Intratumoral peripheral small papillary tufts might be a diagnostic clue of BHD

Contrary to other hereditary kidney cancer conditions, BHD-associated renal tumours are known to be histologically diverse and discordant within families, meaning that members of the same family do not necessarily get the same type of kidney tumour (Pavlovich et al., 2005). Kuroda et al. (2014) recently reported on the histology of tumours from six BHD patients, and found that, despite being histologically diverse, all had intratumoral peripheral small papillary tufts – clusters of papillary cells – suggesting that these microscopic lesions might be a hallmark of BHD.

The authors selected BHD kidney tumours from six patients who were clinically diagnosed with BHD at Kochi Red Cross Hospital in Japan, between January 2010 and October 2013. These six cases correspond to five families and three of these cases have been previously reported (Furuya et al., 2012, Nagashima et al., 2012). Germline DNA samples were available for genetic analysis for five cases, and a pathogenic  FLCN mutation was found in all five. No sample was available for the sixth patient, so a genetic diagnosis could not be made for this patient, although she has been clinically diagnosed with BHD.

The series consisted of three men and three women, and the average age at diagnosis was 60. One patient had a history of spontaneous pneumothorax, three patients had skin lesions, and all six had lung cysts. All patients are alive without disease following treatment, and show no signs of recurrence or disease in a follow up period ranging between 10 and 46 months.

Five patients had multi-focal kidney tumours, and two had bilateral kidney tumours. Only one patient had a solitary tumour, which may be because she was the youngest patient in this cohort at 46 years old.  The tumours analysed in this study consisted of three hybrid oncocytic/chromophobe tumours; a tumour of unclassified histology, but with features resembling hybrid chromophobe/ clear cell histology; a collision tumour consisting of chromophobe, clear cell and papillary primary tumours; a chromophobe tumour; and a clear cell tumour. This wide range of tumour histologies in such a small sample series supports previous observations that BHD renal tumours are highly variable.

However, small papillary tufts were found in all samples. These papillary tufts were present mainly at the interface between the tumour and normal kidney tissue, or in the case of the collision tumour, at the interface between the chromophobe and clear cell tumours. Given their histology and their presence at the periphery of tumours, the authors termed these microscopic lesions intratumoral peripheral small papillary tufts (ITPSPTs). The authors hypothesise that these microscopic lesions could be precursor lesions that subsequently develop into tumours.

Although ITPSPTs have not been previously reported, similar lesions were been reported in patient with acquired renal cystic disease (Cheuk et al., 2002). Although cytogenetic analysis was performed on these papillary tufts, germline or tumour DNA sequencing for FLCN mutations was not performed. Thus it is possible this patient was an undiagnosed BHD patient, as they had multiple kidney cysts and a tumour with both clear cell and papillary histology.

As ITPSPTs were found in all tumours in their cohort, Kuroda et al. suggest that the presence of ITPSPTs might be a hallmark of BHD tumours, and therefore a diagnostic clue. Analysing ITPSPTs in a larger series of BHD renal tumours and control non-BHD kidney tumours, is required to confirm that ITPSPTs are specific to BHD tumours. They also suggest that patients who present with collision tumours or multiple tumours of different histologies may have BHD, and that these patients should be referred for genetic testing.

 

  • Cheuk W, Lo ES, Chan AK, & Chan JK (2002). Atypical epithelial proliferations in acquired renal cystic disease harbor cytogenetic aberrations. Human pathology, 33 (7), 761-5 PMID: 12196929
  • Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, Hsu YH, Fujii T, Okada A, Kuroda N, Moritani S, Mizuno H, Nagashima Y, Nagahama K, Hiroshima K, Yoshino I, Nomura F, Aoki I, & Nakatani Y (2012). Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. The American journal of surgical pathology, 36 (4), 589-600 PMID: 22441547
  • Kuroda N, Furuya M, Nagashima Y, Gotohda H, Moritani S, Kawakami F, Imamura Y, Bando Y, Takahashi M, Kanayama HO, Ota S, Michal M, Hes O, & Nakatani Y (2014). Intratumoral peripheral small papillary tufts: a diagnostic clue of renal tumors associated with Birt-Hogg-Dubé syndrome. Annals of diagnostic pathology, 18 (3), 171-6 PMID: 24767893
  • Nagashima Y, Furuya M, Gotohda H, Takagi S, Hes O, Michal M, Grossmann P, Tanaka R, Nakatani Y, & Kuroda N (2012). FLCN gene-mutated renal cell neoplasms: mother and daughter cases with a novel germline mutation. International journal of urology : official journal of the Japanese Urological Association, 19 (5), 468-70 PMID: 22211584
  • Pavlovich CP, Grubb RL 3rd, Hurley K, Glenn GM, Toro J, Schmidt LS, Torres-Cabala C, Merino MJ, Zbar B, Choyke P, Walther MM, & Linehan WM (2005). Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. The Journal of urology, 173 (5), 1482-6 PMID: 15821464

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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