Metastatic renal cell carcinoma presenting as a gallbladder polyp

Clear cell renal cell carcinoma accounts for approximately 3% of all adult malignancies and 85% of all primary renal malignancies. Clear cell renal cell carcinoma (ccRCC) metastasis to the gallbladder is extremely rare and often presents as a metachronous metastasis following several years of tumour free disease. We report a case of a 78-year-old female with metastatic ccRCC to the gallbladder. During follow-up ultrasound imaging, a polypoid gallbladder mass was discovered incidentally. The previous medical history is significant for total nephrectomy for left-sided ccRCC 6 years ago. A new suspicious intraluminal polypoid gallbladder mass in a patient with a history significant for clear cell renal cell carcinoma should alert the physician to consider metastatic clear cell renal cell carcinoma.     

Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinoma

Tumour metastasis is the result of a complex sequence of events, including migration of tumour cells through stroma, proteolytic degradation of stromal and vessel wall elements, intravasation, transport through the circulation, extravasation and outgrowth at compatible sites in the body (the ‘seed and soil’ hypothesis). However, the high incidence of metastasis from various tumour types in liver and lung may be explained by a stochastic process as well, based on the anatomical relationship of the primary tumour with the circulation and mechanical entrapment of metastatic tumour cells in capillary beds. We previously reported that constitutive VEGF‐A expression in tumour xenografts facilitates this type of metastatic seeding by promoting shedding of multicellular tumour tissue fragments, surrounded by vessel wall elements, into the circulation. After transport through the vena cava, such fragments may be trapped in pulmonary arteries, allowing them to expand to symptomatic lesions. Here we tested whether this process has clinical relevance for clear cell renal cell carcinoma (ccRCC), a prototype tumour in the sense of high constitutive VEGF‐A expression. To this end we collected and analysed outflow samples from the renal vein, directly after tumour nephrectomy, in 42 patients diagnosed with ccRCC. Tumour fragments in venous outflow were observed in 33% of ccRCC patients and correlated with the synchronous presence or metachronous development of pulmonary metastases (p < 0.001, Fisher's exact test). In patients with tumours that, in retrospect, were not of the VEGF‐A‐expressing clear cell type, tumour fragments were never observed in the renal outflow. These data suggest that, in ccRCC, a VEGF‐A‐induced phenotype promotes a release of tumour cell clusters into the circulation that may contribute to pulmonary metastasis. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

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.     

Thyroid metastasis of clear cell renal carcinoma: Report of a case

Renal cell carcinoma can recur many years after diagnosis and nephrectomy metastasizing even in uncommon sites, including thyroid gland. Thyroid metastases are extremely rare, the most frequent site of origin are renal tumors. Metastases in thyroid gland appear as painless nodules or masses, “cold” at scintiscan. We report the case of a 67‐year‐old male patient affected by clear cell renal carcinoma, diagnosed by fine‐needle aspiration cytology procedures, and treated with anticancer medical therapy, who noticed after some months a mass in the neck‐thyroid region requiring deeper medical investigations. By this way, thyroid fine‐needle aspiration cytology reported a lesion made of malignant epithelial cells compatible with metastases of renal carcinoma (clear cell). Clinical and pathological data, together with immunostaining, supported the diagnosis of metastatic clear cell renal carcinoma. The diagnosis of metastatic disease, although difficult clinically and pathologically, should be suspected in patients with a clinical history of cancer, particularly in case of renal cell carcinoma, but fine‐needle aspiration cytology can provide the clue for diagnosis. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

The current World Health Organisation (WHO) classification of renal tumours is based on characteristic histological features or specific molecular alterations. von Hippel‐Lindau (VHL) alteration is the hallmark of clear cell renal cell carcinoma (RCC). After identification of the MiT translocation family of tumours, clear cell papillary renal cancer and others, the group of ccRCC with wild‐type VHL is small. TCEB1 mutation combined with chromosome 8q loss is an emerging tumour entity with wild‐type VHL. Inactivation of TCEB1 increases HIF stabilisation via the same mechanism as VHL inactivation. Importantly, recent molecular analyses suggest the existence of another ‘VHL wild‐type’ evolutionary subtype of clear cell RCC in addition to TCEB1 mutated RCC and clear cell papillary renal cancer. These tumours are characterised by an aggressive behaviour, high tumour cell proliferation rate, elevated chromosomal instability and frequent presence of sarcomatoid differentiation. Future clinicopathological studies will have to provide data to determine whether TCEB1 tumours and clear cell RCC with wild‐type VHL are separate tumour entities or represent variants of a clear cell RCC tumour family.     

Synchronous renal cell carcinoma and clear cell hepatocellular carcinoma mimicking metastatic disease

Double carcinomas of hepatocellular and renal cell carcinoma (RCC) are extremely rare, and among the reported cases, none of the hepatocellular carcinomas show clear cell change. We report a case of synchronous double primary clear cell tumor in the liver and the kidney of a 70-year-old male. The renal mass was a renal cell carcinoma of mixed clear and granular cell types, and the hepatic mass was a hepatocellular carcinoma with extensive clear cell change that mimicked a metastatic renal cell carcinoma. A simple battery of immunohistochemical stains composed of hepatocyte antigen, and CD10 was performed to make a definite diagnosis.     

Proliferating cell nuclear antigen in gallbladder carcinoma

Proliferating cell nuclear antigen (PCNA) expression was studied in 103 gallbladder carcinomas and 23 metastatic lesions as well as in 25 control non-neoplastic gallbladder specimens. Positive nuclear staining was observed in 88% of controls, in 92% of carcinomas and in 70% of metastases. The mean number of positive cells was 21.2% in controls, 44.1% in primary carcinomas and 32% in metastatic cancer cells. Differences which were significant were control v . primary tumour, P <0.000001; control v . metastasis, P <0.01 and primary tumour v . metastasis, P <0.006. In 57 (60%) of the primary tumours there was positive staining in over 40% of tumour cells. We were not able to demonstrate any relationship between macroscopic or microscopic features and PCNA expression. However, tumours confined to the mucosa expressed PCNA more frequently than did more advanced tumours.     

Basosquamous cell carcinoma of the skin with metastases

Two cases of basosquamous cell carcinoma of the skin with lymph node, lung and bone metastases are reported. Metastases occurred 4 and 7 years after identification of the primary tumour. Both the primary and metastatic lesions had areas of typical basal cell carcinoma and squamous cell carcinoma and also intermediate carcinomatous tissue. In the bone metastasis of one case there were rudimentary hair follicles and areas of matrical differentiation. These cases further support the existence of basosquamous cell carcinoma and emphasize its metastatic potential.     

Cytogenetic analysis of myoepithelial cell carcinoma of salivary gland

Myoepithelial cell carcinoma (MCC) of the salivary gland is a rare entity. Here, we describe the karyotype of MCC. The patient was a 53-year-old man, with a rapidly growing lesion of the palate. Despite complete surgical excision, radio- and chemotherapy, the lesion rapidly harboured local and distant metastases leading to the death of the patient, 4 months after the diagnosis. On histological and ultrastructural examination, the primary tumour and the related metastases were composed of oval and spindle cells, with features of myoepithelial cell differentiation reported in the literature. Cytogenetic analysis showed a composite karyotype in the primary tumour: 45~46,XY, +3[cp3]/ 44~45,XY, -17[cp4]/ 46,XY[5]. The lymph-node metastasis was near-triploid and showed a complex karyotype. Our cytogenetic data differ from those described in benign or slowly growing salivary gland tumours showing myoepithelial cell differentiation. It is suggested that highly aggressive tumours might follow a different pathway of malignant transformation.     

Benign clear cell tumor of the lung (sugar tumor). Morphologic, immunohistochemical and ultrastructural evaluation

Clear cell tumour or "sugar tumour" of the lung is a rare primary neoplasm with unique histologic and electron microscopic features that may resemble those of metastatic renal cell carcinoma. An immunohistochemical studies are useful in a differential diagnosis these tumours: HMB45 in combination with a panel of various antibodies. The authors present a benign clear cell tumour of the lung, diagnosed on the base of its morphological, immunohistochemical and ultrastructural features.     

Spindle and cuboidal renal cell carcinoma,a tumour having frequent association with nephrolithiasis: report of 11 cases including a case with hybrid conventional renal cell carcinoma/ spindle and cuboidal renal cell carcinoma components

AIMS: We present the largest series of an unclassified subtype of renal cell carcinoma, which seems to be a distinct morphological entity and which is sometimes designated as spindle and cuboidal renal cell carcinoma. METHODS AND RESULTS: Eleven cases of spindle and cuboidal renal cell carcinoma were found among 7000 primary renal cell tumours in Pilsen's routine and consultation files. The patients were five men and six women. They ranged in age from 22 to 65 years (mean 56.8). Microscopically, the tumours were composed of two main populations of cells. First, the preponderant type of cells was formed by flattened, spindle cells with sparse cytoplasm. The second cell type was a small cuboidal cell with clear to light eosinophilic cytoplasm. Spindle-shaped cells were arranged in a fascicular pattern often reminiscent of low-grade smooth muscle tumours. Solid areas of spindle cells were also present. Small cuboidal cells formed sparse tubular structures lined by a row of single cells. In addition to all previous published cases of spindle and cuboidal renal cell carcinoma we observed an association of nephrolithiasis in our cases. It was seen in 3/11 of our patients. A previously unreported feature is the occurrence of a conventional renal cell carcinoma component in one of our cases. Seven of our patients are currently well without signs of recurrence or metastasis, one had metastasis in a regional lymph node at the time of nephrectomy, one died of an unrelated condition, and two were lost to follow-up. CONCLUSIONS: We present 11 cases of spindle and cuboidal renal cell carcinoma, which is believed to be a distinctive morphological entity. Our cases were histologically, immunohistochemically and ultrastructurally similar to the previously reported cases of spindle and cuboidal renal cell carcinoma. In contrast to all previously reported cases of spindle and cuboidal renal cell carcinoma, we observed an association with nephrolithiasis in three of our cases; moreover, one of our tumours had a conventional renal cell carcinoma component and another revealed a metastatic focus in a regional lymph node. None of our patients died of the disease. This study confirms that spindle and cuboidal renal cell carcinoma has a low malignant potential.     

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.     

Targeted next‐generation sequencing and non‐coding RNA expression analysis of clear cell papillary renal cell carcinoma suggests distinct pathological mechanisms from other renal tumour subtypes

Clear cell tubulopapillary renal cell carcinoma (CCPRCC) is a recently described rare renal malignancy that displays characteristic gross, microscopic and immunohistochemical differences from other renal tumour types. However, CCPRCC remains a very poorly understood entity. We therefore sought to elucidate some of the molecular mechanisms involved in this neoplasm by carrying out targeted next‐generation sequencing (NGS) to identify associated mutations, and in addition examined the expression of non‐coding (nc) RNAs. We identified multiple somatic mutations in CCPRCC cases, including a recurrent [3/14 cases (21%)] non‐synonymous T992I mutation in the MET proto‐oncogene, a gene associated with epithelial‐to‐mesenchymal transition (EMT). Using a microarray approach, we found that the expression of mature (n = 1105) and pre‐miRNAs (n = 1105), as well as snoRNA and scaRNAs (n = 2214), in CCPRCC cases differed from that of clear cell renal cell carcinoma (CCRCC) or papillary renal cell carcinoma (PRCC) tumours. Surprisingly, and unlike other renal tumour subtypes, we found that all five members of the miR‐200 family were over‐expressed in CCPRCC cases. As these miRNAs are intimately involved with EMT, we stained CCPRCC cases for E‐cadherin, vimentin and β‐catenin and found that the tumour cells of all cases were positive for all three markers, a combination rarely reported in other renal tumours that could have diagnostic implications. Taken together with the mutational analysis, these data suggest that EMT in CCPRCC tumour cells is incomplete or blocked, consistent with the indolent clinical course typical of this malignancy. In summary, as well as describing a novel pathological mechanism in renal carcinomas, this study adds to the mounting evidence that CCPRCC should be formally considered a distinct entity. Microarray data have been deposited in the GEO database [GEO accession number (GSE51554)]. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Whole‐exome sequencing reveals critical genes underlying metastasis in oesophageal squamous cell carcinoma

Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, owing to a high frequency of metastasis. However, little is known about the genomic landscape of metastatic ESCC. To identify the genetic alterations that underlie ESCC metastasis, whole‐exome sequencing was performed for 41 primary tumours and 15 lymph nodes (LNs) with metastatic ESCCs. Eleven cases included matched primary tumours, synchronous LN metastases, and non‐neoplastic mucosa. Approximately 50–76% of the mutations identified in primary tumours appeared in the synchronous LN metastases. Metastatic ESCCs harbour frequent mutations of TP53, KMT2D, ZNF750, and IRF5. Importantly, ZNF750 was recurrently mutated in metastatic ESCC. Combined analysis from current and previous genomic ESCC studies indicated more frequent ZNF750 mutation in diagnosed cases with LN metastasis than in those without metastasis (14% versus 3.4%, n = 629, P = 1.78 × 10^–5). The Cancer Genome Atlas data further showed that ZNF750 genetic alterations were associated with early disease relapse. Previous ESCC studies have demonstrated that ZNF750 knockdown strongly promotes proliferation, migration, and invasion. Collectively, these results suggest a role for ZNF750 as a metastasis suppressor. TP53 is highly mutated in ESCC, and missense mutations are associated with poor overall survival, independently of pathological stage, suggesting that these missense mutations have important functional impacts on tumour progression, and are thus likely to be gain‐of‐function (GOF) mutations. Additionally, mutations of epigenetic regulators, including KMT2D, TET2, and KAT2A, and chromosomal 6p22 and 11q23 deletions of histone variants, which are important for nucleosome assembly, were detected in 80% of LN metastases. Our study highlights the important role of critical genetic events including ZNF750 mutations, TP53 putative GOF mutations and nucleosome disorganization caused by genetic lesions seen with ESCC metastasis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Solitary delayed contralateral testicular metastasis from renal cell carcinoma

We report a 60 year old male presenting with contralateral testicular metastasis 7 years following radical nephrectomy for renal cell carcinoma. Testicular metastases from renal cell carcinoma reported in literature are predominantly ipsilateral and invariably on the left side. Usually these are present simultaneously with the renal primary or precede the diagnosis of renal tumors. Delayed contralateral testicular metastatic has not been reported to the best of our knowledge. The case highlights the unique behaviour of renal cell carcinoma with an unusual site of recurrence. The clinical presentation, pathogenesis and management of this rare presentation along with review of recent literature are discussed.     

Distinct angiogenic and non-angiogenic growth patterns of lung metastases from renal cell carcinoma

AIMS: We have recently evaluated a classification of non-small-cell lung cancer based upon the presence of an angiogenic or a non-angiogenic growth pattern. The aim of the present study was to test the hypothesis that lung metastases of clear cell renal cell carcinoma (RCC) can grow without eliciting angiogenesis and give rise to the same set of growth patterns. METHODS AND RESULTS: Tissue sections of 24 patients with lung metastases from clear cell RCC were analysed. Haematoxylin and eosin and reticulin staining were performed to evaluate growth pattern. Double-labelling with antibodies to CD34 and proliferating cell nuclear antigen (PCNA) was performed to determine the endothelial cell proliferation fraction (ECPF) and the microvessel density (MVD). Three growth patterns were observed. In the destructive growth pattern (54%), the architecture of the lung was not preserved. In the alveolar (33%) and interstitial growth patterns (13%), the normal lung parenchyma was preserved within the metastases. MVD was higher in the destructive than in the alveolar growth pattern (P = 0.009). ECPF was higher in the destructive (mean 31.1 +/- 22.7%, median 30.0) than in the alveolar growth pattern (mean 3.6 +/- 2.8%, median 3.2; P = 0.005). CONCLUSIONS: The present study demonstrates that highly angiogenic primary tumours can give rise to non-angiogenic metastases. This type of metastasis may be resistant to antiangiogenic therapy.     

Acinic cell carcinoma of minor salivary glands

Three cases of acinic cell carcinoma of minor salivary glands, located respectively in the larynx, base of the tongue, and right tonsil, were encountered at the Section of Pathology of the ENT Department of the University of Padua between 1974 and 1978. Such neoplasms arising in minor salivary gland tissue are extremely rare, but may be found in all sites containing normal or aberrant salivary gland tissue. The histological and histochemical characteristics of the tumour are discussed together with the differential diagnosis from other neoplasms, particularly clear-celled tumours such as glycogen rich adenocarcinoma, mucoepidermoid carcinoma, metastatic clear cell renal adenocarcinoma and clear cell squamous carcinoma. In general, acinic cell carcinoma can be defined as a tumour of low-grade malignancy, though not too rarely it may recur and occasionally metastasize.     

Expression of bcl-2 oncoprotein in renal cell tumours

Expression of bcl-2 is associated with inhibition of apoptosis and extension of cell survival. The importance of apoptosis in relation to the development and progression of renal cell neoplasia remains undefined so far. In order to determine the expression of bcl-2 oncoprotein in normal and neoplastic renal cells, 37 renal tumours were investigated by immunolabelling, including 13 clear cell carcinomas, ten tubulopapillary carcinomas, four chromophobic renal cell carcinomas, and ten oncocytomas. Twenty-six samples of adjacent normal renal tissue served as controls. bcl-2 expression was correlated with cell proliferation activity as estimated by Ki67 antigen expression, and p53 protein expression in the tumour samples. The results demonstrate that in the normal kidney, positive bcl-2 immunostaining was present in glomerular parietal epithelial cells, in distal tubular cells, and in sparse proximal tubule cells. Renal cell tumours showed heterogeneous bcl-2 expression according to the tumour cell type. While the majority of carcinomas of clear cell type were usually negative or contained sparsely distributed positive cells, all tubulopapillary carcinomas were consistently positive for bcl-2. In oncocytomas and chromophobic carcinomas, there was a low percentage of bcl-2 immunoreactive tumour cells; some nuclear bcl-2 positivity was detected in one chromophobic tumour. These findings indicate variable bcl-2 oncoprotein expression in different types of renal cell tumours, with the highest level of expression in tubulopapillary carcinomas. No clear relationship was found between nuclear grade, cell proliferation activity, and level of bcl-2 expression. p53 protein was detected in only one tubulopapillary carcinoma.     

Effects of suramin on metastatic ability,proliferation, and production of urokinase-type plasminogen activator and plasminogen activator inhibitor type 2 in human renal cell carcinoma cell line SN12C-PM6

Effects of suramin, a polysulfonated naphthylurea compound, on metastatic ability, proliferation, and production of plasminogen activators and plasminogen activator inhibitors were studied using the highly metastatic human renal cell carcinoma cell line, SN12C-PM6. After renal subscapular implantation of tumor cells in nude mice, suramin significantly inhibited metastasis of tumor cells to the lungs and liver. In vitro growth of tumour cells was inhibited by suramin in a dose-dependent manner, at relatively low doses (ID₅₀ = 105 µg/ml). Plasminogen activator inhibitor type 2 (PAI-2) production by tumor cells was enhanced by suramin (100 µg/ml), whereas urokinase-type plasminogen activator (uPA) production was suppressed. Thus, the increase in PAI-2 and the decrease in uPA production correlated with the inhibitory effects on tumour growth and metastasis by suramin. Therefore suramin may be beneficial for the treatment of patients with an early stage of renal cancer with potential risk of metastasis.     

Comparison of vascularity and angiogenesis in primary invasive mammary carcinomas and in their respective axillary lymph node metastases

It is well established that the ability of a neoplasm to induce a blood supply from a pre-existing circulation (angiogenesis) is a major factor in tumour growth, invasion and metastasis. However, the angiogenic potential of metastases and their subsequent growth have not been extensively studied. The question arises: can metastatic clones induce the same level of angiogenesis as in the primary neoplasm they emanated from? In this study it is hypothesised that in the same patient the level of vascularity and angiogenesis is the same in both the primary invasive ductal carcinoma and in the axillary lymph node metastasis at the time of surgery, according to Kerbels theory of clonal-dominance. To directly address the hypothesis, morphological measures of the established blood/lymphatic circulation (vascularity) as well as estimates of angiogenesis (endothelial cell proliferation) were measured in primary tumours and directly compared to the same parameters in the corresponding lymph node metastasis in a case by case basis (n=17). The results demonstrate varying associations between the level of vascularity and angiogenesis between matched individual tumours and their metastatic lymph nodal deposits. It is possible that either variations in the angiogenic characteristics of the metastasising clone or local or systemic promoters or inhibitors of angiogenesis influence tumour angiogenesis at the different sites.