Reappraisal of Morphologic Differences Between Renal Medullary Carcinoma, Collecting Duct Carcinoma, and Fumarate Hydratase–deficient Renal Cell Carcinoma

Abstract

Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH/2SC or FH/2SC with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-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 RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion-like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. 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. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded.

New and emerging renal entities: a perspective post‐WHO 2016 classification

“…FH‐deficient RCC is an RCC characterised by aggressive behaviour, morphology comprising variable and often mixed architectural patterns, markedly enlarged, viral‐like nucleoli, and germline mutation in FH . This gene is located at 1q42.3–q43, and codes for an enzyme involved in the tricarboxylic acid or Krebs cycle, which hydrates fumarate to form malate, but, when mutated, leads to HLRCC .…”

“…Patients with renal tumours confirmed as having an FH mutation can be referred to as having ‘FH‐deficient RCC’, as well as ‘HLRCC‐associated RCC’, if the patient syndromic setting is known. However, in our view, ‘FH‐deficient RCC’ is a term that can also refer to RCCs in patients that: (i) show compatible morphology; (ii) show negative IHC staining for FH, and/or positive IHC staining for S ‐(2‐succino)‐cysteine (2SC); (iii) have an uncertain clinical and family history regarding skin and uterine leiomyomas and RCC; and (iv) have unknown genetic status at the time of the pathology case sign‐out, which is not an uncommon scenario in practice …”

“…Both FH‐deficient RCC and HLRCC‐associated RCC are characterised by inactivating germline mutations in FH , and both occur more frequently at a younger age, and show an aggressive clinical course and adverse morphological features at presentation. On histology, both typically show a multiplicity of morphological patterns, represented mostly by papillary architecture admixed with other patterns, and at least focal, viral‐like macronucleoli (Figure A–D) . Most HLRCC patients show a syndromic association with either skin leiomyomas (73% frequency in FH mutation‐confirmed patients) or uterine leiomyomas in females (77% frequency in FH mutation‐confirmed patients) .…”

High grade infiltrative adenocarcinomas of renal cell origin: New insights into classification, morphology, and molecular pathogenesis

“…Recently, we have performed a comprehensive and semiquantitative study of the morphologic patterns of RMC and key tumors in the differential (specifically, CDC and FH‐deficient RCC), which we believe sheds some light on the morphologic differential diagnosis. Specifically, based on evaluation of 100 examples of these morphologically overlapping high grade distal nephron‐related adenocarcinomas, we identified the majority of cases of RMC showed at least a focal pattern of reticular (85%) and cribriform (88%) appearance . Though this reticular/yolk sac tumor‐like and cribriform adenoid cystic‐like pattern was usually only seen as a minor component, in the context of the myxoid and inflammatory stroma often seen in these tumors, we felt that it was sufficiently distinctive to propose as a morphologic clue to aid in choice of “next steps” in case workup.…”

“…Though this reticular/yolk sac tumor‐like and cribriform adenoid cystic‐like pattern was usually only seen as a minor component, in the context of the myxoid and inflammatory stroma often seen in these tumors, we felt that it was sufficiently distinctive to propose as a morphologic clue to aid in choice of “next steps” in case workup. In contrast, tubulopapillary patterns are less commonly seen in RMC, favoring consideration of other RCC types …”