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 .
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.
|ANTIGEN/ANTIBODY||CLONE||MANUFACTURER||DILUTION||CCRCC PATTERN (PRESENT CASE)||CDC PATTERN (PRESENT CASE)|
|CA-IX||MRQ-54 (M75)||Cell Marque, California||1 : 100||Diffuse, strong||Diffuse strong|
|CD10||56C6||Novocastra, Leica BioSystems, Germany||1 : 50||Diffuse, strong||Patchy, very weak, luminal|
|CK7||OV-TL 12/30||Dako, Denmark||1 : 50||Patchy, weak||Diffuse, strong|
|CK903 (HMWK)||34E12||Dako, Denmark||1 : 50||Negative||Very weak, luminal|
|GATA3||L50-823||Cell Marque, California||1 : 200||Negative||Negative|
|P63||1 : 50||Negative||Negative|
|PSA||35H9||Leica BioSystems, Germany||Predilute||Negative||Negative|
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.
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 . 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 . One patient was treated with radiotherapy and adjuvant sunitinib . Survival among these patients varied, from 6 weeks after nephrectomy to no sign of disease progression 12 months after nephrectomy.
|STUDY AND YEAR OF PUBLICATION||AGE (YEARS)/SEX||CLINICAL PRESENTATIONS||LOCATION OF CCRCC||LOCATION OF CDC||DIMENSION(CM)||METASTASES||TREATMENT(S)||SURVIVAL||NOTE|
|Salazar-Mejía et al., 2020||47/M||Persistent dry cough, weight loss||Left||Left||16 as a single mass||Lung metastases, adrenal involvement and regional adenopathy before nephrectomy||Left Radical Nephrectomy, followed by combined therapy of cabozantinib and nivolumab; switched to nivolumab only 10 months after combined treatment||15 months after initial diagnosis|
|Yavuzsan et al., 2018 (1)||54/M||Right flank pain||Right upper pole||Right upper pole||7 as a single mass||Para-aortic lymph nodes involvement and lung metastasis before nephrectomy||Right Radical Nephrectomy||6 weeks after surgery|
|Yavuzsan et al., 2018 (2)||62/M||No presentation, discovered in routine checkups||Right middle pole||Right middle pole||5 as a single mass||No||Right Radical Nephrectomy||No signs of metastases for 10 months after surgery|
|Burch-Smith et al., 2014||67/F||Back and abdominal pain, urinary frequency||Left upper pole||Left upper pole||6 as a single mass||Lung metastases (CDC component) at 5 months post-nephrectomy; soft tissue and bone metastasis in thoracic spine||Left Radical Nephrectomy; paclitaxel and carboplatin after lung metastasis was discovered; switched to doxorubicin and gemcitabine after neuropathy was developed||14 months after initial diagnosis|
|Hennessey et al., 2013||21/M||Back pain||Left lower pole||Left lower pole||10.3 as a single mass||Spinal metastases (CDC component) and retroperitoneal nodes involvement before nephrectomy||Left Radical Nephrectomy; urgent radiotherapy for progression of spinal metastases; adjuvant sunitinib||8 months after surgery|
|Tsai et al., 2009||57/M||Acute pyelonephritis||Right||Right||Not provided||Lung and bladder metastases (RCC component) 1-month post-nephrectomy; Multiple metastases to the liver, inferior vena cava and psoas muscle occurred||Right Radical Nephrectomy followed by adjuvant chemotherapy; transurethral resection of the bladder after bladder metastases were discovered||3 months after initial diagnosis||Coexistence of urothelial carcinoma of renal pelvis|
|Cho et al., 2004||24/M||Left abdominal mass||Left inner nodule||Left outer nodule||1.5 for ccRCC; 14 for CDC||No||Left Radical Nephrectomy||No signs of metastases for 12 months after surgery||Nodule to nodule pattern|
|Nagamoto., 2001||51/M||Gross hematuria||Right||Right||Not provided||Not provided||Right Radical Nephrectomy||Not provided||Coexistence of multiple renal cysts|
|Auguet et al., 2000||73/M||Microscopic hematuria||Right upper pole||Right lower pole||1.3 for ccRCC; 6 for CDC||Bone metastases at 8 months post-nephrectomy||Right Radical Nephrectomy||Not provided|
|Our case||89/M||Back pain||Left middle pole||Left middle pole||6 as a single mass||Retroperitoneal lymph nodes involvement before nephrectomy; lung, liver metastases and paraaortic involvement 2 months post nephrectomy||Left Radical Nephrectomy, followed by combined therapy of nivolumab and ipilimumab|
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 .
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 . A systematic review suggested that gemcitabine and cisplatin should be considered as the standard treatment of metastatic CDC . The benefit of cytoreductive nephrectomy in patients with metastatic CDC is unclear .
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 . 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 . 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 . 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 . 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 . More studies are needed to clarify its sensitivity in the differential diagnosis of CDC.
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.
ccRCC, clear cell renal cell carcinoma; CDC, collecting duct carcinoma; CT, computed tomography; HMWCK, High molecular weight cytokeratin; WHO, World Health Organisation.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief on request.
The authors have no competing interests to declare.
CS: Investigation, Data Curation, Writing – Original Draft; MK: Investigation, Data Curation, Writing – Original Draft; WK: Investigation, Resources, Writing – Review & Editing, Supervision; GB: Resources, Writing – Review & Editing, Visualization; BS: Conceptualization, Investigation, Resources, Writing – Review & Editing, Visualization, Supervision; OL: Investigation, Resources; MZ: Resources, Writing – Review & Editing; SAS: Resources, Writing – Review & Editing, EM: Resources, Writing – Review & Editing, DL: Resources, Writing – Review & Editing.
Chun Ho Szeto, MPH and Muhammad Krenawi, MD have contributed equally to this work and shared first authorship.
Agha RA, Franchi T, Sohrabi C, et al. The SCARE 2020 Guideline: Updating Consensus Surgical CAse REport (SCARE) Guidelines. Int J Surg. 2020; 84: 226–230. DOI: https://doi.org/10.1016/j.ijsu.2020.10.034
Cho NH, Kim S, Ha MJ, Kim HJ. Simultaneous heterogenotypic renal cell carcinoma: Immunohistochemical and karyoptic analysis by comparative genomic hybridization. Urol Int. 2004; 72(4): 344–348. DOI: https://doi.org/10.1159/000077691
Salazar-Mejía CE, Oyervides-Juárez VM, Wimer-Castillo BO, Vidal-Gutiérrez O, Garza-Guajardo R, Grande E. Collision tumor of the kidney composed of clear cell carcinoma and collecting duct carcinoma treated with cabozantinib and nivolumab. Curr Probl Cancer Case Reports. 2020 October; 2: 100039. DOI: https://doi.org/10.1016/j.cpccr.2020.100039
Burch-Smith R, Tannir NM, Resetkova E, Tamboli P, Rao P. Collision tumor of the kidney composed of clear cell carcinoma and collecting duct carcinoma: report of a case with unusual morphology and clinical follow up. Chin J Cancer. 2014; 33(7): 351–355. DOI: https://doi.org/10.5732/cjc.013.10155
Yavuzhan AH, Eksi M, Baytekin F, Tugcu V. Aggressive co-existence: Collecting duct and clear cell carcinoma in the same kidney. Türk Üroloji Dergisi/Turkish J Urol. 2019; 45(Supp. 1): 131–134. DOI: https://doi.org/10.5152/tud.2018.44342
Tsai TH, Tang SH, Chuang FP, et al. Ipsilateral Synchronous Neoplasms of Kidney Presenting as Acute Pyelonephritis and Bladder Metastasis. Urology. 2009; 73(5): 1163.e9–1163.e11. DOI: https://doi.org/10.1016/j.urology.2008.03.049
Auguet T, Molina JC, Lorenzo A, Vila J, Sirvent JJ, Richart C. Synchronus renal cell carcinoma and Bellini duct carcinoma: A case report on a rare coincidence. World J Urol. 2000; 18(6): 449–451. DOI: https://doi.org/10.1007/s003450000157
Hennessey DB, Thomas AZ, Lynch TH. Mixed collecting duct and renal cell carcinoma presenting with spinal cord compression. Case Reports. 2013; 2013(apr19 1): bcr2013008987–bcr2013008987. DOI: https://doi.org/10.1136/bcr-2013-008987
Nagamoto A, Kijima H, Tsuchida T, Nomura S, Kumagai H. Collecting duct carcinoma mixed with common renal cell carcinoma: analysis of morphological characteristics using lectin histochemistry. Anticancer Res. 2001; 21(1B): 567–570. http://www.ncbi.nlm.nih.gov/pubmed/11299805.
Thompson RH, Ordonez MA, Iasonos A, et al. RENAL CELL CARCINOMA IN YOUNG AND OLD PATIENTS: IS THERE A DIFFERENCE? J Urol. 2008; 180(4): 1262. DOI: https://doi.org/10.1016/j.juro.2008.06.037
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018; 378(14): 1277–1290. DOI: https://doi.org/10.1056/NEJMoa1712126
Dason S, Allard C, Sheridan-Jonah A, et al. Management of renal collecting duct carcinoma: A systematic review and the McMaster experience. Curr Oncol. 2013; 20(3): 223–232. DOI: https://doi.org/10.3747/co.20.1230
Rimar KJ, Meeks JJ, Kuzel TM. Anti-programmed Death Receptor 1 Blockade Induces Clinical Response in a Patient With Metastatic Collecting Duct Carcinoma. Clin Genitourin Cancer. 2016; 14(4): e431–e434. DOI: https://doi.org/10.1016/j.clgc.2016.02.013
Yasuoka S, Hamasaki T, Kuribayashi E, et al. Nivolumab therapy for metastatic collecting duct carcinoma after nephrectomy. Med (United States). 2018; 97(45): 1–4. DOI: https://doi.org/10.1097/MD.0000000000013173
Mizutani K, Horie K, Nagai S, et al. Response to nivolumab in metastatic collecting duct carcinoma expressing PD L1: A case report. Mol Clin Oncol. 2017; 988–990. DOI: https://doi.org/10.3892/mco.2017.1449
Koshkin VS, Barata PC, Zhang T, et al. Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma. J Immunother Cancer. 2018; 6(1): 1–7. DOI: https://doi.org/10.1186/s40425-018-0319-9
Watanabe K, Sugiyama T, Otsuka A, Miyake H. Complete response to combination therapy with nivolumab and ipilimumab for metastatic collecting duct carcinoma of the kidney. Int Cancer Conf J. 2020; 9(1): 32–35. DOI: https://doi.org/10.1007/s13691-019-00389-z
Moch H, Amin MB, Argani P, Cheville J, Delahunt B. WHO Classification of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC; 2016. https://linkinghub.elsevier.com/retrieve/pii/S0090429504011148.
Skinnider BF, Folpe AL, Hennigar RA, et al. Distribution of Cytokeratins and Vimentin in Adult Renal Neoplasms and Normal Renal Tissue. Am J Surg Pathol. 2005; 29(6): 747–754. DOI: https://doi.org/10.1097/01.pas.0000163362.78475.63
Kobayashi N, Matsuzaki O, Shirai S, Aoki I, Yao M, Nagashima Y. Collecting duct carcinoma of the kidney: an immunohistochemical evaluation of the use of antibodies for differential diagnosis. Hum Pathol. 2008; 39(9): 1350–1359. DOI: https://doi.org/10.1016/j.humpath.2007.11.020
Gupta R, Billis A, Shah RB, et al. Carcinoma of the collecting ducts of bellini and renal medullary carcinoma: Clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship. Am J Surg Pathol. 2012; 36(9): 1265–1278. DOI: https://doi.org/10.1097/PAS.0b013e3182635954