Intranuclear inclusions are a distinguishing morphological feature of renal cell carcinoma with leiomyomatous stroma

Renal cell carcinoma with leiomyomatous stroma (RCCLMS) is an uncommon neoplasm classified as a provisional entity in the 2016 World Health Organization classification of kidney tumours. The relationship of RCCLMS to clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma remains unclear, although increasing evidence supports it as a distinct entity with a unique molecular profile. In particular, RCCLMS does not appear to harbour alterations in chromosome 3p or the VHL gene as seen in conventional RCC. A recent study showed recurrent mutations of TSC1/TSC2, MTOR, and/or TCEB1 genes in all 14 tested cases of RCCLMS, supporting the hypothesis that these tumours represent the sporadic counterpart of histologically similar tumours presenting in patients with tuberous sclerosis. Further elucidation of the morphological features of RCCLMS could assist pathologists to identify this rare tumour.

We retrospectively compiled four cases of RCCLMS; three were reported at our institution and one was an external consultation (Table 1). None of the patients had tuberous sclerosis or end stage kidney disease. The tumours were small and confined to the kidney (pT1a), with no recurrence or metastasis documented in the limited follow-up period (<2 years). The morphology and immunohistochemical findings were similar to previously reported cases. The tumours were circumscribed by an irregular pseudocapsule and showed nodules of clear cells with inconspicuous nucleoli arranged in nests, tubules and occasional papillary structures (Fig. 1). Immunohistochemistry revealed a consistent pattern with positive staining for CK7 and CD10 in the epithelium and smooth muscle actin positivity in the leiomyomatous stroma (Fig. 1). In addition, all four cases showed optically clear to pale eosinophilic inclusions within the nuclei of the lesional clear cells (Fig. 2). The inclusions could be appreciated at 200× magnification and occupied most of the nucleus. Ultrastructural analysis by electron microscopy showed invaginations of the nuclear membrane containing cytoplasmic organelles (Fig. 2) within tumour cells, consistent with intranuclear cytoplasmic inclusions. Tumour cells with intranuclear inclusions varied in proportion across and within the tumours but were present at least focally in all sections examined. Interestingly, one of the patients (Case 1) had three discrete synchronous tumours each resected separately from the same kidney. The RCCLMS, papillary RCC and clear cell papillary RCC each had distinct morphological and immunohistochemical profiles, consistent with previous reports. Intranuclear inclusions were present within the RCCLMS only.

A search of the literature did not reveal any prior documentation of intranuclear inclusions in RCCLMS, however such inclusions could be appreciated in multiple micrographs of published case reports of RCCLMS (Fig. 2).^{,  ,}  Intranuclear inclusions have been reported in RCC, with a higher frequency in papillary and chromophobe carcinoma. However, these inclusions were described as eosinophilic in colour and were associated with tumours of grade 3/4. In contrast, the inclusions in our series were colourless and present in tumours with inconspicuous nucleoli consistent with WHO/ISUP grade 1/2.

Intranuclear inclusions are a previously unreported histological characteristic of RCCLMS, present in all tumours in this series and appreciable in published images of previous case reports. Formal analysis in a larger series is required to determine the prevalence of intranuclear inclusions in RCCLMS and their relationship to molecular findings. The limited available data suggest that RCCLMS has indolent biological behaviour and this readily assessable morphological feature may prove useful in distinguishing RCCLMS from other clear cell renal neoplasms.