Positive GPNMB Immunostaining Differentiates Renal Cell Carcinoma With Fibromyomatous Stroma Associated With TSC1/2/MTOR Alterations From Others

Li, Huili; Argani, Pedram; Halper-Stromberg, Eitan; Lotan, Tamara L.; Merino, Maria J.; Reuter, Victor E.; Matoso, Andres

doi:10.1097/pas.0000000000002117

Cited by 9 publications

(2 citation statements)

References 29 publications

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“…It is also worth noting that GPNMB, a transmembrane protein transcriptionally activated by TFE3/TFEB, has been identified as a significant screening marker not only for MiT translocation RCC but also for TSC/mTOR mutated-associated renal tumors 26,27 . The discovery of recurrent TSC/mTOR mutations in renal HB further promoted us to conduct GPNMB immunohistochemistry to assess its potential as a specific screening marker.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Tuberous Sclerosis Complex/Mammalian Target of Rapamycin Mutations Define Primary Renal Hemangioblastoma as a Unique Entity Distinct From Its Central Nervous System Counterpart

Wang,

Fang,

et al. 2024

American Journal of Surgical Pathology

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Renal hemangioblastoma (HB) is a rare subset of HBs arising outside of the central nervous system (CNS), with its molecular drivers remaining entirely unknown. There were no significant alterations detected in previous studies, including von Hippel-Lindau gene alterations, which are commonly associated with CNS-HB. This study aimed to determine the real molecular identity of renal HB and better understand its relationship with CNS-HB. A cohort of 10 renal HBs was submitted for next-generation sequencing technology. As a control, 5 classic CNS-HBs were similarly analyzed. Based on the molecular results, glycoprotein nonmetastatic B (GPNMB) immunohistochemistry was further performed in the cases of renal HB and CNS-HB. Mutational analysis demonstrated that all 10 renal HBs harbored somatic mutations in tuberous sclerosis complex 1 (TSC1, 5 cases), TSC2 (3 cases), and mammalian target of rapamycin (2 cases), with the majority classified as pathogenic or likely pathogenic. The CNS-HB cohort uniformly demonstrated somatic mutations in the von Hippel-Lindau gene. GPNMB was strong and diffuse in all 10 renal HBs and completely negative in CNS-HBs, reinforcing the molecular findings. Our study reveals a specific molecular hallmark in renal HB, characterized by recurrent TSC/mammalian target of rapamycin mutations, which defines it as a unique entity distinct from CNS-HB. This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.

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Section: Discussionmentioning

confidence: 99%

Recurrent Tuberous Sclerosis Complex/Mammalian Target of Rapamycin Mutations Define Primary Renal Hemangioblastoma as a Unique Entity Distinct From Its Central Nervous System Counterpart

Wang,

Fang,

et al. 2024

American Journal of Surgical Pathology

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“…Hence, although the routine application of expensive sequencing studies to distinguish between these 2 entities for the presence of underlying ELOC1 or TSC1 / 2 aberrations may not be recommended or clinically feasible, it is prudent to consider or interrogate for the possibility of syndromic associations in such cases. Li et al, 21 in a recent study demonstrated that GPNMB can effectively distinguish RCCFMS with TSC/MTOR alterations from ELOC -mutated RCC and other mimics. In this study, GPNMB was strongly and diffusely positive in all tumors with TSC1/2/MTOR alterations (6/6), whereas negative in all ELOC - mutated RCCs (0/6), or CCPRCTs (0/7) ( P =0.002).…”

Section: Differential Diagnosis Of Renal Tumors With Clear Cytoplasm ...mentioning

confidence: 99%

Renal Cell Carcinoma Associated With TSC/MTOR Genomic Alterations: An Update on its Expanding Spectrum and an Approach to Clinicopathologic Work-up

Shah,

Mehra

2023

Advances in Anatomic Pathology

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Renal cell carcinoma (RCC) with tuberous sclerosis complex (TSC)/mammalian target of rapamycin (MTOR) pathway-related genomic alterations have been classically described in hereditary TSC syndrome setting involving germline mutations, whereby cells with a bi-allelic inactivation of genes originate tumors in a classic tumor-suppressor “two-hit” Knudson paradigm. Initial studies of TSC-associated RCC categorized tumors into 3 broad heterogeneous morphologic groups: RCC with smooth muscle stroma, chromophobe-like, and eosinophilic-macrocytic. Recently, a similar morphologic spectrum has been increasingly recognized in novel and emerging entities characterized by somatic mutations in the TSC1/2 and MTOR in patients who do not suffer from the TSC. Correct recognition of RCC with TSC/MTOR mutations is critical for accurate prognostication because such tumors with aggressive behavior have the potential to be tailored to mTOR inhibitors. Whether TSC/MTOR mutated renal epithelial neoplasms represent a distinct molecular class has been confounded by the fact that TSC1/2, and the gene encoding the downstream protein MTOR, are mutated secondarily in ∼5% of the more common subtypes of RCC, including the commonest subtype of clear cell RCC. This review summarizes the expanding morphologic spectrum of renal tumors with TSC/mTOR pathway alterations, specifically for sporadically occurring tumors where these genomic alterations likely are primary pathologic events. Finally, a practical surgical pathology approach to handling these tumors, and a conceptual framework of renal epithelial tumors with TSC/MTOR mutations as a “family of tumors”, is presented.

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Acceptance of emerging renal oncocytic neoplasms: a survey of urologic pathologists

Mohanty,

Lobo,

Jha

et al. 2024

Virchows Arch

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Oncocytic renal neoplasms are a major source of diagnostic challenge in genitourinary pathology; however, they are typically nonaggressive in general, raising the question of whether distinguishing different subtypes, including emerging entities, is necessary. Emerging entities recently described include eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low-grade oncocytic tumor (LOT), eosinophilic vacuolated tumor (EVT), and papillary renal neoplasm with reverse polarity (PRNRP). A survey was shared among 65 urologic pathologists using SurveyMonkey.com (Survey Monkey, Santa Clara, CA, USA). De-identified and anonymized respondent data were analyzed. Sixty-three participants completed the survey and contributed to the study. Participants were from Asia (n = 21; 35%), North America (n = 31; 52%), Europe (n = 6; 10%), and Australia (n = 2; 3%). Half encounter oncocytic renal neoplasms that are difficult to classify monthly or more frequently. Most (70%) indicated that there is enough evidence to consider ESC RCC as a distinct entity now, whereas there was less certainty for LOT (27%), EVT (29%), and PRNRP (37%). However, when combining the responses for sufficient evidence currently and likely in the future, LOT and EVT yielded > 70% and > 60% for PRNRP. Most (60%) would not render an outright diagnosis of oncocytoma on needle core biopsy. There was a dichotomy in the routine use of immunohistochemistry (IHC) in the evaluation of oncocytoma (yes = 52%; no = 48%). The most utilized IHC markers included keratin 7 and 20, KIT, AMACR, PAX8, CA9, melan A, succinate dehydrogenase (SDH)B, and fumarate hydratase (FH). Genetic techniques used included TSC1/TSC2/MTOR (67%) or TFE3 (74%) genes and pathways; however, the majority reported using these very rarely. Only 40% have encountered low-grade oncocytic renal neoplasms that are deficient for FH. Increasing experience with the spectrum of oncocytic renal neoplasms will likely yield further insights into the most appropriate work-up, classification, and clinical management for these entities.

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Positive GPNMB Immunostaining Differentiates Renal Cell Carcinoma With Fibromyomatous Stroma Associated With TSC1/2/MTOR Alterations From Others

Cited by 9 publications

References 29 publications

Recurrent Tuberous Sclerosis Complex/Mammalian Target of Rapamycin Mutations Define Primary Renal Hemangioblastoma as a Unique Entity Distinct From Its Central Nervous System Counterpart

Recurrent Tuberous Sclerosis Complex/Mammalian Target of Rapamycin Mutations Define Primary Renal Hemangioblastoma as a Unique Entity Distinct From Its Central Nervous System Counterpart

Renal Cell Carcinoma Associated With TSC/MTOR Genomic Alterations: An Update on its Expanding Spectrum and an Approach to Clinicopathologic Work-up

Acceptance of emerging renal oncocytic neoplasms: a survey of urologic pathologists

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