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Case Report

Renal Collision Tumor Composed of Clear Cell Carcinoma and Collecting Duct Carcinoma Treated with Nivolumab and Ipilimumab: Case Report and Literature Review

Authors:

Chun Ho Szeto,

Medical School of International Health, Ben Gurion University of the Negev, Be’er Sheva, IL
About Chun Ho

MPH

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Muhammad Krenawi,

Department of Urology, Yoseftal Medical Center, Eilat, IL
About Muhammad

MD

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Gal Ben-Arie,

Medical School of International Health, Ben Gurion University of the Negev, Be’er Sheva; Department of Radiology, Soroka University Medical Center, Be’er Sheva, IL
About Gal

MD

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Benzion Samueli,

Medical School of International Health, Ben Gurion University of the Negev, Be’er Sheva; Department of Pathology, Soroka University Medical Center, Be’er Sheva, IL
About Benzion

MD

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Oleg Lavon,

Department of Pathology, Soroka University Medical Center, Be’er Sheva, IL
About Oleg

MD

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Shadi Abu-Swis,

The Legacy Heritage Oncology Center & Dr. Larry Norton Institute, Soroka Medical Center & Ben-Gurion University, Be’er Sheva, IL
About Shadi

MD

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Melanie Zemel,

The Legacy Heritage Oncology Center & Dr. Larry Norton Institute, Soroka Medical Center & Ben-Gurion University, Be’er Sheva, IL
About Melanie

MD

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Dina Levitas,

The Legacy Heritage Oncology Center & Dr. Larry Norton Institute, Soroka Medical Center & Ben-Gurion University, Be’er Sheva, IL
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MD

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Waleed Kian ,

The Legacy Heritage Oncology Center & Dr. Larry Norton Institute, Soroka Medical Center & Ben-Gurion University, Be’er Sheva, IL
About Waleed

MD

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Elad Mazor

Department of Urology, Soroka University Medical Center, Be’er Sheva, IL
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MD

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Abstract

Introduction and importance: 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.

Case presentation: An 89-year-old male presented to the emergency room with back pain. Imaging studies demonstrated a large tumor in the left kidney with renal vein thrombosis. After radical nephrectomy, the histopathological report showed collision tumors with ccRCC and CDC components. The patient was included in a treatment protocol based on nivolumab (220 mg) and ipilimumab (73 mg) every 21 days, however, obtaining no clinical responses after 5 cycles of treatments.

Clinical Discussion: Immune checkpoint inhibitors have become a new standard of care for patients with advanced ccRCC. However, current literatures showed inconclusive evidence on the efficacy of immune checkpoint inhibitor for metastatic CDC. As collision tumors with ccRCC and CDC components were infrequently reported in the literature, we also discuss the histological and immunohistochemical findings, clinical outcomes, and a literature review on this type of renal collision tumors.

Conclusion: CDC is a rare and highly aggressive type of renal neoplasms, with limited treatment choices. More studies are needed to evaluate the efficacy of immune checkpoint inhibitors on CDC and its associated collision tumors.

Highlights:

  • Collecting duct carcinoma is a rare and highly aggressive type of renal neoplasms, with a poor clinical outcome.
  • Radical nephrectomy alone is rarely curative.
  • The use of immune checkpoint inhibitors for collecting duct carcinoma needs further evaluation.
  • The use of HMWCK as a histologic marker for differential diagnosis of collecting duct carcinoma may need to be evaluated.
How to Cite: Szeto CH, Krenawi M, Ben-Arie G, Samueli B, Lavon O, Abu-Swis S, et al.. Renal Collision Tumor Composed of Clear Cell Carcinoma and Collecting Duct Carcinoma Treated with Nivolumab and Ipilimumab: Case Report and Literature Review. International Journal of Surgery: Oncology. 2021;6(1):50–8. DOI: http://doi.org/10.29337/ijsonco.128
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  Published on 11 Aug 2021
 Accepted on 02 Aug 2021            Submitted on 28 Jul 2021

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.

Figure 1 

Axial image of Contrast enhanced CT demonstrating an exophytic hypodense lesion in the left kidney with some fat stranding around it. Later phases did not demonstrate any filling defect in the renal calyces (not shown).

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.

Figure 2 

Histologic appearance of the tumors. H&E. Panels (A) and (B) (original magnification 2× and 4×, respectively) with ccRCC on the top and collecting duct carcinoma on the bottom. Panels of ccRCC (C) and collecting duct carcinoma (D) at original magnification 10×.

Figure 3 

Immunostains of the tumors, with ccRCC on the top and collecting duct carcinoma on the bottom, original magnification 10×. (A) CAIX, (B) CD10, (C) CK7, and (D) CK903.

Table 1

Antibodies Used at Soroka University Medical Center.


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.

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.

Table 2

Summary of Clinicopathologic Findings in Reported Cases of Collision Tumors composed of ccRCC and CDC.


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 [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.

Abbreviations

ccRCC, clear cell renal cell carcinoma; CDC, collecting duct carcinoma; CT, computed tomography; HMWCK, High molecular weight cytokeratin; WHO, World Health Organisation.

Ethics and Consent

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.

Competing Interests

The authors have no competing interests to declare.

Author Contributitons

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.

Guarantor

Waleed Kian

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