Introduction

Collision tumors refer to the phenomenon where two or more different and unrelated tumors occur in the same location of an organ and form a single lesion. We present the first case of renal collision tumors composed of clear cell carcinoma (ccRCC) and collecting duct carcinoma (CDC) treated with combined therapy of nivolumab and ipilimumab. In addition, we discuss the histological and immunohistochemical findings, clinical outcomes, and a literature review on other renal collision tumors. This case report has been reported in line with the SCARE Criteria [1].

Clinical Case

An 89-year-old male presented to the emergency room with back pain. The patient’s medical history was significant for diabetes mellitus, asthma and dyslipidemia. Drug history and family history are unremarkable. Computed tomography (CT) demonstrated a large tumor in the left kidney with renal vein thrombosis (Figure 1). There was also evidence of multiple retroperitoneal lymph nodes involvement. The patient underwent uncomplicated left radical nephrectomy.

The nephrectomy specimen showed a 6 cm × 4 cm × 4 cm tumor in the middle pole of the kidney. On histologic examination of the lesion (Figure 2), two distinct morphologies were seen. On low power, there was a well-demarcated border between the two tumors. One tumor had irregularly shaped glands with a thin fibrovascular stroma containing small blood vessels, whereas the second sat in a more abundant desmoplastic stroma. On high power, the first tumor showed abundant clear cytoplasm with minimal atypia and only occasional small nucleoli (World Health Organisation(WHO) grade 1), whereas the second tumor had frankly malignant cytology (WHO grade 3). On immunostaining (Figure 3, Table 1), both tumors stained with carbonic anhydrase IX (CAIX), consistent with renal origin, but only the ccRCC component showed diffuse reactivity with CD10 while the collecting duct carcinoma was strongly positive for CK7 and extremely weak, mainly luminal reactivity for high molecular weight keratin (HMWCK) and CD10.

Two months after the initial nephrectomy, multiple liver and lung metastases, plus right-sided lymph nodes involvement, were discovered on a follow-up CT. According to Heng risk criteria, the patient belonged to the poor risk group. The patient then underwent combination immunotherapy with nivolumab (220 mg) and ipilimumab (73 mg) every 21 days.

After 5 cycles of treatment, a follow-up CT showed disease progression thus treatment was discontinued. The patient opted for palliative care and succumbed to his disease 6 months following diagnosis.

Discussion

Collision tumors in the kidney are rare. To date, there have been 9 reports, including our report, presenting 10 cases of collision tumors composed of ccRCC and CDC (Table 2) [2, 3, 4, 5, 6, 7, 8, 9]. Of these 10 patients, 9 were male. These patients were aged from 21 to 89, with a median age of 55.5 years, which was lower than the median age (64 years) of patients with RCC in general [10]. Laterality was equal, with five tumors occurring on each side. Lung was the most common place where metastases were found (50%), followed by lymph nodes (40%), bone (30%, including one spinal metastasis), liver (20%), bladder (10%), inferior vena cava (10%) and psoas muscle (10%). All patients underwent radical nephrectomy. Adjuvant chemotherapy was used on 2 patients [4, 6]. One patient had combined therapy of cabozantinib and nivolumab [3]. One patient was treated with radiotherapy and adjuvant sunitinib [8]. Survival among these patients varied, from 6 weeks after nephrectomy to no sign of disease progression 12 months after nephrectomy.

In recent years, immune checkpoint inhibitors have become a new standard of care for patients with advanced ccRCC. In particular, a phase III clinical trial demonstrated that a first line combined therapy of nivolumab and ipilimumab significantly prolonged survival in patients with intermediate or poor risk ccRCC, compared to sunitinib [11].

While the treatment protocol for ccRCC has been well established, treatment choices for CDC are limited. CDC is a rare and highly aggressive type of renal neoplasms, with a mean survival of 11 months [12]. A systematic review suggested that gemcitabine and cisplatin should be considered as the standard treatment of metastatic CDC [12]. The benefit of cytoreductive nephrectomy in patients with metastatic CDC is unclear [12].

Evidence supporting the use of immune checkpoint inhibitors in patients with CDC is scarce. To date, three case reports have documented a clinical response with nivolumab monotherapy in patients with metastatic CDC [13, 14, 15]. In a retrospective study, four patients with CDC were treated with nivolumab. Only one patient achieved partial response, while others had progressive disease [16]. With respect to combined therapy, there is one case report presenting a complete response with nivolumab and ipilimumab in a patient with metastatic CDC after radical nephrectomy [17]. In our case, the patient did not show a clinical response to combined therapy of nivolumab and ipilimumab. More studies should be conducted to evaluate the efficacy and criteria of using immune checkpoint inhibitors against CDC.

The diagnosis of CDC relies heavily on histological study, according to WHO’s classification of urological tumors [18]. Immunohistochemical staining can be useful in the differential diagnosis of CDC. In our case, CDC was strongly positive for CK7 and extremely weak, mainly luminal reactivity for HMWCK. Skinnider et al. suggested that expression of HMWCK could help differentiate CDC from tubulocystic carcinoma and renal medullary carcinoma [19]. Nonetheless, recent studies with larger sample sizes showed only 26–29% of CDCs were immunoreactive with HMWCK [20, 21]. In addition, Gupta et al showed CDC and renal medullary carcinoma expressed HMWCK in a similar rate [21]. More studies are needed to clarify its sensitivity in the differential diagnosis of CDC.

Conclusion

In this report, we presented the first documented case of collision tumors composed of ccRCC and CDC, which was treated with combined therapy with nivolumab and ipilimumab, despite no clinical response. Treatment choices for CDC are limited. More studies are needed to evaluate the efficacy of immune checkpoint inhibitors on CDC and its associated collision tumors.