12-p21 tumour suppressor genes in clear cell renal cell carcinoma: analysis of VHL dependent and VHL independent pathways of tumorigenesis.

AIMS: Chromosome 3p deletions and loss of heterozygosity (LOH) for 3p markers are features of clear cell renal cell carcinoma but are rare in non-clear cell renal cell carcinoma. The VHL tumour suppressor gene, which maps to 3p25, is a major gatekeeper gene for clear cell renal cell carcinoma and is inactivated in most sporadic cases of this disease. However, it has been suggested that inactivation of other 3p tumour suppressor genes might be crucial for clear cell renal cell carcinoma tumorigenesis, with inactivation (VHL negative) and without inactivation (VHL positive) of the VHL tumour suppressor gene. This study set out to investigate the role of non-VHL tumour suppressor genes in VHL negative and VHL positive clear cell renal cell carcinoma. METHODS: Eighty two clear cell renal cell carcinomas of known VHL inactivation status were analysed for LOH at polymorphic loci within the candidate crucial regions for chromosome 3p tumour suppressor genes (3p25, LCTSGR1 at 3p21.3, LCTSGR2 at 3p12 and at 3p14.2). RESULTS: Chromosome 3p12-p21 LOH was frequent both in VHL negative and VHL positive clear cell renal cell carcinoma. However, although the frequency of 3p25 LOH in VHL negative clear cell renal cell carcinoma was similar to that at 3p12-p21, VHL positive tumours demonstrated significantly less LOH at 3p25 than at 3p12-p21. Although there was evidence of LOH for clear cell renal cell carcinoma tumour suppressor genes at 3p21, 3p14.2, and 3p12, both in VHL negative and VHL positive tumours, the major clear cell renal cell carcinoma LOH region mapped to 3p21.3, close to the lung cancer tumour suppressor gene region 1 (LCTSGR1). There was no association between tumour VHL status and tumour grade and stage. CONCLUSIONS: These findings further indicate that VHL inactivation is not sufficient to initiate clear cell renal cell carcinoma and that loss of a gatekeeper 3p21 tumour suppressor gene is a crucial event for renal cell carcinoma development in both VHL negative and VHL positive clear cell renal cell carcinoma.