SDH-deficient renal cell carcinoma: a clinicopathological analysis highlighting the role of genetic counselling

Abstract

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) accounts for 0.05–2% of all RCCs. The majority of patients have germline mutations, most frequently in the SDHB gene. People with these mutations are predisposed to developing paragangliomas, phaeochromocytomas and gastrointestinal stromal tumours. Patients should be referred to genetic services for further workup and close surveillance imaging due to the risk of development of further tumours. We present a woman with SDH-deficient RCC and review the literature associated with this uncommon entity.

Introduction

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) was first identified in 2004 and is estimated to account for 0.05–2% of all RCCs. SDH is an enzyme complex required for energy metabolism within cells, encoded by four genes – SDHA, SDHB, SDHC and SDHD. The majority of people with SDH-deficient RCC have germline mutations, most commonly affecting the SDHB gene. People with these mutations are predisposed to developing paragangliomas, phaeochromocytomas and gastrointestinal stromal tumours. We report a woman with SDH-deficient RCC managed at our institution and review the literature associated with the condition.

Case history

A 41-year-old woman with no previous medical history presented with a 3-year history of intermittent left iliac fossa pain. Abdominal ultrasound examination incidentally identified a 4.9cm right renal mass. The mass was further characterised and staged with computed tomography of the thorax, abdomen and pelvis. This confirmed a 55mm enhancing mass arising from the upper pole of the right kidney. There was no evidence of metastatic disease, no nodal involvement and no sinister thoracic pathology. The left kidney appeared normal. The radiological appearances were indicative of RCC. The radiological stage was T1N0M0 RCC.

The woman underwent an uncomplicated right laparoscopic radical nephrectomy following discussion at the local urology oncology multidisciplinary team meeting. She made an uneventful postoperative recovery.

Histopathological examination of the renal tumour showed an SDH-deficient carcinoma, specifically with loss of SDHB expression on immunohistochemical staining. Based on this, the woman was referred to the clinical genetics team for further workup, including a pedigree analysis and a panel of genetic screening tests. This revealed a maternal history of phaeochromocytoma when her mother was in her twenties, increasing the possibility that this RCC was a result of a hereditary germline mutation in the SDHB gene. Subsequent genetic testing confirmed a mutation in the SDHB gene with the c.72+1G>T SDHB pathogenic variant.

The woman was diagnosed with familial paragangliomatosis and counselled regarding the likely inheritance from her mother. The implication of the diagnosis was that she and other family members may be at risk of further paragangliomas and require surveillance screening.

Given the diagnosis, the woman’s mother and sister were offered genetic screening for paragangliomas. The woman remains on lifelong imaging surveillance under the care of the endocrinology team, with annual clinic review with plasma metanephrines, annual renal ultrasound, and magnetic resonance imaging of the neck, chest, abdomen and pelvis every three years.

Figure 1.

Coronal computed tomography image demonstrating a heterogenous 55mm mass arising from the right upper pole

Figure 2.

Gross bisected nephrectomy specimen

Figure 3.

H&E-stained tissue section showing solid sheets of cells with classical flocculent pale eosinophilic cytoplasm (arrow)

Figure 4.

SDHB-immunostained tissue section showing normal expression (positive brown staining) in background renal tubules (top right) and loss of expression (negative staining) within tumour

Discussion

There are many subtypes of RCC. They are often found incidentally due to their asymptomatic presence in the population. SDH-deficient RCC remains a very rare and aggressive subtype of RCC. Although there is a paucity of literature, SDH-deficient RCCs are understood to be found in young adults, with an estimated incidence of 0.05–0.2% of all RCCs.¹ Limited studies have reported a male predominance of 1.75:1 and an average initial presentation age of 36.8 years. SDH-deficient RCC was recognised in 2016 by the World Health Organization.²

SDH-deficient RCC is linked with SDH germline mutations alongside paragangliomas, phaeochromocytomas, pituitary adenomas and gastrointestinal stromal tumours.³ In particular, SDHB subunit mutations have been associated with a predisposition for early incidence of RCC, histologically characterised by the loss of immunohistochemical SDHB expression, with distinctive morphological features, as in our case.⁴

SDH-deficient RCCs have a well-circumscribed pushing margin, often entrapping native renal tubules, which were observed in this case. Tumour cells are classically arranged in solid sheets or nests and have smooth nuclei with evenly dispersed chromatin. The most distinctive morphological feature is the presence of flocculent, pale eosinophilic cytoplasmic inclusions. Loss of immunohistochemical staining for SDHB is a requirement for tissue diagnosis.

Although aggressive, the SDHB mutation confers a more positive prognosis in RCC following complete surgical resection, unless there is evidence of sarcomatoid dedifferentiation.⁵

Once identified as an RCC, the histopathology of the specimen became key to understanding whether this tumour had the clinical potential for germline mutation, which was then confirmed and explored with DNA testing.

The role of genetic testing for this patient allowed confirmation of her familial paragangliomatosis. Without knowledge of this hereditary germline mutation, she and other family members would not have undergone lifelong surveillance for future incidence of paragangliomas. This case highlights the important recommendation for taking detailed family history and genetic counselling in young people with new diagnoses of RCC when SDH deficiency is suspected.