Abstract
Background/Aim: Renal cell carcinoma (RCC) of unknown primary origin is rarely identified and accounts for only 5% of cancers of unknown primary origin (CUP). The disease prognosis is typically poor because of no standard and effective therapy. Our review indicated that 23 cases have been reported and treated with conventional chemotherapy or tyrosine-kinase inhibitors alone; accordingly, most patients showed partial response or progression diseases with short survival time. Case Report: Herein, we present two cases of metastatic RCC of unknown primary origin. One case was papillary type and the other was clear cell type. According to the recent clinical trials in patients with metastatic RCC, a combination of immunotherapy and tyrosine-kinase inhibitors exhibited better response than conventional therapy or tyrosine-kinase inhibitors alone. Both present cases accepted a combination treatment with immunotherapy and tyrosine-kinase inhibitor and showed stable diseases. The radiological progression-free time for the case with metastatic papillary RCC was 5 months, and that with clear cell RCC was 6 months until now. Conclusion: The combination of immunotherapy and tyrosine-kinase inhibitors is at least as effective as a tyrosine-kinase inhibitor alone, and superior to conventional chemotherapy for treating metastatic RCC of unknown primary origin.
Cancer of unknown primary site (CUP) is a type of metastatic cancer that represents 3% to 5% of all cancers and is characterized by the absence of a detectable primary tumor site (1). The prognosis for CUP is generally poor, with median survival time ranging from 4 to 12 months (2). The diagnosis of CUP depends on a thorough clinical examination, computed tomography (CT) of the chest, abdomen, and pelvis, as well as basic blood and biochemical analyses, and a tumor biopsy from the metastatic site using immunohistochemistry (IHC) and/or molecular analyses (3, 4).
CUP-RCC is a rare subtype of CUP. The pathologic diagnosis of metastatic renal cell carcinoma (mRCC) shows recognized histologic and immunohistochemistry (IHC) characteristics. Empiric chemotherapy for CUP has little effect on mRCC. However, mRCC is treated with VEGF tyrosine-kinase inhibitors (TKIs) or mTOR inhibitors, and more recently, immune checkpoint inhibitors (ICIs) have shown promising results (5-7). In this case report and literature review, we present two cases of metastatic RCC of unknown primary origin. We believe that this information will provide important insights for the diagnosis and treatment of CUP-RCC. The cases were structured according to the CARE Case Report Guidelines. The study was conducted in accordance with the Declaration of Helsinki, but ethical review and approval were waived for this retrospective case report, which did not impact the management of the patient. Informed consent was obtained from the subjects involved in this case report.
Case Report
Case 1. A 63-year-old man with a medical history of coronary artery disease, hypertension, and stage 4 chronic kidney disease presented with persistent neck pain for two months. He sought medical attention at an otolaryngologist clinic due to the presence of a painful neck mass. The neck mass showed a non-mobile, left supraclavicular lymph node measuring 1.2 cm in the greatest dimension. The lymph node biopsy exhibited large epithelioid tumor cells with ovoid nuclei, occasional prominent nucleoli, eosinophilic cytoplasm, and arranged in a mixed acinar, papillary, and infiltrating pattern (Figure 1A). These tumor cells showed positive reactivity for CK and PAX8 and negativity for GATA3, p63, and TTF-1 in IHC studies. The tumor morphology and IHC characteristics were diagnosed as metastatic papillary RCC.
Histology of the biopsy. (A) Case 1: Hematoxylin and eosin (HE) stain of the lymph node biopsy exhibited large epithelioid tumor cells with ovoid nuclei, occasional prominent nucleoli, eosinophilic cytoplasm, and arranged in a mixed acinar, papillary, and infiltrating pattern. (B) Case 2: HE stain of the biopsy of bone lesions revealed epithelioid tumor cells with clear cytoplasm and oval nuclei in a delicate vascular stroma.
The patient was referred to the urology department with the impression of metastatic RCC. Abdominal and chest CT revealed many enlarged lymph nodes in various locations throughout the body, including the left gastric chain, common hepatic chain, retro-caval space, celiac axis, para-aortic region, aorto-caval space, mesentery, bilateral Gerota’s fascia, inferior-mesentery-artery chain, perirectal space, bilateral common iliac chains, bilateral hypogastric chains, bilateral external iliac chains, bilateral obturator spaces, and both inguinal regions. The imaging also showed left renal vein thrombosis extending from the renal vein to the inferior vena cava, as well as involvement of the left adrenal vein (Figure 2). There was no evidence of a solid renal mass on either side of the kidney.
Case 1. (A-D) a series of computed tomography (CT) scans depicting the retroperitoneal lymphadenopathy of patient 1 throughout the treatment course. (A) the initial state, (B) at 3-month follow-up, (C) at 6-month follow-up, and (D) at 9-month follow-up after the initial diagnosis. The retroperitoneal lymph node size (arrowhead) remained stable after the initiation of cabozantinib+nivolumab, while the size of the inferior vena cava thrombus slightly decreased following combination therapy (asterisk). (E) Displays the absence of ascites at initial diagnosis. (F) The presence of ascites (arrow) and omental cake (triangle) 5 months after initial diagnosis, which prompted us to add ipilimumab under the impression of disease progression.
The patient was diagnosed with metastatic RCC, International-Metastatic-RCC-Database-Consortium (IMDC) intermediate risk. The treatment plan included systemic therapy with cabozantinib at a dosage of 40 mg per day since July of 2022, followed by the addition of nivolumab at 200 mg every two weeks in August of 2022, until present. Three months later, a CT scan revealed that the retroperitoneal lymph-node size remained stable, and the renal vein thrombosis decreased in size (Figure 2B). However, the patient presented with massive ascites and omental cakes for 5 months after initial treatment (Figure 2E and F). Under the suspicion of disease progression, ipilimumab was added at a dosage of 50 mg since January of 2023. A recent CT scan showed stable disease of the metastatic lesions.
Case 2. A 71-year-old man presented a low back pain lasting for 2 months. Imaging studies revealed one osteolytic lesion in the spine lumbar 4 (L4) vertebral body and another one on the left iliac bone (Figure 3). Biopsies of the L4 and left iliac bone lesions revealed epithelioid tumor cells with clear cytoplasm and oval nuclei in a delicate vascular stroma (Figure 1B), and IHC analysis showed positive reactivity for CK, PAX8, CD10 and CA-IX, and negativity for NKX3.1, p63, CK7 and AMACR, compatible with the pathologic diagnosis of metastatic clear cell RCC.
Case 2. A series of computed tomography (CT) scans showing the spine metastasis over the course of treatment. (A) at the initial state, (B) at the 3-month follow-up, (C) at the 7-month follow-up, and (D) at the 1-year follow-up after the initial diagnosis. The bone metastasis of lumbar 4 (arrow) remained stable during the treatment period.
The patient underwent PET/CT revealing no the other lesions in addition to the two bone metastases. Laboratory data, including hemoglobin, corrected calcium, neutrophil counts, and platelets, were all within normal limits, and Karnofsky performance score was 100%. Magnetic resonance imaging showed no tumor in bilateral kidneys. According to the IMDC classification, the patient received systemic therapy with cabozantinib 40 mg daily since September of 2022 until present. In addition, palliative intensity modulated radiation therapy to L4 spine and left iliac bone metastases for 36Gy/12Fr. Now the patient has remained stable for 6 months. In contrast to case 1, where combination therapy was administered, the patient in this case could only be treated with cabozantinib. Combination therapy with nivolumab was not administered due to the lack of coverage by the national health insurance reimbursement in Taiwan and the patient’s financial constraints.
Discussion
CUP-RCC is rarely identified, and it represents only 5% of all CUP cases (1). To our knowledge, only 23 CUP-RCC cases have been reported with a median age of 63 years (ranging from 37 to 77 years). The detailed characteristics of the reported cases are summarized in Table I and Table II. Sex was more prevalent in males (19 cases, 82.6%) than in females. The most common site of metastasis was retroperitoneal lymph nodes, and the most common histology was clear cell RCC. The initial treatments for CUP-RCC vary among the reported cases as shown in Table III. Initial treatment with surgery alone was performed in ten cases (43.5%), and nine out of 23 cases (39.1%) received systemic therapy including TKIs, radiotherapy, and concurrent chemotherapy. Accordingly, most cases received sunitinib alone and only two cases were treated with combined ipilimumab and nivolumab. The treatments with immunotherapy, mainly immune checkpoint inhibitors (ICIs) alone or combination therapy were not routinely described in these reported cases. A case report of CUP-RCC treated with the combination of pembrolizumab and anti-VEGF TKI axitinib demonstrated a durable and dramatic response to liver metastasis and retroperitoneal lymph nodes (36).
Characteristics of 24 reported cases in literature.
Details of included cases. Details of 23 reported and two present cases.
Initial treatments of 23 reported cases.
Several explanations have been proposed for the presence of CUP-RCC (8). Janiszewska and colleagues provided statistical evidence that RCC can regress spontaneously (9). It is possible that the primary renal tumor is too small to be detected using current imaging modalities or by the limited resolution of the imaging technique, and regular follow-up imaging studies would identify the primary renal tumor after the initial diagnosis of CUP (8). Another possibility is that mRCC-CUP may possess unique genetic features leading to early dissemination and an independent route aggressive metastasis from the known primary cancer that becomes undetectable (8). Additionally, the mRCC-CUP may represent malignant transformation of embryologic renal or mesonephric tissue remnants (10, 11).
The combination of an ICI such as pembrolizumab and TKIs including axitinib, sunitinib, cabozantinib, everolimus, nivolumab and lenvatinib is a well-established systemic therapy for mRCC. In the KEYNOTE-426 trial, the combination of axitinib and pembrolizumab demonstrated a significantly longer overall survival and progression-free survival than sunitinib alone across all advanced RCC risk groups (12, 13). The CheckMate-9ER trial also showed the efficacy of cabozantinib and nivolumab, which provided superior overall survival and progression-free survival (PFS) over the sunitinib in all risk groups (6). Both trials supported the use of ICI-TKI combination as the first-line treatment in all metastatic RCC risk groups based on IMDC criteria. Furthermore, the CLEAR trial compared the combination of lenvatinib and pembrolizumab with two other treatments (lenvatinib plus everolimus, and sunitinib alone) and demonstrated a significantly longer progression-free survival than lenvatinib plus everolimus or sunitinib (14). The ICI-TKI combination also showed a superior overall response rate (ORR) according to RECIST 1.1 in all trials mentioned above. In the IMDC poor and intermediate risk groups, the combination of ipilimumab and nivolumab in the CheckMate 214 trial showed significantly higher ORR and OS than the sunitinib, although PFS was not statistically longer (7). This combination remains the preferred option as first-line treatment for poor and intermediate risk groups based on the CheckMate 214 trial. However, whether the results of these clinical trials could be applied in patients with CUP-RCC remains unclear (15). Both our present cases showed stable diseases after treatment with the combination of ICI and TKIs. The radiological progression-free time was 5 and 6 months, respectively, since the initial management; this demonstrates the efficacy of combining ICI and TKIs in treating CUP-RCC. Accordingly, the ICI-TKI combination might be a potential regimen for treating CUP-RCC. While ICI-TKI is the current standard treatment for mRCC, there is still a need for new drugs and therapeutic modalities due to the prevalence of resistance to ICI-TKI. Various new treatment modalities are currently being explored as potential options, including anti-cancer vaccines, anti-sense oligonucleotides, and cellular therapy (37). This is an important field that warrants further investigation.
It is a great challenge to make a correct pathological diagnosis of CUP-RCC, despite the well-established RCC profile using IHC and molecular studies (16). Core needle biopsy provides a small specimen that may be insufficient to obtain a complete RCC profile. Moreover, bone metastatic tissues could reveal poor antigen reserve during the decalcification process, resulting in inadequate IHC and molecular results (16). Nevertheless, these tissues are usually positive for PAX8, CD10, vimentin, CK AE1/AE3, and RCC markers, and negative for CK20, CK7 (positive only in the papillary type), TTF1, and calretinin markers (4). In addition, several molecular diagnostic methods, known as Molecular Cancer Classifier Assays (MCCA), have been used to determine the tissue of origin of CUP when IHC is inconclusive (3, 17). These assays allow physicians to use site-specific therapy instead of empiric chemotherapy. CUP-RCC is usually responsive to targeted therapy, such as sunitinib or pazopanib, and refractory to empiric chemotherapy (8, 18). Thus, the combination of IHC and molecular profiling tools might be critical for accurate treatment and better outcomes.
Conclusion
Since there is no sufficient data on TKI combined with ICI or/and ICI alone in CUP-RCC, it might be reasonable to conclude that these combinations are effective for these patients based on the evidence of clinical trials on mRCC. More studies will follow to determine the efficacy of combination therapy in CUP-RCC.
Footnotes
Authors’ Contributions
Conceptualization: Chao-Hsiang Chang; Methodology: Chao-Hsiang Chang, Wei-Hsuan Huang; Pathology review: Han Chang, Radiology review: Wei-Ching Lin, Writing—original draft preparation: Hao Xiang Chen, Lu-Ting Yu; Writing—review and editing: Hao Xiang Chang, Han Chang, Chao-Hsiang Chang. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received April 6, 2023.
- Revision received May 2, 2023.
- Accepted May 3, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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