Introduction

Birt-Hogg-Dubé syndrome (BHD, MIM #135150) is an autosomal dominant hereditary predisposition for fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma (RCC). The estimated RCC risk in BHD is 16–21% until age 70 [1, 2] and patients with BHD are advised to undergo regular renal surveillance [3]. BHD-associated RCC may be bilateral and/or multifocal and often has a chromophobe component [4, 5]. In general, BHD-associated renal tumors are considered to be of indolent behavior and therefore, treatment of renal tumors can be postponed until the tumor reaches a diameter of 3 cm (3 cm rule) [6, 7].

Case description

A 53 year old women presented with acute back pain. Ultrasound examination showed a right-sided renal mass measuring 2.5 × 1.5 × 2 cm. On CT, the tumor had a maximal diameter of 2.8 cm (indicated by the arrow in Fig. 1).

Fig. 1
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Renal tumor

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She was initially treated by partial nephrectomy. Histological evaluation showed a 2.8 cm eosinophilic chromophobe RCC, Fuhrmann grade 2, positive for cytokeratin 7, 8 and 18, EMA, CD10, and colloidal iron and negative for vimentin. As not all resection margins were free of tumor, a radical nephrectomy was performed subsequently. No residual tumor was detected in the remaining kidney tissue. Follow-up took place according to appropriate guidelines for RCC. At age 59, six years after removal of the primary tumor, six omental metastases were identified on abdominal CT. A biopsy showed a malignancy, histologically comparable to the previously removed primary tumor (PAX8, CK7, CD117 and CD10 positive). Since the patient had no lesions in her remaining kidney, the omental lesions were considered metastases from the primary tumor diagnosed 6 years previously. Molecular testing to get extra evidence for clonality between the primary tumor and the metastases was not possible, as no suitable material of the primary tumor was available. After diagnosis of the omental metastases, the patient was treated with immunotherapy in a phase II study (4 cycles nivolumab and iplimumab followed by 14 cycles nivolumab). The metastases show minimal progression despite immunotherapy and currently she is in a wait-and-see policy.

The family history was negative for RCC and pneumothorax. On physical examination, the patient had multiple small papules compatible with fibrofolliculomas (Fig. 2). They were subtle on the face, more prominent in the neck and innumerable on chest and abdomen. Genetic testing at age 59 confirmed the clinical diagnosis of BHD: A previously reported pathogenic germline variant was identified in FLCN (c.619-1G > A) [1]. Family members were offered genetic testing and upon detection of the FLCN variant, renal surveillance.

Fig. 2
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Skin lesions on abdomen

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Chest imaging was performed as part of staging and follow-up from age 53 onwards. Chest CT’s retrospectively showed around 10–20 bilateral thin-walled cysts, most prominent in the basal parts of the lungs, consistent with BHD (indicated by the arrows in Fig. 3, chest CT at age 60). Since these cysts were quite subtle, they had not been recognized as possibly related to BHD initially [8].

Fig. 3
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Lung cysts

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Discussion

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.