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ASCO GU 2020

ASCO GU 2020: Best of the Journals – Renal Cell Carcinoma: Pathology Perspective

San Francisco, California (UroToday.com) At the GU ASCO 2020 renal cell carcinoma session, Donna Hansel, MD, provided the pathologist’s perspective of the ‘Best of the Journals’ in 2019.

The first study Dr. Hansel discussed highlighted that large scale studies to define rare entities are increasingly necessary.1 The goal of the study was to define histopathology and distinguishing immunohistochemical/genomic markers to correctly diagnose rare, morphologically overlapping tumors. The relevant background is that all three carcinomas (renal medullary carcinomas, collecting duct carcinomas, and fumarate hydratase-deficient phenotype) may involve the medulla, are high-grade and high-stage, and have been difficult to distinguish in routine diagnostics. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three renal medullary carcinomas, 38 collecting duct carcinomas, and 29 RCCs defined by the fumarate hydratase-deficient phenotype were selected. Twenty-five percent of cases initially diagnosed as collecting duct carcinomas were reclassified as fumarate hydratase-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor-like patterns favored renal medullary carcinomas, whereas intracystic papillary and tubulocystic patterns favored fumarate hydratase-deficient RCC. The tubulopapillary pattern favored both collecting duct carcinomas and fumarate hydratase-deficient RCCs, and the multinodular infiltrating papillary pattern favored collecting duct carcinomas. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the three groups. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. The diagnostic classification algorithm is as follows:


Diagnostic_Classification_Algorithm.png
Dr. Hansel’s summary of this study is as follows:
  • While some morphology favors one tumor entity over another, there is overlap
  • Fumarate hydratase-deficient RCC are under-called by pathologists
  • Immunostains with confirmatory genetic testing is important to exclude fumarate-hydratase deficient RCC

The second study selected by Dr. Hansel highlighted the importance of refinement of tumor classification in rare tumors defined by genetic alterations.2 The goal of this study was to refine diagnostic classification in fumarate-hydratase RCC. The relevant background is that rare RCC associated with hereditary leiomyomatosis and RCC (HLRCC) syndrome may be associated with uterine and cutaneous leiomyomas. RCC in this setting is aggressive and may have metastasis even with small primary tumors. There were 32 patients identified with fumarate hydratase-deficient RCC, confirmed by fumarate hydratase immunohistochemistry and/or fumarate hydratase mutation analysis. The median age at presentation was 43 years (range, 18 to 69 years), and the median tumor size was 6.5 cm (range, 2.5 to 28 cm). This included 71% of patients presenting at stage ≥pT3a. The vast majority of cases showed multiple histologic growth patterns, with papillary (52%) being the most common predominant pattern, followed by solid (21%), cribriform/sieve-like (14%), sarcomatoid (3%), tubular (3%), cystic (3%), and low-grade oncocytic (3%). All cases were evaluated using fumarate hydratase immunohistochemistry, and 3 cases showed retained FH expression. There were 79% of patients showing mutations within coding regions and 21% showing mutations within intronic splice-sites. By immunohistochemistry, 97% of cases were negative for CK7, 93% were negative for p63, and 52% were negative for GATA3. All cases stained were positive for PAX8 and showed retained succinate dehydrogenase B expression. Dr. Hansel’s summary of this study provided the following points:

  • Many cases of fumarate-hydratase deficient RCC are under-called due to a broad range of morphological features
  • Fumarate hydratase immunohistochemistry and/or fumarate hydratase mutation testing is important to exclude the diagnosis
  • Fumarate hydratase immunostain may miss up to 9% of cases in some missense mutation settings – further work up should occur with CK7 loss in a tumor, highlighting the importance of clinical history and family history in clinical notes
  • Family members of patients diagnosed with this entity should also undergo genetic testing for fumarate hydratase deficiency/HLRCC

The third study highlighted assessed the important of redefining entities based on evolving genomic findings. The goal of this study was to define clinicopathological and TFEB gene features associated with TFEB-altered renal carcinomas. The relevant background is that TFEB-associated RCC may be caused by rearrangement of the TFEB gene locus t(6;11) or by amplification of 6p21.1, which includes the TFEB, VEGFA, and CCND3 genes. Although amplified tumors may have worse outcomes, clinicopathological correlation with TFEB expression status has not been assessed in detail. This study included 37 TFEB-altered tumors: 15 6p21.1-amplified and 22 TFEB-rearranged. TFEB status was verified using a combination of fluorescent in situ hybridization (n=27) or comprehensive molecular profiling (n=13) and digital droplet PCR was used to quantify TFEB mRNA expression in 6p21.1-amplified (n=9) and TFEB-rearranged renal tumors (n=19). These results were correlated with TFEB immunohistochemistry. TFEB-altered tumors had higher TFEB expression when normalized to B2M (mean: 168.9%, n=28), compared with non-TFEB-altered controls (mean: 7%, n=18, P=0.005). Interestingly, TFEB expression in tumors with rearrangements (mean: 224.7%, n=19) was higher compared with 6p21.1-amplified tumors (mean: 51.2%, n=9; p=0.06). Dr. Hansel’s take-home points included:

  • TFEB altered carcinomas may show either TFEB translocation or TFEB amplification
  • Amplified tumors may show lower overall TFEB mRNA levels
  • Amplified tumors (6p21.1) may show alterations in other cancer associated factors (VEGFA, CCND3)
  • Confirms that amplified tumors may behave more aggressively than rearranged tumors

The fourth study discussed by Dr. Hansel highlighted the importance of categorizing immune cell infiltrate in the era of immune checkpoint blockade.4 The goal of this study was to evaluate B cell markers in responders and non-responders to immunotherapy using melanoma and metastatic RCC specimens. The relevant background is that tumor infiltrating B cells may be relevant to response to immune checkpoint blockade and may be relevant in the context tertiary lymphoid structures. In this study, the authors performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumors of responders versus non-responders. These findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other immune checkpoint blockade-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. Next, the authors assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrated clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Dr. Hansel’s take-away messages for this study included:

  • Immune checkpoint blockade is relatively recent and important advance in cancer therapy, including RCC
  • Biomarkers that predict response are not optimal – currently PD-1/PD-L1 immunohistochemistry is performed in many pathology departments
  • Recent advances focus on other features of the tumor and immune infiltrate, including tumor mutational burden and immune cell subtype
  • This study raises the possibility that tertiary lymphoid structures reporting and/or CD20 density may be relevant to pre-therapy pathology testing

            The final study discussed by Dr. Hansel assessed the importance of the use of ancillary testing in challenging RCC cases to help with classification.5 The goal of this study is to test chromosome genomic array (OncoScan) in classifying morphologically challenging, unclassified RCC cases. The relevant background is that approximately 4-5% of RCCs remain unclassified. Given the ever-expanding molecular tests that are possible, cytogenetic array may provide an opportunity to categorize many unclassified RCC based on chromosome findings, with additional work up for specific entities as needed. Among 23 cases of unclassified renal tumors, 19 were reclassified with incorporation of cytogenetic and histologic features, including 10 as clear cell RCC, two as collecting duct carcinoma, two as papillary RCC, and one as novel TFEB-amplified tumor lacking TFEB translocation. Of 5 tumors with "hybrid" oncocytic features, three were reclassified as an eosinophilic variant of chromophobe RCC and one as oncocytoma. Of 11 cases of metastatic clear cell RCC, seven (63%) had cytogenetic features associated with a poor prognosis. The summary points of this study are as follows:

  • Cytogenetic analysis may be useful in the following settings: (i) investigating unclassified RCC, (ii) better segregation of tumors with mixed oncocytic features, (iii) testing if multiple tumors represent multiple primaries or a primary-metastasis combination, (iv) identifying chromosomal abnormalities associated with worse outcomes in metastatic ccRCC, (v) identifying new entities
  • Cost of chromosome genomic array testing includes $200,000 for equipment and $600 in reagents per sample

Dr. Hansel provided the following concluding remarks regarding the best of RCC papers in 2019 from a pathologist’s perspective:

  • There is extensive overlap in morphological appearances with many RCC entities – at what point is histopathological review for classification still valuable?
  • Fumarate hydratase RCC is a relatively new entity, but is often underdiagnosed. While best attempts to use fumarate hydrate immunostains can help in most cases, approximately 9% of cases may not show immunohistochemical staining abnormalities
  • Immunohistochemical stains are now often used as a panel to help with the diagnosis, but are not perfect
  • Given the multiple molecular modalities for testing, how should these be prioritized? FISH, cytogenetic mutation profiling, and how do they combine with immunostaining? What is the cost to benefit ratio with many rare RCC subtypes in the mix?
  • Biopsy diagnosis is an additional challenge – with limited materials, what testing should get prioritized? 

Presented by: Donna E. Hansel, Oregon Health and Science University, Portland, OR

Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

References:

  1. Ohe C, Smith SC, Sirohi D, et al. Reappraisal of morphologic differences between renal medullary carcinoma, collecting duct carcinoma, and fumarate hydratase-deficient renal cell carcinoma. Am J Surg Pathol 2018 Mar;42(3):279-292.
  2. Lau HD, Chan E, Fan AC, et al. A clinicopathologic and molecular analysis of fumerate hydratase-deficient renal cell carcinoma in 32 patients. Am J Surg Pathol 2020 Jan;44(1):98-110.
  3. Gupta S, Argani P, Jungbluth AA, et al. TFEB expression profiling in renal cell carcinomas: Clinicopathologic correlations. Am J Surg Pathol 2019 Nov;43(11):1445-1461.
  4. Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 2020 Jan;577(7791):549-555.
  5. Andeen NK, Qu K, Antic T, et al. Clinical Utility of chromosome genomic array testing for unclassified and advanced-stage renal cell carcinomas. Arch Pathol Lab Med 2019 Apr;143(4):494-504.