(UroToday.com) Dr. Payal Kapur kicked off the session “Managing Renal Cell Carcinoma at All Stages From Research to Practice” with an excellent talk reviewing the ever-changing pathologic classification of renal cell carcinoma.
She started off by noting that the renal tumor classifications have continued to evolve with better understanding of RCC biology. She highlighted the drastic changes between the 2016 WHO classification and the recently updated 2022 4th Edition WHO Classification.
The main differences:
- For the first time, there is a subgroup that is Molecularly Defined Renal Carcinomas (bottom right) – which have a unique constellation of morphologic and clinical findings, but may need genetic testing for confirmation
- No more Papillary Type II RCC – Papillary Renal tumors has been limited to just papillary adenoma or classic Papillary RCC (previously type 1). This is because Papillary Type 2 are a mixed bag.
She summarized the new nomenclature terms and new entities in 2022 edition:
She noted that many of these new entities (which she went through later) were first recognized in Tuberous Sclerosis patients, but then went on to be identified in sporadic cases.
1. Eosinophilic solid and cystic (ESC) RCC
- Sporadic, <10% of TSC patients
- Mostly females
- Wide age range, including pediatrics
- Characterized by Biallelic loss of TSC1 or TSC2 with activation of mTOR complex 1 signaling
- Most are indolent, 5-10% aggressive (complete response to everolimus)
- Pathologic features: As name suggests, solid and cystic architecture – cyst lined by hobnail cells. Abundant eosinophilic cytoplasm. Coarse cytoplasmic stippling and leishmania-like granules. CK20+ / Cathepsin K + / CD117 - / CK 7 - / vimentin -.
- Does NOT need molecularly testing
2. Low grade oncocytic tumor (LOT)
- Have characteristic morphology and IHC patterns
- Previously characterized as eosinophilic variant of chromophobe tumors
- They have more of this edematous clearing that almost look like “boats on a bay” (below):
- IHC stain classinc: CD117 – (typically seen in other oncocytic tumors) / diffuse CK7 +
- LOTs have a unique gene expression different than other eosinophilic tumors
- Typically older patients, indolent clinical nature – none of these patients identified so far have metastatized, so it is important to not call it an RCC
- Can present in sporadic patients, TSC patients and in ESRD patients
3. Eosinophilic Vacuolated tumor (EVT)
- Small solitary tumors / renal masses
- Sporadic – rare in TSC patients
- Most are indolent (limited data) – she has one case of metastates, so this will likely be classified as an RCC eventually.
- In contrast to LOT, have strong Phos S6 expression on IHC
- Vacuoles with large nuclei. No need for molecular testing.
4. ELOC (formerly TCEB1)-mutated RCC – ELOC is elongin-C
- Rare, Largely in Males
- Harbor mutations in ELOC (TCEB1) gene at 8q21.11 – need genetic testing to confirm diagnosis
- Inactivating mutations exclusively involving VHL protein binding residue Y79 and loss of chromosome 8
- Most are indolent, but metastases have been reported
- Overlapping histomorphology with other entities of RCCs with mutations in mTOR pathway genes – nodular, thick transecting fibromuscular bands. Elongated branching tubules. Cells with voluminous cystoplasm.
- CAIX + / CK 7+ / CD 10 + / CK20- / 34bE12-
5. ALK-rearrangement RCC
- Was an emerging entity in 2016 WHO
- Characterized by ALK gene fusion with various partner genes resulting in aberrant ALK activation
- Children: ALK-vinculin & ALK-TPM3 with sickle cell trait
- Asian Adults: EML4-ALK, HOOK1-ALK
- ALK IHC positive OR ALK rearrangement by FISH or RNAseq
- Targeted inhibitors: crizotinib
6. Fumarate hydratase-deficient RCC (formerly Hereditary Leomyomatosis and RCC)
- Name changed to incorporate patients with biallelic somatic FH mutation in addition to patients with HLRCC
- Biallelic somatic FH mutation – but no personal or family history of HLRCC
- HLRCC – autosomal dominant mutations in FH gene. Usually young females, familial. Characterized by multiple cutaneous and uterine leiomyomas, Pheo/paraganglioma and Leydig cell tumors of the testis
7. SMARCB1-deficient RCC
- Includes SMARCB1-deficiient Renal Medullary carcinoma (previously Renal medullary carcinoma) – usually young AA patients with sickle cell trait
- Incldues Unclassified RCC with Medullary phenotype – No hemoglobinopathy
- Includes Dedifferentiated RCC with secondary SMARB1 Loss – lack medullary phenotype
Lastly sarcomatoid / rhabdoid dedifferentiation she touched upon – these represent dedifferentiated forms of any RCC subtype. They are present in 10-15% of all metastatic RCC.
These are highly response to immune checkpoint inhibitors and refractory to targeted therapies.
Enriched with BAP1 and CDKN2A deletions.
Display an immune-inflamed and angio-poor phenotype.
She concluded that you should maintain good communication with your pathologists, especially if you have any questions regarding your pathology specimens!
Presented by: Payal Kapur, MD, University of Texas Southwestern Medical Center
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Associate Professor of Urology, University of California, Davis @tchandra_uromd on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.