A rare case of FH-deficient renal cell carcinoma with signet ring cells features

Abstract

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a clinically aggressive tumor with high rates of progression and mortality. A wide range of morphological variations has been observed in FH-deficient RCC, initially described as type 2 papillary RCC or unclassified RCC. Here, we report a case of FH-deficient RCC with rare signet ring cells features. The patient was diagnosed with FH-deficient renal cell carcinoma and suspected to have hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. After 4 months, pulmonary metastasis occurred in the patient. We herein describe the first case of FH-deficient renal tumor with signet ring cells features, which expands the morphological spectrum of this tumor. More importantly, this variant can be a diagnostic pitfall, we emphasize that pathologists should consider not only the diagnosis of metastatic signet ring cell carcinoma and ALK rearrangement renal cell carcinoma but also FH-deficient renal cell carcinoma.

Introduction

FH-deficient RCC was first included as a separate entity in the 2016 WHO classification of renal cell tumors [1]. Germline mutations in tumor are associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). FH is located on chromosome 1q42.3-43 and encodes fumarate hydratase. The latter catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle. Elevated levels of fumarate lead to the accumulation of HIF1a protein, resulting in the dysregulation of cellular metabolism and promotion of tumorigenesis [2]. FH-deficient RCC, previously categorized as type 2 papillary RCC or unclassified RCC, is reported to occur in approximately 15–30% of patients with HLRCC [3]. Elevated levels of fumarate lead to the succination of proteins and the production of S-(2-succino)-cysteine (2SC), which can serve as a marker for detecting tumors in FH-deficient RCC. Herein, we report a rare case of FH-deficient RCC with signet ring cells features.

Case presentation

A 60-year-old woman with a history of uterine leiomyoma, underwent hysterectomy 20 years previously. The patient had no relevant family history. Abdominal magnetic resonance imaging (MRI) revealed a 35 × 33 × 32 mm mass in the right kidney (Fig. 1a), suggesting the possibility of oncocytoma or chromophobe renal cell carcinoma. Recently, nodules or papules have been observed on the patient’s trunk skin (Fig. 2d), suggesting the potential presence of cutaneous leiomyomas. However, this remains to be confirmed by pathology. The patient underwent partial nephrectomy. Histological examination of the gross specimen revealed an encapsulated mass measuring 41 × 35 × 33 mm (Fig. 2c). Microscopically, a variety of growth patterns were observed in the tumor, including papillary, tubulocystic, cystic, and cribriform patterns (Fig. 3e-g). The tumor cells displayed eosinophilic cytoplasm and a high nuclear grade (WHO/ISUP 3), characterized by viral inclusion-like macronucleoli and perinucleolar halos (Fig. 3j). Additionally, some areas demonstrated intracytoplasmic mucin resembling signet ring cells (Fig. 3h-i). Foamy macrophages and hemosiderin were also observed. Immunohistochemically, the tumor cells were positive for CK8/18, Pax-8, Pax-2, P504s, SDHB, and 2-succinylcysteine (2SC) protein (Fig. 4l) but negative for CK7, CD10, CD117, CAIX, FH (Fig. 4k), ALK, and TFE3 protein. Intracytoplasmic mucin was detected by MUC1 (Fig. 4m) and Alcian blue staining (Fig. 4n). The proliferation rate of Ki-67 was approximately 20%.

Finally, the patient was diagnosed with FH-deficient renal cell carcinoma. Owing to the presence of uterine leiomyomas and suspected cutaneous leiomyomas, we strongly considered it to be associated with hereditary leiomyomatosis and renal cell cancer syndrome.

The postoperative course of the patient was uneventful, and neither adjuvant radiotherapy nor chemotherapy was performed. After a period of four months, a nodule measuring 8 × 7 mm was observed in the right pulmonary area (Fig. 1b), indicating the presence of pulmonary metastasis.

Fig. 1

Abdominal magnetic resonance imaging (MRI) revealed a right renal tumor measuring 35 × 33 × 32 mm (the white head of arrow) (a). Enhanced computed tomography (CT) showed an 8 mm diameter nodule in the right pulmonary (the red head of arrow) (b)

Fig. 2

Gross specimen examination revealed a predominantly solid and encapsulated mass (c). Multiple papules or nodules were observed on the skin of the trunk, suspected to be cutaneous leiomyomas (d)

Fig. 3

Various growth patterns of FH-deficient RCC. There were papillary (e), tubulocystic/cystic (f) and cribriform (g) patterns observed in the tumor. Prominent intracytoplasmic mucin or non-mucous vacuole was observed in the section of the tumor, resembling signet ring cells (h-i). These tumor cells displayed a high nuclear grade (WHO/ISUP 3), with eosinophilic cytoplasm, viral inclusion-like macronucleoli and perinucleolar halos (j)

Fig. 4

Immunohistochemical staining showed diffuse loss of FH staining in tumor cells, with stromal cells and blood vessel endothelial cells serving as internal positive controls (k). The tumor cells showed diffuse expression of 2SC staining (l). Intracytoplasmic mucin was demonstrated by MUC1 (m) and Alcian blue staining (n)

Discussion

The term “FH-deficient RCC” is increasingly used to describe RCC with FH protein loss by IHC, especially in cases where the genetic status is unknown [4] or there is no evidence of an FH germline mutation [5] at pathological diagnosis. Tumors with FH germline mutations are associated with HLRCC. FH-deficient RCC occurs in approximately 15–30% of patients with HLRCC, with a risk 6.5-fold higher than that in the general population [6]. Therefore, it is important to recognize of this entity. FH-deficient RCC often show a morphologically overlapping spectrum with type 2 papillary renal cell carcinoma. Several studies [5, 7,8,9] have described a rare, low-grade form of FH-deficient RCC, characterized by abundant eosinophilic cytoplasm with variable flocculence and vacuolization. These tumors morphologically resemble low-grade oncocytic renal tumors, such as oncocytoma, succinate dehydrogenase (SDH)-deficient RCC, or other oncocytic tumors. In this study, we report a case of FH-deficient renal cell carcinoma with rare signet ring cells morphology and intracytoplasmic mucin. The differential diagnosis we initially considered are metastatic signet ring cell carcinoma and ALK rearrangement renal cell carcinoma. Interestingly, it has been reported that the presence of signet ring cells morphology was observed in renal cell carcinoma with a novel STRN::ALK fusion [10]. Signet ring cells features are commonly observed in poorly differentiated adenocarcinomas of the stomach, breast and colorectum. Tumor with predominant signet ring cells features (> 50%) can be categorized as signet ring cells carcinoma, which represents a subset of tumors with an aggressive biological behavior that is prone to a peritoneal spreading pattern [11] and has a poor prognosis [12,13,14,15]. It is crucial for pathologists to identify and report the presence of signet ring cells features from a clinical perspective.

FH and 2-SC IHC are highly sensitive and reliable adjunct tools for the detection of FH-deficient RCC. However, FH is not 100% sensitive for detecting FH-deficient RCC [8, 16,17,18]. Up to 20-25% of FH-deficient RCC may still show FH expression, which can be a diagnostic pitfall, especially without access to 2SC immunohistochemistry. There are similar reports on missense mutations in the FH gene that may retain FH expression [6, 19, 20]. Additionally, it is uncommon to observe heterogeneous FH expression in some genomically proven FH-deficient RCC [6]. Therefore, it is crucial to recognize and confirm FH mutation analysis. Member B10 of the aldo-keto reductase family 1 (AKR1B10), is a potential biomarker for FH-deficient uterine leiomyomas [21], with 100% sensitivity and 99% specificity. A recent new study [22] indicated that AKR1B10 is a significant diagnostic biomarker with 100% sensitivity and 91.4% specificity for FH-deficient RCC. Therefore, the combination of FH, AKR1B10, and 2SC is expected to improve the detection rate of FH-deficient RCC.

Notably, there is a high incidence of early and extensive distant metastases in FH-deficient RCC, although the primary tumor is small, which is the primary factor contributing to mortality. The most recent common ancestor (MRCA)-dominated punctuated evolutionary pattern [23] was primarily proposed in FH-deficient RCC, suggesting that metastatic competence is acquired in primary MRCA and leads to rapid progression. Similar findings were also observed by TRACERx renal team [24]. In our case, the patient developed rapid lung metastasis. We attribute this to two potential factors. First, occult micro-metastases may be present at the time of initial diagnosis or even earlier. Second, signet ring cells features may indicate poor prognosis, leading to rapid metastasis and potentially fatal consequences. However, we currently lack adequate evidence to establish that the presence of signet ring cell features is indicative of a poor prognosis in this highly aggressive malignant tumor, which requires more clinical cases and related clinical experiments. Although it was not possible to alter the inherent invasiveness of the FH gene mutation, according to the MRCA-dominated punctuated evolutionary pattern, primary tumors may act as a reservoir of metastasis and early intervention can lead to a positive clinical therapeutic outcome. To eliminate tumors to the maximum extent possible, radical nephrectomy may be the preferred local treatment for individuals without metastasis. Several prospective clinical trials have recommended cytoreductive nephrectomy (CN) for metastatic ccRCC patients [23, 25, 26]. Therefore, some scholars have proposed that patients with metastatic FH-deficient RCC could also benefit from CN [23].

In recent years, there has been growing focus on exploring the potential therapeutic value of FH-deficient renal cell carcinoma. CDKN2A promoter hypermethylation is commonly observed in FH-deficient RCC, suggesting the potential of CDK4/6 inhibitors in this type of RCC. The study conducted by Liang et al. [23] reported an unfavorable response to PD-1/PD-L1-based therapy and a poor prognosis in patients with NF2 mutations. Several studies have revealed that bevacizumab plus erlotinib (Bev/Erlo) therapy shows promising results for advanced HLRCC-associated RCC [27, 28]. A prospective study showed that VEGF treatment presented an ORR of 22.2% and a disease control rate (DCR) of 30% in FH-deficient RCC, while combined therapy with VEGF and checkpoint inhibitors in the tumor had an ORR of 40% and a DCR of 100% [29]. A clinical trial of patients with advanced FH-deficient RCC showed that ICI/TKI combination therapy was associated with more favorable OS and PFS on first-line therapy than Bev/Erlo combination therapy [30]. In a prospective clinical trial, a 49-year-old man with HLRCC-associated RCC showed a complete response to combination immunotherapy with nivolumab and ipilimumab [31]. Although some clinical trials have shown encouraging results, owing to limited clinical data, there is currently no consensus on the treatment of FH-deficient RCC.

Conclusion

We are the first to describe signet ring cells features in FH-deficient RCC, which expands the morphological spectrum of FH-deficient tumors. Early identification and clinical intervention are crucial for patients. Subsequent genetic counseling and screening for FH variants are advised for patients and their family members.