To the best of our knowledge, this is the first report of metastasized chromophobe RCC, after complete resection of a primary tumor smaller than 3 cm, in a patient with BHD.

In patients with BHD, the 3 cm rule is commonly applied in the treatment of renal tumors. The 3 cm rule was initially established for patients with von Hippel-Lindau disease (VHL). Two prospective studies showed that the 3 cm rule was effective in minimizing the risk of metastases while maximizing renal function in patients at risk for multifocal and bilateral RCC [9, 10]. These studies were mainly performed in patients with VHL and hereditary papillary RCC; only one patient with a chromophobe RCC and BHD was included. Nonetheless, the 3 cm rule was also implemented for BHD patients [6]. Indirect evidence that the 3 cm rule is safe in BHD is that (1) until now, to our knowledge, no reports of metastases associated with renal tumors smaller than 3 cm were described in BHD patients, and (2) the growth rate of BHD-associated renal tumors is slower than VHL-associated RCC [11]. This is in contrast to Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), in which even small tumors have a high potential to metastasize [12].

Chromophobe RCC, as in our patient, is common in patients with BHD, although other histological subtypes occur as well [3]. Chromophobe RCC is less aggressive as compared to other RCC subtypes and in general rarely metastasizes [13, 14]. The omentum is an uncommon location for metastases, with the most common locations being lung, bone, liver and lymph nodes [15]. Few cases have been reported in literature of omental metastases of a primary RCC [16,17,18,19]. However, these primary tumors were not of chromophobe origin. The mechanism for peritoneal involvement in RCC is not fully understood, but it might be caused by hematogenous spread and/or direct spreading. Although probably rare, tumor seeding due to surgery also has to be taken into consideration [20,21,22]. However, no abnormalities were documented during the surgical procedure of the primary tumor in our patient.

Since our patient presented with metastatic chromophobe RCC, even though the primary tumor of many years ago was smaller than 3 cm on imaging and upon histological evaluation, the question arises whether applying the 3 cm rule in BHD patients is the right strategy. On one hand, it may not be justified to adjust existing screening recommendations based on exceptional observations in single cases. Most likely, the patient presented here might be a single outlier, as these are expected in screening for (inherited) diseases. For example, renal surveillance in BHD often starts at age 20 [3], but a patient with BHD and RCC at age 14 has been reported [23]. Screening guidelines aim to strike a balance between the benefits of screening and the burdens on the patient, taking into account cost-effectiveness. Thus, surveillance recommendations often do not provide complete certainty. On the other hand, metastases in smaller BHD-associated renal tumors may be more common than is currently known. For example because cases may not have been published in the literature, or these patients might not have been recognized as having BHD. Another potential explanation for the lack of data on tumors smaller than 3 cm that metastasized could be that part of the BHD-associated tumors are treated upon detection, even when smaller than 3 cm. However, it is reassuring that metastases in patients with a primary tumor smaller than 3 cm have not been reported. In two BHD cohorts combined, over 70 BHD-associated RCC were reported and the small number of tumors that metastasized were all larger than 6 cm at diagnosis [4, 5].

In conclusion, it is necessary to report experiences with screening, surveillance and treatment in this patient group. Further research in large BHD case series is required to establish whether screening recommendations should be reconsidered.