Renal Cell Carcinoma Metastasizing to Oral Soft Tissues: Systematic Review

Background  Renal cancer metastasis to oral region is very rare. Studies have been published analyzing the cases of metastatic tumors to the oral cavity by many researchers. Very few research studies have been conducted till date to analyze the renal cancer metastasis as the sole primary source to the oral soft tissues. The goal of this study was to examine the published cases of oral soft tissue metastasis from renal cell carcinoma as the only primary source from 1911 to 2022. Materials and Methods  An electronic search of the published literature was performed without publication year limitation in PubMed/Medline, Scopus, Google Scholar, Web of Science, Science Direct, Embase, and Research Gate databases, using mesh keywords like (“Renal cancer,” or “Renal carcinoma” or “Renal cell cancer” or “Renal cell carcinoma”), and (“Metastasis” or “Metastases”), and (“Oral soft tissues” or “Tongue” or “Palate” or “Tonsil” or “Buccal mucosa” or “Salivary glands”). We also searched related journals manually and the reference lists. Results  Our research revealed a total of 226 relevant articles with 250 patients. Parotid glands and tongue were the most common sites of metastasis. 23% patients died with a survival time of 10 days to 4 years. Conclusions  Oral soft tissue metastasis from renal cell carcinoma has a bad prognosis. More cases need to be published in order to raise awareness of these lesions.


Introduction
According to GLOBOCAN databases, renal cell carcinoma (RCC) is one of the lethal neoplasms leading to approximately 2% of global cancer diagnoses and deaths, projecting to increase in burden worldwide. 1RCC is the most common primary renal neoplasm constituting about 80 to 85% of all renal malignancies.Renal cortex and pelvis are the most predominant sites.In the recent years, the incidence of RCC has increased worldwide owing to the development of newer imaging aids.In most of the cases, RCC is diagnosed as an incidental finding during radiological investigations.Only in 10% of patients, "classic triad" of symptoms (i.e., hematuria, flank pain, and palpable masses) has been noticed. 2One of the unique features of RCC is its long-term asymptomatic clinical behavior and high risk of distant organ metastasis in the advanced stages.Studies have reported that approximately 18% of patients with RCC have metastasis at the time of diagnosis, and in more than 50% of cases, metastasis is detected during the follow-up period after nephrectomy. 3he most common organs involved in distant metastasis of RCC are lungs (45%), followed by bones (30%), lymph nodes (22%), liver (20%), adrenal glands (9%), and brain (9%). 4etastasis from RCC to oral cavity is very rare-tongue, gingiva, and mandible being the most affected sites. 5The prognosis of metastatic lesions in the oral cavity is unfavorable because of their late detection owing to resemblance of benign growths.7][8] But a very few research work has been published till date to analyze solely the RCC metastasis to the oral soft tissues (OSTs).Thus, this review was conducted to examine the published cases of OST metastasis (OSTM) from RCC as the sole primary source in the literature from 1911 to 2022, and to learn about their characteristics.

Materials and Methods
The current research was carried out following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.Owing to the nature of the current review, any ethical approval was not required.

Focused Question
To conduct the study, CoCoPop (context, condition, population) framework, designed by Joanna Briggs Institute, was used focusing on the research question "how many cases of RCC metastasizing to OST have been documented in the literature, and what is the prognosis of these metastatic lesions."Pop (population): Patients with RCC.Co (condition): Salivary gland metastasis.Co (context): Characteristics of these patients.

Search Strategy for Identification of Studies
An electronic search of the published literature was performed without publication year limitation in PubMed/Medline, Scopus, Google Scholar, Web of Science, Science Direct, Embase, and Research Gate databases, using mesh keywords such as "Renal cancer" or "Renal carcinoma" or "Renal cell cancer" or "Renal cell carcinoma" and "Metastasis" or "Metastases," and "Oral soft tissues" or "Tongue" or "Palate" or "Tonsil" or "Buccal mucosa" or "Salivary glands." We also searched all related journals manually.The reference list of all articles was also checked (►Fig. 1).

Screening of Studies
The current review involved three steps of screening the studies.In the first step, titles were reviewed by two authors (H.V.P., R.S.) independently and duplicates were removed.Then the other two authors (S.G., H.S.) reviewed the selected abstracts of all the reports independently.The reviewers were calibrated on the basis of their assessment of their titles and abstracts of the first 50 references retrieved.The kappa value of agreement between reviewers was 0.82.If the title/abstracts met the eligibility rule, they were included in the study.In the final stage, the text of selected studies was screened by the remaining two authors (J.K., J.K.) separately.The full report was collected, discussed, and resolved for cases among all authors that appeared to fit the inclusion criteria or for which evidence was insufficient to make a clear determination.

Inclusion Criteria
• Confirmed cases of OSTM from RCC as the sole primary source were included.Articles included were from 1911 to 2022.• Type of studies: Case reports, case series, retrospective analysis, clinicopathological studies, prospective studies, original researches, systematic reviews, and correspondence.• Cases were selected beyond the restriction of limitations on parameters such as age, gender, ethnicity, or socioeconomic status.• Articles published in any language were included.

Exclusion Criteria
• Cases with no definite diagnosis of OSTM from RCC as the sole primary source.• Publications reporting the OSTM from any site other than kidney.
• Cases with RCC metastasis to jaw bones were not included.
• Studies which did not provide individual patient's data were excluded.• Review articles, editorials, conference abstracts, hypothesis articles, web news, media reports, animal studies.

Outcome Measures
Primary outcome measures: To evaluate the number of cases of RCC metastasizing to OST documented in the literature.
Secondary outcome measures: To evaluate other factors such as world-wide distribution of cases of OSTM from RCC, patient's demographic details, associated risk factors, predominant site of OSTM, clinical features of these metastatic lesions, most prevalent type of metastatic RCC, and type of therapies used.

Risk of Bias Assessment
Most of the studies included in this review were case reports and case series.Risk of bias was appraised following CARE and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklists. 9,10In several articles, there was missing information regarding many parameters used for data extraction.We tried reaching the authors of those cases to clarify this bias; however, we were unable to recover the missing information.

Data Extraction and Analysis
After study selection, screening, and a thorough examination, the data were extracted.The information gathered was cross-checked and tabulated into three tables (►Tables 1-3).In case of missing data, 6 weeks' time was given to gather the information.If the information was still missing, we then

Results
Our research strategy revealed a total of 226 relevant articles.Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al. 83  Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al.Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al. 85  Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al.Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al. 87  Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al.Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al. 89  Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al.Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al. 91  Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al.Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al. 93  Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al.Oral Soft Tissues Metastasis from Renal Cancer Prajapati et al. 95   RCC is the third most common tumor metastasizing to oral cavity after lung, and liver cancer. 34In the current research, we found 250 cases of primary RCC metastasizing to OST.RCC is the most common solid renal tumor originating from the proximal renal tubular epithelium.Worldwide, 403,000 new cases of RCC and 175,000 deaths due to this malignancy were recorded in 2018.In India, the incidence of RCC among males is about 2/100,000 population and among females is about 1/100,000 population. 35RCC has rapidly become more common in the developed world over the past decades, 36 more than doubling in incidence in the United States since 1975.In our research also, the maximum number of cases were from the United States followed by Japan, United Kingdom, Turkey, India, Spain, Poland, and Europe (►Table 4).
RCC occurs predominantly during fifth to sixth decades exhibiting a male predilection with a male:female ratio of 1.5:1.In the current study also, there was a male predominance, with a male:female ratio ¼ 2.5:1.However, the age ranged between first and ninth decades.
Multiple risk factors favor the development of RCC which include smoking, tobacco chewing, alcohol, obesity, hypertension, cardiac, liver and renal diseases, urinary stones, diabetes, drug usage, and malnutrition. 2Studies have reported that cigarette smoke contains many carcinogens as well as the highly addictive substance called nicotine.As they are filtered through the nephron, these particles are metabolized and promote inflammation and induce DNA damage, paving the way for carcinogenesis.Smokers are known to exhibit more risk of RCC than non-smokers. 37However, in the current research, only 10.5% of cases have revealed the habit of smoking.Many had variable comorbidities, including renal, cardiac, and endocrinal diseases, and history of other malignancies.One patient revealed the family history of RCC.
Pathogenic mechanisms of metastasis to the OST are not completely recognized.Route of secondary metastasis may be hematogenous, lymphatic, or direct invasion.Metastatic RCC spreads predominantly following the hematogenous route.One of the proposed pathways is via Batson's valve plexus system.Angiogenesis plays a crucial role in the development of tumor metastasis.The tumor-derived micro vesicles break off from the primary site.These micro vesicles appear to carry a cancer stem cell phenotype and microRNAs which stimulate angiogenesis. 4RCC is naturally a pre-angiogenetic cancer.It is hypothesized that the kidneys receive about 25% of the circulating blood volume per minute, in addition to the release of vascular endothelial growth factor The most common malignant neoplasms of the palatal mucosa are known to be minor salivary gland tumors and metastatic tumor from a distant organ in this region is uncommon. 38In the present research, only 13 cases were found in the palate region.According to a research, only 0.8% of malignant palatine tonsillar tumours was from an extra-tonsillar source. 39Lymphatic spread to tonsils is rare due to lack of afferent lymphatic capillaries except retrograde spread via cervical lymph nodes or direct spread; thus, metastatic pathway is unclear.In the current literature, only six cases of palatine tonsillar metastasis from RCC have been observed.Oral metastatic tumours are of high clinical importance because they may be the only symptom of an undiagnosed underlying malignancy or the first sign of the metastasis.In our study, 31.2%cases of OSTM from RCC presented as the initial site of metastasis, whereas in 51.2% cases, metastasis was detected after the nephrectomy done for RCC, with an average time of 3 weeks to 26 years.The clinical aspects of kidney metastasis in the OST vary according to the anatomical site involved characterized by rapidly growing painful or asymptomatic swellings that bleed easily, difficulty in chewing, and dysphagia.One of the characteristic features of metastatic RCC is their intense vascularization.These metastatic lesions often become difficult to diagnose because their variable appearances bear close resemblance to some benign hyperplastic or reactive oral lesions.In the present research, rapidly increasing vascular swelling was the most predominant clinical feature observed.Other lesions appeared as ulcerative, exophytic, pedunculated, nodular, and edematous.A history of primary tumor could help in the detection of secondary metastatic deposits.Before the metastatic spread to the oral cavity, the majority of patients are aware of their primary tumours.However, metastasis to OST via RCC is a late indication.In the current research, 50.4% of patients had a previous history of primary RCC with nephrectomy; 31.6% of patients did not reveal such history.
Histopathological examination is required to provide a conclusive diagnosis of the type of metastatic lesion.However, it might be difficult to make an exact diagnosis because of varied histological appearance, particularly when the major focus of primary site is unknown.Other tools, such as special staining, immunohistochemistry, and electron microscopy, may be necessary in some circumstances to determine the initial tumor's nature.Histopathologically, RCC has been divided into various subgroups.The World Health Organization classification of urogenital tumors in 2022 have introduced many new entities in the RCC. 40CCC is the most predominant type and has been discovered to be the most prevalent metastasizing to the OST.The finding was same in this study as well.96.4% cases were diagnosed to be CCC.Although RCC entails multiorgan distant metastases, OST might occasionally be the only site of metastasis.Out of 250 instances in this study, 143 had OST as the only location of RCC metastasis, whereas 62 had metastasis to other regions as well, such as lungs, brain, adrenals, liver, vertebrae, spine, pelvis, skin, and skeletal muscles.
Treatment options for metastatic RCC include biopsy, surgery, chemotherapy, radiotherapy, brachytherapy, and/or combination therapy.The most commonly used therapeutic aids in this study were surgical aids (41.2%) and combination therapy (22%).Salivary gland lesions were treated by parotidectomy, superficial, deep, partial, or total depending on the site.Unfortunately, OSTM by RCC has a bad prognosis with a maximum survival rate of approximately 5 years.In some cases, a patient's terminal stage of disease results in a loss of follow-up or death.Even after treatment, 57 people died, according to the current study with a survival time of 10 days to 4 years.Multiple metastases, deteriorated systemic condition, hepatic insufficiency, and uncontrolled bleeding were the most common causes of death.Forty-eight patients had a good prognosis with no signs of recurrence.In seven patients, treatment is going on.Eleven cases are under follow-up.

Limitations of the Current Study
One of the limitations of current research was small sample size.Most of the included studies were case reports and case series.And in many of the included studies, individual data of patients were not available.

Conclusions
During the last 111 years (1911-2022), we found only 250 cases of OSTM from RCC as the sole primary source.This signifies a rare occurrence of OSTM from RCC.The prognosis was poor involving 23% deaths with a survival rate of few days to 4 years.Parotid, tongue, and gingiva were the most prevalent sites to get metastasized.Because of their resemblance to other pathologies, and late clinical signs, these lesions go unnoticed the majority of the time.Diagnosis of oral metastatic lesions is a challenging task for the clinicians and pathologists.A thorough examination of the metastatic lesions is required, including a review of the patient's medical history, clinical presentation, and early diagnosis in order to identify the primary site of metastasis and choose the best course of treatment.

Table 1
Details of publications included in the current review(1911-2022)

Table 2
Clinical details of patients with renal cell carcinoma mediatizing to oral soft tissues(1911-2022)

Table 3
Data describing treatment and prognosis of patients with renal cell carcinoma metastasizing to the oral soft tissues(1911-2022)

Table 4 (
Continued)Feature NumberHP, SP, uvula, and tonsils are the rare sites of OSTM from distant resources.Few cases of lip metastasis have been reported from colon and gastric cancers.In the present review, only 12 cases of lip and 11 cases of BM from RCC were notified.