PEComas: the past, the present and the future Martignoni, Guido; Pea, Maurizio; Reghellin, Daniela ...
Virchows Archiv : an international journal of pathology,
02/2008, Letnik:
452, Številka:
2
Journal Article
Recenzirano
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The perivascular epithelioid cell (PEC) is a cell type constantly present in a group of tumors called PEComas. PEC expresses myogenic and melanocytic markers, such as HMB45 and actin. Recently, ...recurrent chromosomal alterations have been demonstrated in PEC. At present, PEComa is a widely accepted entity. In the past 10 years, the use of this term has allowed to report and describe numerous cases permitting to start highlighting the biology of this group of lesions. PEComas are related to the genetic alterations of tuberous sclerosis complex (TSC), an autosomal dominant genetic disease due to losses of TSC1 (9q34) or TSC2 (16p13.3) genes which seem to have a role in the regulation of the Rheb/mTOR/p70S6K pathway. There are some open questions about PEComas regarding its histogenesis, the definition of epithelioid angiomyolipoma and the identification of the histological criteria of malignancy. An innovative therapeutic trial using rapamycin is under way for tumors occurring in TSC such as renal angiomyolipoma and lymphangioleiomyomatosis. Its success could provide the rationale for the use of the same drug in other lesions composed of PECs, especially in the malignant ones.
Cathepsin K is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. TFE3 and TFEB are members of the same transcription factor subfamily as MITF and all ...three have overlapping transcriptional targets. We have shown that all t(6;11) renal cell carcinomas, which harbor an Alpha-TFEB gene fusion, as well as a subset of the Xp11 translocation renal carcinomas, which harbor various TFE3 gene fusions, express cathepsin K, while no other common renal carcinoma does. We have hypothesized that overexpression of TFEB or certain TFE3 fusion proteins function like MITF in these neoplasms, and thus activate cathepsin K expression. However, the expression of cathepsin K in specific genetic subtypes of Xp11 translocation carcinomas, as well as alveolar soft part sarcoma, which harbors the same ASPSCR1-TFE3 gene fusion as some Xp11 translocation carcinomas, has not been addressed. We performed immunohistochemistry for cathepsin K on 14 genetically confirmed t(X;1)(p11;q21) carcinomas, harboring the PRCC-TFE3 gene fusion; eight genetically confirmed t(X;17)(p11;q25) carcinomas, harboring the ASPSCR1-TFE3 gene fusion; and 18 alveolar soft part sarcomas (12 genetically confirmed), harboring the identical ASPSCR1-TFE3 gene fusion. All 18 alveolar soft part sarcomas expressed cathepsin K. In contrast, all eight ASPSCR1-TFE3 carcinomas were completely negative for cathepsin K. However, 12 of 14 PRCC-TFE3 carcinomas expressed cathepsin K. Expression of cathepsin K distinguishes alveolar soft part sarcoma from the ASPSCR1-TFE3 carcinoma, harboring the same gene fusion. The latter can be useful diagnostically, especially when alveolar soft part sarcoma presents in an unusual site (such as bone) or with clear cell morphology, which raises the differential diagnosis of metastatic ASPSCR1-TFE3 renal cell carcinoma. The difference in expression of cathepsin K between the PRCC-TFE3 and ASPSCR1-TFE3 carcinomas, together with the observed clinical differences between these subtypes of Xp11 translocation carcinomas, suggests the possibility of functional differences between these two related fusion proteins.
Lymphangioleiomyomatosis is a rare and progressive lung cystic disease, caused by the infiltration of lung parenchyma by mesenchymal cells characterized by co-expression of contractile proteins and ...melanocytic markers. The pathogenesis of lymphangioleiomyomatosis is determined by mutations affecting tuberous sclerosis complex (TSC) genes, with eventual deregulation of the Rheb/mTOR/p70S6K pathway, and the potential therapeutic activity of mTOR inhibitors is currently under investigation. To better understand the molecular mechanisms involved in the pathogenesis of lymphangioleiomyomatosis, we investigated the expression of cathepsin-k (a papain-like cysteine protease with high matrix-degrading activity). The rationale of this choice was based on the recent demonstration that mTOR inhibitors can regulate major functional activities of osteoclasts, including the expression of cathepsin-k. The immunohistochemical study included 12 cases of lymphangioleiomyomatosis. Twelve angiomyolipomas and several lung diseases (sarcoidosis, organizing pneumonia, usual interstitial pneumonia, emphysema) were investigated as controls. In all lymphangioleiomyomatosis cases, strong cathepsin-k immunoreactivity was demonstrated, restricted to lymphangioleiomyomatosis cells. Similar expression levels were observed in renal angiomyolipomas. These observations extend the knowledge regarding the immunophenotypic profile of lymphangioleiomyomatosis cells, and provide a useful new marker for diagnosis in difficult cases (eg, in small transbronchial biopsies). The strong expression of such a potent papain-like cysteine protease in lymphangioleiomyomatosis cells can significantly contribute to the progressive remodelling of lung parenchyma observed in this deadly disease, with eventual formation of lung cysts. It is possible to speculate that mTOR inhibitors may exert part of their action by limiting the destructive remodelling of lung structure.
The perivascular epithelioid cell (PEC) is a unique cell type coexpressing contractile proteins (mainly α-smooth muscle actin), melanocytic markers, including microphthalmia-associated transcription ...factor (MITF), and estrogen and progesterone receptors. It is constantly present in a group of tumors called PEComas. Renal PEComas include the common angiomyolipoma as well as less common lesions such as microscopic angiomyolipoma, intraglomerular lesions, angiomyolipoma with epithelial cysts, epithelioid angiomyolipoma, oncocytoma-like angiomyolipoma and lymphangioleiomyomatosis of the renal sinus. It has been demonstrated that most of these lesions are determined by mutations affecting genes of the tuberous sclerosis complex, tuberous sclerosis 1 (TSC1) and tuberous sclerosis 2 (TSC2), with eventual deregulation of the RHEB/MTOR/RPS6KB2 pathway, and it has been observed that some PEComas regressed during sirolimus therapy, an MTOR inhibitor. Recently, overexpression of MITF has been related to the expression of the papain-like cysteine protease cathepsin K in osteoclasts where it has inhibited MTOR. The aim of this study is to evaluate cathepsin K immunohistochemically in the entire spectrum of PEComa lesions in the kidney. The study population consisted of 84 renal PEComa lesions, including 5 composed predominantly of fat (lipoma-like angiomyolipoma), 15 almost exclusively composed of spindle-shaped smooth muscle cells (leiomyoma-like angiomyolipoma) and 31 common angiomyolipomas composed of a mixture of fat, spindle and epithelioid smooth muscle cells, and abnormal thick-walled blood vessels, 15 microscopic angiomyolipomas, 5 intraglomerular lesions, 2 oncocytoma-like angiomyolipomas, 8 epithelioid angiomyolipomas, 2 angiomyolipomas with epithelial cysts and 1 example of lymphangioleiomyomatosis of the renal sinus. In all of the renal PEComas, cathepsin K was found to be constantly and strongly expressed and seems to be a more powerful marker than other commonly used markers for their identification, especially to confirm the diagnosis on needle biopsies.
We validated the Mayo Clinic SSIGN score in an independent European sample of patients who were surgically treated for conventional RCC.
In our kidney cancer database we identified 388 patients who ...were treated with radical or partial nephrectomy for conventional RCC between 1986 and 2000. Associations of the pathological features studied with death from RCC were evaluated using the log rank test and Cox proportional hazards regression model. The predictive ability of competing models was evaluated using the c index.
Median followup in the 290 patients who were alive at last followup was 5 years (range 5 months to 17 years). The estimated cancer specific survival rate 5 years following surgery was 81.3%. All features that comprise the SSIGN score except tumor size were significantly associated with death from RCC in a multivariate setting, resulting in a c index of 0.90. The median SSIGN score in the 388 patients studied was 3 (range 0 to 15). The c index in a model containing the clear cell SSIGN score was 0.88. Five-year cancer specific survival rates in patients with a score of 0 to 2, 3 to 4, 5 to 6, 7 to 9 and 10 or more were 100.0%, 90.5%, 63.6%, 46.8% and 0%, respectively.
We provide the first external validation of the Mayo Clinic SSIGN score for conventional RCC. This simple algorithm resulted in a high degree of prognostic accuracy.
Abstract PEComas are mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells that are characterized by the coexpression of muscle and ...melanogenetic markers. This group of lesions includes angiomyolipoma, clear cell “sugar” tumor of the lung and extrapulmonary sites, lymphangioleiomyomatosis, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, and rare clear cell tumors of other anatomical sites. In the genitourinary tract, PEComas have been described in the kidney, bladder, prostate, testis, and urethra. Although most PEComas behave as benign tumors, some are potentially malignant, and criteria for malignancy have been suggested for both and renal and extrarenal lesions. Recently, the expression of cathepsin K has been demonstrated in a large number of PEComas and has been proposed as a relatively specific marker to distinguish these proliferations from the majority of human cancers. In addition, a distinctive subset of PEComas harboring TFE3 gene fusions has been reported, giving rise to a possible relationship between them and MiTF/TFE family translocation renal cell carcinomas. The genetic alterations of tuberous sclerosis complex that promote activation of the mTOR pathway have been identified in PEComas. Therapy with mTORC1 inhibitors has been shown to be effective in some cases.
To evaluate concordance, using the kappa statistic, between tumour histotypes assigned at initial diagnosis and those after slide revision, and to assess the independent predictive value of reviewed ...tumour histotype.
We analysed records of 491 patients who had undergone partial or radical nephrectomy for renal cell carcinoma (RCC) in our department from 1986 to 2000. Pathologic slides were reviewed by one uropathologist blinded to original diagnoses and follow-up data, who reassigned histologic subtype and nuclear grades.
Concordance between original and reviewed histotypes was substantial (kappa=0.52). Data were affected by the year of initial diagnosis: Concordance was moderate (kappa=0.43) in patients treated from 1986 to 1997 and substantial (kappa=0.73) in those observed thereafter. The original histotype did not stratify the cancer-related outcome. According to the reviewed histotypes, the 5-year cancer-specific survival probabilities of conventional, papillary and chromophobe RCC patients were 81.3%, 90.1% and 100%, respectively (p=0.009). Patients with conventional RCC showed significantly lower cancer-specific survival than those with papillary or chromophobe RCC, even in the cases with locally advanced (p=0.04) or high-grade (p=0.02) neoplasms. The reviewed histologic subtype was not an independent prediction of cancer-specific survival on multivariate analysis.
Concordance between histologic subtype assigned before 1997 and after slide revision was only moderate. In univariate analysis, reviewed tumour histotype stratified cancer-related outcome, but the data of multivariate analysis were strongly influenced by the prevalent number of conventional RCC.
Slide revision significantly refined the evaluation of cases diagnosed before UICC/AJCC introduced the Heidelberg classification. Slide revision should be strongly recommended in all retrospective studies.
Perivascular epithelioid cell tumors (PEComas) are mesenchymal tumors composed of histologically, immunohistochemically, ultrastructurally, and genetically distinctive cells. PEComas have been ...described in different organs and are considered ubiquitous tumors. In this review we discuss recent informations related to PEComas in the genitourinary tract.
The hallmark of chromophobe renal cell carcinoma is multiple chromosomal losses from among chromosomes 1, 2, 6, 10 and 17. Chromophobe renal cell carcinoma with distant metastases or sarcomatoid ...transformation are uncommon and little is known about their chromosomal abnormalities. We collected six sarcomatoid chromophobe renal cell carcinomas and three primary chromophobe renal cell carcinomas with distant metastases. A cytogenetic analysis by fluorescent in situ hybridization on paraffin-embedded tissue was performed using centromeric probes for chromosomes 1, 2, 6, 10 and 17. We found more than one signal in four of six (66%) sarcomatoid chromophobe renal cell carcinomas, in both sarcomatoid and adjacent epithelial components. Both primary chromophobe renal cell carcinomas and matched metastases showed single signals for all chromosomes studied in two cases and no abnormalities in the remaining case. We concluded that: (1) both epithelial and sarcomatoid components of sarcomatoid chromophobe renal cell carcinoma show different genetic abnormalities from those characteristic of chromophobe renal cell carcinoma; (2) sarcomatoid chromophobe renal cell carcinomas frequently have multiple gains (polysomy) of chromosomes 1, 2, 6, 10 and 17; (3) distant metastases show the same genetic patterns, usually chromosomal losses (monosomy), found in the primary tumors.
Angiomyolipoma is the most common mesenchymal tumour of the kidney, even if for a long time it has been viewed as a hamartoma rather than a neoplasm. It belongs to a family of neoplasms, named ...PEComa, characterised by the constant presence of perivascular epithelioid cells that co-express smooth muscle and melanogenesis markers. Angiomyolipoma can occur in patients with tuberous sclerosis, a hereditary syndrome due to the alteration of TSC1 or TSC2 genes, or sporadically. Angiomyolipoma and its variants are indolent tumours; however, some epithelioid angiomyolipomas/pure epithelioid PEComas are aggressive, and criteria for malignancy have been proposed to identify those cases. Although typical angiomyolipoma is a straightforward diagnosis, pathologists should be aware of the wide morphological spectrum of its variants which could be tricky in routine clinical practice and could require immunohistochemical analysis for resolution. The differential diagnosis may range from an inflammatory process (for instance xanthogranulomatous pyelonephritis) to the most common renal cancers and sarcomas. The immunoexpression of melanogenesis markers (HMB45 and Melan-A) and cathepsin K is extremely helpful in the majority of cases. Recently, a subset of epithelioid angiomyolipoma/pure epithelioid PEComa harbouring TFE3 gene fusions has been described, raising questions about its relationship with the family of perivascular epithelioid cell tumour. The activation of the mTOR pathway due to genetic alterations of tuberous sclerosis complex in TSC1 or TSC2 genes in angiomyolipoma has also been reported as well as the subsequent therapeutic implications.
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