The majority of hereditary tumor syndromes involve germline mutations, which effectively inactivate tumor suppressor genes (for example TSC1 and TSC2), whereby cells with a bi-allelic inactivation of such genes originate tumors in a classic tumor suppressor “two-hit” paradigm. The diverse morphologic spectrum of neoplasms found in the tuberous sclerosis complex (TSC) integrates many fundamentals of cellular biology, with the MTOR pathway showing frequent activation, as evidenced by expression of multiple downstream targets of MTOR and an increased neoplastic cell size (now well known to be a functional consequence of enhanced MTOR activity)1.
While angiomyolipomas and cysts are the most common renal manifestations of TSC, ~4% of patients will develop renal cell carcinoma (RCC)2. Careful morphologic studies of these RCC have permitted their subdivision into three main groups: first, RCC with clear cytoplasm, papillary architecture, and prominent smooth muscle stroma; second, RCC with granular eosinophilic cytoplasm and macrocystic architecture; and third, RCC resembling the eosinophilic variant of chromophobe RCC3,4. One would predict that there should be sporadic counterparts to each of these neoplasms, effected by somatic mutations in the TSC1/2 genes in patients who do not suffer from the tuberous sclerosis complex. Identification of such neoplasms, however, has been confounded by the fact that the TSC1/2 genes, as well as the gene coding the downstream protein mammalian target of rapamycin (MTOR), are mutated secondarily in ~5% of the more common subtypes of RCC, including bonafide clear cell and chromophobe RCC cases5,6. Parenthetically, these mutations may be associated with clinical response to MTOR inhibitors, emphasizing their therapeutic relevance. However, in recent years and in several studies in the current issue of Modern Pathology, sporadic counterparts to the hereditary tuberous sclerosis complex-associated RCC that are associated with somatic TSC/MTOR pathway mutations have now been described.
First, representing a somatic counterpart to group one, a RCC characterized by prominent fibromuscular brands transecting acinar and tubulopapillary architecture, and clear cells with voluminous cytoplasm and well-defined cell borders7 has been demonstrated to harbor somatic TSC or MTOR mutations8,9. Interestingly, these neoplasms demonstrate morphologic overlap with renal tumors recently described as harboring mutations in the ELOC (formerly known as TCEB1) gene at 8q21.11, in an absence of concurrent VHL or chromosome 3p alterations10. These neoplasms typically label for cytokeratin 7 and carbonic anhydrase IX like clear cell papillary RCC/renal angiomyoadenomatous tumor, but in contrast also label for CD10, have voluminous cytoplasm, and lack subnuclear vacuolization. Second, corresponding to group 2, eosinophilic solid and cystic RCC (ESC RCC), characterized by solid and cystic architecture, polygonal neoplastic cells with voluminous eosinophilic cytoplasm and basophilic cytoplasmic stippling, and frequent patchy immunoreactivity for cytokeratin 2011, has been shown to harbor somatic TSC1 or TSC2 mutations12,13,14. While typically indolent and presenting in adult females, this neoplasm often occurs in children15 and may rarely present with metastatic disease which in one case has dramatically responded to treatment with MTOR inhibitors. Finally, corresponding to group three, a neoplasm provisionally termed “low-grade oncocytic tumor” (LOT)16 has been described and in this issue of Modern Pathology demonstrated to be associated with somatic TSC1/2 gene mutations17,18,19. These neoplasms resemble the eosinophilic variant of chromophobe RCC in that they are composed of solid areas of low-grade oncocytic cells with perinuclear halos, which label with cytokeratin 7. In contrast, however, the neoplasm typically features transitions from solid growth to elongated cords/sheaths of neoplastic cells in edematous stroma, has fewer nuclear irregularities and less well-developed perinuclear halos, and does not label diffusely for CD117. Not surprisingly, LOT shares morphologic and biomarker overlap with a subset of eosinophilic variant of chromophobe RCC described in literature with negative CD117 expression and presence of MTOR mutations20. Apart from the sporadic and hereditary settings, LOT have now also been reported in patients with end-stage renal disease (ESRD)21.
Also included among chromophobe RCC-like tumors in patients with tuberous sclerosis complex are neoplasms with hyalinized stroma, prominent nucleoli, and eosinophilic cytoplasm with prominent cytoplasmic vacuoles22. Such tumors were originally described in nonsyndromic patients on morphologic grounds under the term “high-grade oncocytic tumor”23, given their prominent nucleoli; however, these neoplasms typically lack mitoses and have thus far have had benign outcomes. Somatic TSC or MTOR mutations24 have now been found in these neoplasms (reported under the term eosinophilic and vacuolated RCC). These neoplasms are recognized as an evolving entity by both the International Society of Urologic Pathology25, and Genitourinary Pathology Society26, and the latter has proposed the provisional term eosinophilic and vacuolated tumor (EVT). An additional study reported in this issue of Modern Pathology confirms the presence of somatic TSC/MTOR mutations in EVT27.
While remarkable progress has been made over the past decade in the delineation of TSC/MTOR-mutation-related renal neoplasia in both of the hereditary and sporadic settings28, several questions remain to be answered. One query is whether there are other distinctive RCCs that may prove to be associated with TSC1/2 or MTOR gene mutations. Along these lines, a recent report described TSC2 mutations in a subset of acquired cystic disease-associated RCC29. Another is how frequent are TSC1/2 or MTOR-mutated RCC that do not cleanly fit a given category but instead have overlapping features of ESC, LOT, and/or EVT. In addition, it is currently not very clear how TSC related neoplasia may be affected at the phenotypic and molecular level by aberrations involving other genes from related/unrelated pathways; for example, deletions involving TSC2 and the adjacent PKD1 gene have been linked to a distinct subtype of TSC exhibiting significant cystic kidney disease30. Further studies in the upcoming few years should help further clarify this fascinating area of study with a successful definition of specific genomic insults that link aberrations in TSC genes with a spectrum of morphologic and clinical phenotypes.
Finally, the current National Comprehensive Cancer Network as well as American Urology Association guidelines recommend these clinical criteria for genetic risk evaluation of patients with potential hereditary kidney cancer: diagnosis at age equal to or less than 46 years, bilateral or multifocal tumors, and a first degree relative with RCC. However, specific pathologic findings (such as succinate dehydrogenase deficient or Birt–Hogg–Dubé-related tumor histology) should also trigger such evaluation. Indeed, pathologists not infrequently suggest the genetic consultation and germline testing that first establishes the diagnosis of hereditary renal neoplasia in a family following examination of a renal core biopsy or resection in a proband. The expanding spectrum of TSC-related renal neoplasia may further expand the pivotal role pathologists play in the initial identification of hereditary renal neoplasia.
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Argani, P., Mehra, R. Renal cell carcinoma associated with tuberous sclerosis complex (TSC)/mammalian target of rapamycin (MTOR) genetic alterations. Mod Pathol 35, 296–297 (2022). https://doi.org/10.1038/s41379-021-00971-y