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Year : 2021  |  Volume : 58  |  Issue : 2  |  Page : 273--277

Metastases from renal cell carcinoma—Report of three unpredictable cases and literature review

Kiran P Malhotra1, Anurag Gupta1, Saumya Shukla1, Gaurav R Agarwal2, Hardeep S Malhotra3,  
1 Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow, Uttar Pradesh, India
2 Department of Radiodiagnosis, Dr. Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow, Uttar Pradesh, India
3 Department of Neurology, King George Medical University, Lucknow, Uttar Pradesh, India

Correspondence Address:
Kiran P Malhotra
Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow, Uttar Pradesh
India

Abstract

The capacity to metastasize after long periods of discovery and resection of the primary renal lesion or to present as metastasis with undisclosed primary lesions grant renal cell carcinomas (RCC) a formidable and unpredictable behavior. We report three unusual cases of metastasis from RCC. The first patient presented with metastatic clear cell adenocarcinoma in the right shoulder muscles, with unknown primary and revealed an undetected clear cell right RCC on radiology. The second patient presented with a hemorrhagic nasal metastasis of RCC. A history of nephrectomy for RCC, 10 years prior to the development of nasal metastasis was elicited. The third patient presented with axillary and later abdominal wall metastasis of papillary RCC. He had a history of RCC 3 years prior to the discovery of metastasis. RCC has the propensity to appear as a metastatic carcinoma with unknown primary, requiring exclusion of several diagnostic pathologic entities. The appearance of metastasis many years after disease quiescence is challenging and clinicians need to be sensitized to the need for long-term surveillance in RCC. Though the prognosis remains poor, immune checkpoint inhibitors are currently the modalities of choice in such cases.



How to cite this article:
Malhotra KP, Gupta A, Shukla S, Agarwal GR, Malhotra HS. Metastases from renal cell carcinoma—Report of three unpredictable cases and literature review.Indian J Cancer 2021;58:273-277


How to cite this URL:
Malhotra KP, Gupta A, Shukla S, Agarwal GR, Malhotra HS. Metastases from renal cell carcinoma—Report of three unpredictable cases and literature review. Indian J Cancer [serial online] 2021 [cited 2021 Oct 24 ];58:273-277
Available from: https://www.indianjcancer.com/text.asp?2021/58/2/273/315801


Full Text



 Introduction



Renal cell carcinoma (RCC) comprises about 3% of all adult malignancies.[1] The aggressive behavior of the tumor is borne out by the propensity for metastatic spread. Common sites of metastases include lung, liver, bone, and brain. Infrequently, RCCs show an aberrant tendency to metastasize to unusual sites like soft tissues, skin, nasal cavity, and skeletal muscle.[2] Here we report a series of three patients with unusual metastasis from RCC and review the literature available on such lesions. The role of cytology in aiding their diagnosis is also discussed.

Case 1

A 53-year-old man presented with a 6-month history of swelling over the right shoulder region measuring 6 cm in the greatest dimension. Fine-needle aspiration (FNA) of the lesion was performed. FNA revealed clusters of cells with low nucleocytoplasmic ratio, round hyperchromatic nuclei, and abundant clear cytoplasm [Figure 1]a and [Figure 1]b. A suspicion of clear cell adenocarcinoma was raised on cytology. The patient was evaluated for soft-tissue metastases from an unknown primary. Contrast-enhanced computed tomogram (CT) of the thorax revealed a large heterogeneously enhancing necrotic mass lesion in relation to the right scapula and extending into the right axillary region. Another similar lesion was seen in relation to the 3rd/4th ribs anteriorly. An abdominal CT scan revealed a heterogeneously enhancing irregular mass lesion in relation to the upper pole of the right kidney [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f. A right nephrectomy performed subsequently revealed a clear cell RCC. Treatment was initiated with sunitinib, but the patient succumbed to the disease 3 months after diagnosis.{Figure 1}

Case 2

A 55-year-old man presented to the otorhinolaryngology outpatient department with a month-long history of stuffiness of nose and recurrent epistaxis. Examination revealed a hemorrhagic mass in the right nostril. An excision biopsy of the lesion was sent for histopathology which showed a tumor disposed in sheets of large polygonal cells with abundant foamy cytoplasm and small rounded nuclei. This morphology in a nasal mass raised a number of differential diagnoses, including paraganglioma, olfactory neuroblastoma, clear cell myoepithelioma, and metastatic clear cell carcinoma. Immunophenotyping was done wherein pan-cytokeratin and vimentin were positive while synaptophysin, S-100, p-63, cytokeratin-5/6, and smooth muscle actin were negative. The immunophenotype was consistent with nasal metastasis of carcinoma. On questioning, the patient revealed a history of RCC in the right kidney, 10 years back which had been treated with radical nephrectomy. CD-10 immunohistochemistry (IHC) was later performed and was positive in tumor cells, thus confirming a diagnosis of late metastasis of RCC to the nasal cavity [Figure 2]. The patient died a month after diagnosis.{Figure 2}

Case 3

A 60-year-old man presented with right axillary swelling of 1-month duration. The patient had a history of nephrectomy for RCC in the left kidney 3 years back [Figure 3]a. On examination, a 4 × 3 cm, soft to firm pink mass was palpable in the subcutaneous plane of left axilla with inflamed overlying skin. Lymph nodes were not palpable. FNA smears revealed three dimensional and papillaroid clusters of pleomorphic epithelial cells with fibrovascular cores. Cell block was also prepared from the material derived from FNA. IHC done on the cell block sections showed positivity for pan-cytokeratin, CD-10, vimentin, and cytokeratin 7 [Figure 3]b, [Figure 3]c, [Figure 3]d, [Figure 3]e, [Figure 3]f, suggestive of metastasis from papillary RCC. 8 months after the appearance of the axillary metastasis, he presented with an anterior abdominal wall swelling which also showed similar cytological features. Thereafter the patient was lost to follow-up.{Figure 3}

 Discussion



RCC is a deadly tumor. Distant metastases are the cause of death in about 40% of patients. The 5-year survival rate for patients with distant metastases is under 10%.[3],[4] The common sites of metastasis in RCC include lungs, brain, adrenals, and intra-abdominal organs. However, rarely metastases to sites such as head and neck, orbit, tongue, nasal cavity, thyroid, skin, ovary, and testis have been reported.[2]

We report here three patients with metastasis from RCC to uncommon sites. Approximately 3% of renal tumors metastasize to the skin, similar to the third patient in our series.[2] Conversely, RCC is the primary site responsible for about 6% of all malignancies metastasizing to the skin.[5] The suspicion of malignancy in skin lesions is confounded by the inflamed, abscess-like appearance of the lesion. These are usually given empirical antimicrobial therapy and referred for needle aspiration on failure to respond.[6] In our series, the first patient presented with metastasis to the ribs and scapula with extension to the infraspinatus muscle and soft tissue of the shoulder. Skeletal muscle is among the rarest sites for metastasis with less than 40 cases of RCC metastatic to skeletal muscles reported to date.[2],[7] Our second patient presented with nasal metastasis from an RCC treated 10 years back. In a series of 1785 RCC cases, metastases to the nasopharynx were noted in only three cases.[8]

Cytology plays an important role in being an easy and safe outpatient procedure for diagnosing accessible masses. Superficial sites like skin and soft tissue are easily amenable to needle aspiration. A supplementation with cell block and immunocytochemistry is helpful and sufficient to diagnose metastatic RCC as in the third patient in our series. Triple positivity for pan-cytokeratin, vimentin and CD-10 is a specific marker for RCCs.[8] Without the use of cell block and immunocytochemistry, some cases have been reported as “clear cell malignant tumors” on cytomorphology, with a suggestion of metastasis from RCC.[9] A high-index of suspicion is needed in such cases, supplemented by thorough history-taking as RCC metastases are known to occur after many years of nephrectomy.

In case 1 detailed above with shoulder metastasis, there was no past history of known RCC. Such cases are difficult to diagnose on cytology alone and the differentials of clear cell lesions including RCCs, adrenal cortical tumors, hepatocellular carcinomas, and melanoma need to be considered. Complete radiologic workup is essential in such cases. There are occasional reports of soft tissue and skeletal muscle metastasis of RCC diagnosed with the help of fluorodeoxyglucose - positron emission tomography (FDG - PET CT), and magnetic resonance imaging.[10]

Another noteworthy observation in our series was the development of metastatic lesions 10 years after the diagnosis and treatment of RCC. Similar cases with a dormant interval of up to 19 years post-diagnosis of the primary have been reported.[10] Despite long periods of disease quiescence, RCC hence retains the tendency to metastasize late in its course. The prognosis for metastatic RCC remains dismal. These lesions are usually nonresponsive to chemotherapy and hormonal therapy.[4] Targeted therapies used for metastatic RCC include tyrosine kinase inhibitors like sunitinib which act by inhibition of the vascular endothelial growth factor (VEGF) pathway. Cell cycle regulation via the mTOR pathway is hampered by drugs like everolimus and temsirolimus.[11] Both these groups of drugs have improved progression-free survival in metastatic RCC. The 2014 update of the European Association of Urology (EAU) guidelines recommended the use of sunitinib, pazopanib, or bevacizumab and interferon α in previously untreated patients with metastatic RCC with good or intermediate risk. Axitinib or everolimus was suggested to be of use as second-line drugs after progression on VEGF receptor therapy.[12]

Recent randomized trials have focused on the use of immune checkpoint inhibitors including programmed death 1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 inhibitors. The JAVELIN 101 solid tumor trial supports the efficacy of anti-programmed death-ligand 1 drug avelumab immunotherapy in metastatic RCC.[13] The recent KEYNOTE 426 trial also reports improved survival with pembrolizumab and axitinib therapy over sunitinib in advanced RCC.[14] The CHECKMATE 214 trial has shown the efficacy of using nivolumab and ipilimumab over sunitinib in metastatic RCC. The EAU guidelines updated in 2019 based on results of these trials, recommend the use of pembrolizumab and axitinib in untreated patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk. In intermediate and poor-risk patients with metastatic RCC, ipilimumab together with nivolumab is recommended. Sunitinib and pazopanib are currently recommended for untreated metastatic RCC patients who are intolerant to immune checkpoint inhibitor therapy.[15]

Posttreatment recurrence in RCC can be detected and treated early using judicious surveillance tactics. These include history-taking, physical examination, and blood chemistry studies at regular intervals. Data from large multicentric studies have been used to formulate guidelines for surveillance in RCC including the use of cross-sectional imaging using computed tomograms at specified intervals post-diagnosis. The frequency of follow-up is guided by the stage and grade of disease at diagnosis.[12],[16],[17]

 Conclusion



Oddities related to RCC include its tendency to metastasize to unusual sites and to metastasize after prolonged periods of resection of the primary lesion. Through our series of RCC with metastasis to sites like skin, soft tissue, muscle, and nasal cavity, we wish to highlight this fact. Learning points from instances such as these include the utility of stringent long-term follow-up needed in patients with RCC. Cytology aided with ancillary immunocytochemistry, relevant radiologic investigations, and careful history-taking is a vital tool for the diagnosis of such cases. Long-term surveillance and immune checkpoint inhibitors are currently the modalities of choice in metastatic RCC.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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