Oral Soft Tissue Metastasis from Breast Cancer as the Only Primary Source: Systematic Review

Background  Breast cancer is one of the most lethal neoplasms causing death. Oral cavity is the rare site of distant metastasis from breast cancer. Very little research has been conducted to date to analyze breast cancer as the sole primary source of metastasis to the oral soft tissues. The goal of this study was to examine the published cases of oral soft tissue metastasis from breast cancer as the only primary source to date. 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 (“Breast cancer”, OR “Breast carcinoma”) AND (“Metastasis” OR “Metastases”), And (“Oral soft tissues” OR “Tongue” OR “Palate” OR “Tonsil” OR “Buccal mucosa” OR “Floor of mouth” OR “Vestibule” OR “Salivary glands”). We also searched all related journals manually. The reference list of all articles was also checked. Results  Our research revealed 88 relevant papers (September 1967–September 2023) with 96 patients in total. The most predominant oral soft tissues involved were salivary glands followed by the gingiva, tonsils, tongue, and buccal mucosa. A total of 23% of patients died with an average survival time of 1 to 15 months. Conclusions  Oral soft tissue metastasis from breast cancer is a rare event and has a bad prognosis. More cases need to be published to raise awareness of these lesions.


Introduction
Breast cancer (BC) is one of the most lethal neoplasms causing death.Worldwide, approximately 2.3 million new cases of BC and 684,996 deaths due to this malignancy were recorded in 2022 according to GLOBACON databases 1 and metastasis is the prime cause of death.The rate of metastasis even in uncommon sites is on the rise.On the other side, it has been observed that the overall survival of BC patients has been prolonged owing to the more effective therapy and the development of new imaging techniques and early detection.The most common organs involved in distant metastasis of BC are bones, lungs, liver, and brain. 2 The oral cavity is the rarest site of metastasis, and it can involve both osseous and soft tissues.Lung cancer is the most common cancer metastasizing to the oral soft tissues (OST), whereas BC is the most common source of metastasis to the jawbones (JB). 3The prognosis of metastatic lesions in the oral cavity is unfavorable because of their late detection owing to the resemblance of benign growths.Literature has reported several studies analyzing metastatic tumors in the oral region. 3,4But very little research has been conducted to date to analyze BC as the sole primary source of metastasis to the OST.The goal of this study was to examine the published cases of oral soft tissue metastasis (OSTM) from BC as the only primary source to date.

Materials and Methods
The current research was performed following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.Owing to 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 BC metastasizing to OST have been documented in the literature to date, and what is the prognosis of these metastatic lesions"?
• 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 like ("Breast cancer", OR "Breast carcinoma") AND ("Metastasis" OR "Metastases"), And ("Oral soft tissues" OR "Tongue" OR "Palate" OR "Tonsil" OR "Buccal mucosa" OR "Floor of mouth" OR "Vestibule" OR "Salivary glands").We also searched all related journals manually.The reference list of all articles was also checked (►Fig. 1).
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 0.84.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 remaining two authors (M.E.M.H., H.V.P.) 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.

Exclusion Criteria
• Cases with no definite diagnosis of OSTM from BC as the sole primary source.

Outcome Measures
Primary outcome measures: to evaluate the number of cases of OSTM from BC as the sole primary source reported in the literature and to determine their prognosis.
Secondary outcome measures: to evaluate other factors such as worldwide distribution of cases of OSTM from BC, patient's demographic details, the predominant site of OSTM, clinical features of these metastatic lesions, most prevalent type of metastatic BC, immunoprofile, type of therapies used, and the prognosis of these patients.

Risk of Bias Assessment
Most of the studies included in this review were case reports and case series.The risk of bias was appraised following CARE and Strengthening the Reporting of Observational Studies in Epidemiology checklists. 5,6In several papers, 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][2][3][4]. In case of missing data, 6 weeks' time was given to gather the information.If the information was still missing, we then indicated the missing data as "not available" in the text and in the tables.The results were expressed in descriptive statistics.The overall survival rate was calculated by survival analysis with Kaplan-Meier curves.

Results
Our research strategy revealed a total of 88 relevant papers  from September 1967 to September 2023. Th results were expressed in descriptive statistics (►Table 4).A total of 96 patients were included with 83 females and 1 male with a female to male ratio of 83:1.In

Discussion
BC is the first and second leading cause of cancer-related death in developing and developed countries, respectively.In the past few years, the cases of BC have rapidly increased in developed countries, mostly Australia, Western Europe, and Northern America. 2 In the current research, the maximum number of cases were from the United Kingdom (16.7%) followed by India (15.6%),United States (7.3%),Israel (6.2%), Italy and Japan (5.2%).Other regions involved a few cases (►Table 4).BC occurs predominantly during the fifth to sixth decade. 1 In the current study, the age ranged between second and eighth decade.Multiple underlying causes favor the development of BC that include obesity, hormonal and reproductive risk factors, alcohol, drug usage, malnutrition, genetic mutations, etc. 2 In the current research, there were not many associated risk factors, only a few patients had a history of obesity, hypertension, and a family history of BC.
Distant metastasis is the most common cause of death in BC patients.Distant spread of BC most often occurs in the lungs, bones, liver, and brain.The oral cavity is the rarest site.Oral Soft Tissue Metastasis from Breast Cancer Aga et al. 27         Oral Soft Tissue Metastasis from Breast Cancer Aga et al. 31 If this occurs, the JB is more affected than OST. 3 Pathogenic mechanisms of metastasis to the OST are not completely recognized.The route of secondary metastasis may be either hematogenous, lymphatic, or direct invasion.BC spreads to the OST predominantly following the hematogenous route.One of the proposed pathways is via Batson's valve plexus system. 51n the current research, we could document 96 cases of BC metastasizing to OST to date.The first case was reported in 1967. 7The most common OST involved were salivary glands followed by gingiva, tonsils, tongue, and buccal mucosa.Parotid was the most common gland affected (n-46) followed by the submandibular gland (n-7).Only one case involved the sublingual gland.Chronically, the inflamed mucosa of the gingiva, particularly the attached gingiva, contains a dense capillary network that can trap malignant cells and promote metastases. 4In the current research, Studies conclude that gingival metastasis mostly occurs in the mandibular area rather than the maxillary with predominancy of posterior side involvement.In the current research, however, there was maxillary predilection (n-7).The anterior region was mostly affected in the maxilla, whereas there was more involvement of the posterior side in the mandible.In the maxilla, both the right and left sides were affected equally, whereas in the mandible, the right side predominated more than the left.Tonsils are the rarest site of metastasis.According to research, only 0.8% of malignant palatine tonsillar tumors were from an extra-tonsillar source. 3Lymphatic spread to tonsils is rare due to the lack of afferent lymphatic capillaries except for retrograde spread via cervical lymph nodes or direct spread, the metastatic pathway is unclear.In the current literature, only seven cases of palatine tonsillar metastasis from BC have been observed.The tongue is a highly circulatory organ, which creates ideal conditions for the spread of cancer.The posterolateral and dorsal parts are more often involved in metastasis due to the rich capillary and lymphatic network and immobility.In the current research, 6/96 cases of metastatic BC involved the tongue, maximally affecting the base.Lip, buccal mucosa, the floor of the mouth, retromolar region, palate, and other OST are the rarest sites of metastasis.Only a few cases involved these regions affected via BC metastasis.
Oral metastatic tumors are of high clinical importance because they may be the only symptom of an undiagnosed underlying malignancy or the first sign of metastasis. 3,4In our study, 17.7% of cases of OSTM from BC presented as the initial site of metastasis, whereas in 70.6% of cases, metastasis was detected after the mastectomy done for BC, with an average time of 1 week to 26 years.The clinical aspects of BC metastasis in the OST vary according to the anatomical site involved characterized by rapidly growing painful or asymptomatic swellings, lumps or masses, difficulty in chewing, and dysphagia.Facial nerve palsy (FNP) may be a feature of lesions involving salivary glands especially parotid.In our research, seven cases manifested FNP.These metastatic lesions often become difficult to diagnose because their variable appearance bears close resemblance to some benign hyperplastic or reactive oral lesions.In the present research, swelling, lump, and mass were the most predominant clini-cal features observed.Other lesions appeared as ulcerative, exophytic, pedunculated, nodular, and edematous.A history of primary tumors 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 tumors.However, metastasis to OST via BC is a late indication.In the current research, 70.8% of patients had a previous history of primary BC, whereas 17.7% of patients didn't reveal such a 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 the 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.A biopsy is recommended for the histopathological examination 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 the primary site is unknown.Histopathologically, BC has been divided into various subgroups. 95IDC is the most predominant type and has been discovered to be the most prevalent metastasizing to the OST.In the current research, the most prevalent type of metastatic BC was IDC (70.8%) followed by ILC (6.2%).Other types were malignant phyllode tumors, angiosarcoma, hemangiosarcoma, etc. Immunoprofile of the tumor cells in individual patients was also detected, which was variable (►Table 3).In many cases, immunohistochemical analysis data were not available.Imaging techniques such as computerized tomography scans and magnetic resonance imaging can help in the assessment of possible extension or invasion.Positron emission tomography is useful in detecting distant organ metastasis.Although BC entails multiorgan distant metastases, OST might occasionally be the only site of metastasis many times.A total of 32.3% of instances in this study had OST as the only location of BC metastasis, whereas 33.3% had metastasis to other regions as well such as lungs, brain, liver, vertebrae, etc.
The treatment of choice for primary BC ranges from mastectomy to chemotherapy, radiotherapy hormonal therapy, or even palliative treatment.Management for OSTM disease includes a combination of surgical removal of solitary tumors, chemotherapy, radiotherapy, endocrine therapy, and targeted therapy.For single parotid metastasis, parotidectomy (total or superficial) with negative margins (preferably with preservation of facial nerve) and postoperative radiotherapy to obtain local tumor control and to exclude a primary parotid tumor.The most commonly used therapeutic aids in this study were combined therapy (35.4%).Other therapies used were palliative, chemotherapy, radiotherapy, and hormonal.Despite the proposed treatments, patients with metastatic involvement of the OST have poor prognosis, with the 5-year survival rate reported to be 10%.According to the current study, 20.8% of individuals died with an average survival time of 1 to 15 months.A total of 8.7% of patients had a good prognosis with no signs of recurrence.In one patient, treatment is going on.Two cases are under follow-up.

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

Conclusions
During the past 56 years (1967-2023), we found only 96 cases of OSTM from BC as the sole primary source.This signifies a rare occurrence of OSTM from BC.The prognosis was poor involving 20.8% deaths with a survival rate of 1 to 15 months.Salivary glands, gingiva, tonsils, tongue, and buccal mucosa were the most prevalent sites to get metastasize.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 to identify the primary site of metastasis and choose the best course of treatment.

•
Confirmed cases of OSTM from BC as the sole primary source.The papers included were from September 1967 to September 2023.•Type of studies: case reports, case series, retrospective analysis, and original research.• Cases were selected beyond the restriction of limitations on parameters such as age, gender, ethnicity socioeconomic status, etc. • Articles published in any language were included.

•
Publications reporting the OSTM from any site other than breast.•Cases with BC metastasis to JB and paranasal sinuses were not included.• Studies that didn't provide individual patient data were excluded.
• Review articles, editorials, conference abstracts, hypothesis papers, web news, media reports, and animal studies.

Table 1
Details of publications reporting cases of breast cancer metastasizing to oral soft tissues (September 1967-September 2023) Avicenna Journal of Medicine Vol. 14 No. 1/2024 © 2024.The Author(s).Oral Soft Tissue Metastasis from Breast Cancer Aga et al. 25

Table 2
Clinical data of patients with breast cancer metastasizing to oral soft tissues (September 1967-September 2023)

Table 3
Immunoprofile of patients with breast cancer metastasizing to oral soft tissues (September 1967-September 2023)

Table 4
Data describing treatment and prognosis of patients with breast cancer metastasizing to oral soft tissues (September 1967-September 2023)

Table 5
Summary of results documented from literature research describing the characteristics of patients with breast cancer metastasizing to oral soft tissues (September 1967-September 2023)