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Metastatic tumors in oral mucosa and jawbones: Unusual primary origins and unusual oral locations
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Metastatic tumors in oral mucosa and jawbones: Unusual primary origins and unusual oral locations ⁎
Ilana Kaplana,b,c, , Vadim Raiserd, Amir Shusterc,d, Benjamin Shlomic,d, Eli Rosenfelde, Adi Greenberge, Avraham Hirshbergc, Ran Yahalomf, Anna Shnaiderman-Shapirog, Marilena Veredc,g a
Institute of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel Institute of Pathology, Rabin Medical Center, Petah-Tikva, Israel c Department of Oral Pathology and Oral Medicine, Goldschleger School of Dental Medicine, Tel-Aviv University, Israel d Oral and Maxillofacial Surgery Unit, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel e Department of Oral and Maxillofacial Surgery, Rabin Medical Center, Petah-Tikva, Israel f Department of Oral and Maxillofacial Surgery, The Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel g Institute of Pathology, The Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel b
A R T I C LE I N FO
A B S T R A C T
Keywords: Metastases Oral metastases Jawbone metastases
Aim: To perform clinico-pathological characterization of a large series of oral metastases, collected from 3 main medical centers in Israel and compare findings to data on frequency of primary cancer types in the population. Materials: Pathology archives were searched for cases of metastatic tumors to the oral soft tissues and jawbones, 1990 – 2016. Metastases to the skin of face or to major salivary glands have been excluded. Demographic data and histopathological features were analyzed. Results: Study population included 60 patients, 35 females and 25 males (ratio of 1.4:1). The age range was 17–87 years, mean 67.7 + 14.36 years. Only 3 (5%) patients were under 40 years, the remaining clustered predominantly in the 60–80 year age group. The mean age of females (59 + 13.84) was significantly lower than that of males (67.44 + 14) (p = 0.03). There was an almost equal distribution between the oral soft tissue and the jawbones (48.3% and 51.7%, respectively). The five most common organs from which metastases were distributed to the oral cavity and jawbones combined were kidney (20%), breast (15%), cutaneous (predominately melanoma, 13%), lung (11.7%) and soft tissue-sarcomas (8.3%). For comparison, Israel National Cancer Registry 2013 reported that the most frequent malignancies were breast (25.8%), colorectal cancer (16.3%), lung (12%) and prostate (10%). Malignant melanoma was 6th (5.4%), kidney malignancy was only 9th in frequency (4.2%). Although the gingiva and jawbones were the most frequent locations, some cases presented in unusual locations, (mandibular vestibule, lower lip, posterior dorsal tongue), without any specific clinical feature to suggest metastasis. Conclusions: The most frequent primary origins for oral metastasis do not correspond to the relative frequency of the primary tumors in the population, indicating that metastatic spread is not a random process. Although the majority of metastasis involves the gingiva and jawbones, any other oral mucosal location might be involved. Thus, in adult/older patients, metastasis from a distant site should be included in the differential diagnosis of oral masses at any oral location, whether the existence of a primary tumor is reported or not.
1. Introduction Metastases to the oral cavity are rare and account for only 1%–1.5% of all malignant tumors in this region (Hirshberg, 2016; Kumar and Manjunatha, 2013). It is assumed that oral metastases represent secondary spread from other primary metastatic deposits, most frequently
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the lungs (Kumar and Manjunatha, 2013). Yet, oral metastases were reported to be the first sign of metastatic spread of a malignancy in about 30% of the cases (Hirshberg, 2016). In this setting, it is assumed that the metastatic tumor bypasses the lung filtration, spreading to the oral cavity via the vertebral valveless venous plexus, which supplies the axial skeleton as well as the head and neck region.
Corresponding author at: Institute of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. E-mail address: [email protected] (I. Kaplan).
https://doi.org/10.1016/j.acthis.2019.151448
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Please cite this article as: Ilana Kaplan, et al., Acta Histochemica, https://doi.org/10.1016/j.acthis.2019.151448
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cavity and jawbones combined were kidney (20%), breast (15%), skin (13%; malignant melanoma alone - 11.7%), lung (11.7%) and soft tissue sarcoma (8.3%) (Fig. 2). Fig. 3 presents the clinical features of selected cases, Figs. 4–6 present examples of immunohistochemical stains that aided in the identification of the origin of the metastatic disease. Some differences were observed in the distribution of the primary sites of origin between genders, as well as distribution between oral soft tissues and jawbones; the most common primary sites for soft tissue metastases in females were skin (4, 25%), lung and kidney (3, 18.8%, each), while in males, it was kidney and unknown primaries (3, 23%, each). The most common primary sites to send metastases to the jawbones were breast (7, 36.8%) and kidney (3, 15.8%) in females and kidney (3, 25%) and upper aerodigestive tract and prostate (2, 16.7%, each) in males (Table 1). In the patients with soft tissue metastases, there were 16 females and 13 males with a mean age of 63.7 + 13.9 years (range 19–86 years). The most common oral soft tissue location involved with metastasis was the gingiva/alveolar mucosa (19, 65.5%), followed by the buccal mucosa (5, 17.2%). Several lesions occurred in unusual locations for metastatic deposits, such as vestibule (2, 6.9%), lower lip, floor of the mouth, and dorsal aspect of tongue (1 case, 3.4%, each). The present series included four cases of metastatic sarcoma to the oral soft tissues Sarcomas are rare as primary tumors and even less so as oral metastases; two cases were metastases from angiosarcoma and one each liposarcoma and chondrosarcoma, (the latter has been previously published, Taicher et al., 1991). In the group of jawbone metastases, there were 19 females and 12 males, with a mean age of 61.6 + 14.9 years (age range 17–87 years). The vast majority of the tumors involved the mandible (26, 83.9%) and only 5 (16%) the maxilla. Three mandibular metastases (11% of jaw metastasis) became clinically evident at an extraction site. The case of liver metastasis has been previously published (Pesis et al., 2014). There were three cases of metastatic sarcomas: osteogenic sarcoma, rhabdomyosarcoma and a high grade sarcoma of unknown origin. For comparison, the cancer statistics of the Israel National Cancer Registry (last available data is for, 2013) were searched for information regarding the incidence of cancer in different organs in the Israeli population. The most frequent was breast cancer (4768 cases, 25.8%), followed by colorectal cancer (3335 cases, 16.3%), lung (2485 cases, 12%) and prostate (2060 cases, 10%). Malignant melanoma was 6th (1121 cases, 5.4%) and kidney malignancy was only 9th in frequency (861 cases, 4.2%), soft tissue malignancy (217 cases, 1%) (Fig. 2).
The primary sites from which metastases to the oral cavity have been reported include lung, breast, kidney, bone and colorectal regions. The majority of primary tumors, which metastasize to the oral cavity and jaws, have been of epithelial origin (∼70%) and only a minority has been sarcomas (Hirshberg et al., 1994). Some differences have been noted regarding gender and location of metastatic deposits (Hirshberg, 2016; Hirshberg and Buchner, 1995; Hirshberg et al., 2008). In male patients lung is the most common primary site with metastases to the jawbones (22%) and soft tissues (31%), followed by prostate metastasizing to jawbones (11%) and kidney to soft tissues (14%). In female patients, breast is the main primary source for oral metastases to both jawbones (41%) and soft tissues (23.3%), followed by the adrenal gland and genitalia with metastases to jawbones (7.7%) and primary tumors of genital region metastasizing to oral soft tissues (14.8%) (Hirshberg et al., 2008). Patients with oral metastases are usually in the 4th and 7th decades of life. Jawbone metastases have been observed in a younger age group than those with soft tissue metastases (mean 45 years and 54 years, respectively). This difference is mainly related to metastasis from neuroblastoma, a tumor of the pediatric age group (Hirshberg and Buchner, 1995; Hirshberg et al., 2008). The present study has been undertaken to characterize a large series of oral metastases, collected from 3 main medical centers in the central area of Israel. Analysis of clinical and histopathological features, with emphasis on unusual cases of oral metastases will be presented, and compared to data on frequency of primary cancer types in the population. 2. Material and methods The files of 3 principal medical centers that serve the central area of Israel were searched for cases of metastatic tumors to the oral soft tissues and jawbones, between January 1990 and December 2016. Inclusion criteria included adequate demographic data, clinical information on the location and clinical presentation of the metastatic deposit, information on primary tumor of origin if known and detailed histopathological description. Cases of metastases to the skin of the face or to the major salivary glands have been excluded from the study. Statistical analysis was performed by t-test using SPSS package, version 22 (Chicago, IL, USA). Statistical significance was set at p < 0.05. Study was conducted in accordance with the ethical requirements (Israeli and International Conference on Harmonization Good Clinical Practice standards) of clinical trials.
4. Discussion
3. Results
The process of metastatic spread is complex, involving both characteristics of each individual tumor and qualities relating to the host response. For these reasons, there is a wide variety between tumor types regarding the frequency of metastasis and the particular distribution of metastases in distant organs. However, some patterns have been observed and reported in the past in relation to metastasis to the oral soft tissues and bone. Metastasis from carcinomas of prostate were reported to have a predisposition to the jawbones and those from the breast were twice as frequent in the jawbones than in the soft tissue; in contrast, those from lung and kidney were more frequent in the soft tissues (Hirshberg and Buchner, 1995; Hirshberg et al., 1993, 1994, 2008, 2014; Allon et al., 2014). In the present comprehensive series of cases, an unexpected finding was that renal cell carcinoma (RCC) was the most frequent metastasis in both oral soft tissues and jawbones (20%), while kidney malignancy was only 9th in the order of cancer types in Israel comprising only 4.2% of cancer cases. Thus, there is a significantly increased proportion of metastasis from kidney to oral cavity and jawbones than could be expected if metastasis distribution was random. Breast cancer was second in frequency in the metastases group and
A total of 60 cases of metastases have been retrieved. The study population included 35 females and 25 males (ratio of 1.4:1). The age range was 17–87 years, with a mean of 67.7 + 14.36 years. Only 3 (5%) patients were under 40 years (17, 19 and 39 years respectively), the remaining clustered were predominantly in the 60–80 years age group (Fig. 1). The mean age of the female patients (59 + 13.84 years, range 19–87 years) was significantly lower than that of the male patients (67.4 + 14 years, range 17–86 years) (p = 0.03). There was an almost equal distribution between the oral soft tissue and the jawbones (28, 48.3% and 30, 51.7%, respectively). Some of the cases, mainly those from the more recent years, had detailed and updated panels of immunohistochemical stains that aided in identifying the primary tumor or confirmed a metastasis from a known primary tumor. Older cases had less comprehensive immunohistochemical workup; diagnosis also relied on the morphological similarity to the primary tumor (in those cases when the primary tumor was known). The five most common organs from which metastases to the oral 2
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Fig. 1. Age and gender distribution of patients with oral metastatic tumors. Fig. 2. Relative frequency (%) of primary cancers in the Israeli population in 2013 versus relative frequency of origin for metastatic tumors to the oral cavity and jawbones. MET – metastasis according to present study; NHL - Non Hodgkin Lymphoma; Connective tissue – in regard to metastasis, the term referred to sarcomas; Unclassified - in regard to metastasis, the term referred to combined entities of "origin unknown" and "narrowed down differential" from Table 1; UADT - upper aerodigestive tracts; Skin – primary malignant melanoma excluded
first in order in the general population in Israel, thus representing a relatively good correlation in frequency between the incidence in general population and oral metastasis. Oral metastases from skin, (malignant melanoma and squamous cell carcinoma combined), were third in frequency (13.3%), out of which malignant melanoma accounted for the vast majority of these cases (11.7%), although melanoma was only 8th in frequency in the general population (5.4%). Lung was fourth in frequency of oral metastases (11.7%) and the third most frequent malignancy in the general population. The fraction of metastases from skin melanoma was almost identical to that of metastases from the lungs, although the number of annual cases was approximately half that of lung cancer. Thus, similar to metastasis from the kidneys, there were remarkably more metastases from skin melanoma to the oral cavity and jaws than would be expected from the number of cases in the population. Metastases from colorectal cancer were present only in 6.7% of the cases, far less than expected from the incidence in the general population, where colorectal cancer is second in frequency after breast cancer (16.3%), with at least 4 times as many primary cases than kidney cancer, which as mentioned above was the primary cancer with the most frequent oral metastasis. A similar discordance was found regarding prostate cancer, which was among the least frequent origins
in the present series with only 3.3% of the oral metastases, while in the general population it was one of the leading types of cancer (10%), 4th in frequency, with only a slightly lower annual number of cases in comparison to lung or colorectal cancers. Four cases (6.7%) were metastases from soft tissue sarcomas, which are generally rare neoplasms, but the frequency of these metastases was higher than expected, since the number of cases of malignancy from connective tissue in the general population was small (1%). Interestingly, metastases from soft tissue sarcomas to the oral cavity (either soft tissues or jawbones) are extremely rare and account for ∼1% of all metastases in previous reports in the literature (Hirshberg et al., 1993, 1994), far less than the present results (total 7 cases, 11.7%). Angiosarcoma and leiomyosarcoma are the most frequently reported sarcomas metastasizing to oral location (Lo Muzio et al., 2002). Two of the cases in the present series were also angiosarcomas, which is in agreement with the previous literature. However, only one previous report of oral metastasis from liposarcoma had been found (McElderry et al., 2008). Primary oral sarcomas are generally rare. Rhabdomyosarcoma, Ewing's sarcoma and osteogenic sarcoma are among the types of sarcoma that may be encountered as primary oral tumors, and in most cases develop in children and young adults (Gorsky and Epstein, 1998; Ketabchi et al., 2011; Williams et al., 2007;
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Fig. 3. A. Gingival metastasis from carcinoma of breast - rapidly growing erythematous gingival mass. The patient had previous metastasis in lung and brain. B. This rapidly growing erythematous gingival mass was a metastasis from a poorly differentiated liposarcoma, originating in the leg. Several other metastases in various organs were present. C. A bleeding mass in the posterior dorsal tongue was the clinical presentation of a metastasis from renal cell carcinoma, clear cell type, developing approximately 10 years after the primary tumor had been diagnosed. D. Metastasis from renal cell carcinoma, clear cell type, presenting as multiple ulcerated and easily bleeding gingival masses. The patient had been first diagnosed about 20 years, and developed multiple metastases in several organs in recent years. E. A painful and rapidly growing purple mass in the buccal vestibule was the clinical presentation of a metastatic malignant melanoma, originating in the skin of shoulder. Primary tumor had been diagnosed 7 years prior to oral metastasis. Vestibule is an unusual location for metastasis in oral mucosa (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.). Fig. 4. Metastatic angiosarcoma. A. Atypical hyperchromatic endothelial cells lining irregular spaces (hematoxylin and eosin). B. The neoplastic endothelial cells were positively stained by CD34. C. Non-neoplastic endothelial cells were positively stained by CD31. D. Ki67 proliferative marker was positive in ∼20% of the neoplastic endothelial cells. A - scale bar 100μ; B–D – scale bar 200μ.
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Fig. 5. Metastasis from clear cell variant of renal cell carcinoma. A. Clusters of clear cells are seen in a vascular stroma (hematoxylin and eosin). B. PAS stain was positive in the tumor cells. Tumor cells were positive for vimentin (C), pan-cytokeratin (D), CD 10 (E), PAX8 (F). G. Ki67 proliferation marker was positive in about 5–10 % of the cells. A, B - scale bar 100μ; C–G – scale bar 200μ. Fig. 6. Metastatic dedifferentiated liposarcoma. A. bundles of spindle cells lacking any characteristic features, with a high mitotic rate and diffuse hyperchromasia. Inset: single cells exhibited a somewhat vacuolar cytoplasm (hematoxylin and eosin). B. Positive nuclear MDM2 staining was consistent with previously diagnosed liposarcoma of thigh. C. Ki67 proliferation marker was very high, at about 80% of the cells, which correlated with the aggressive clinical behavior. A, B - scale bar 100μ; C – scale bar 200μ.
could provide an adequate microenvironment for the establishment of the pre-metastatic niche and effective chemo-attraction of the circulating metastatic cells (Hirshberg et al., 2014). In addition, the gingivae that are constantly inflamed and has a rich vascular network, is again an appropriate site for initiation of the premetastatic niche (Hirshberg et al., 2014). There also seems to be ethnic or geographic differences in the variability and frequency of oral metastasis. Comparison of the present series and reports from other countries, such as China, the USA, Canada and others revealed significant differences. The most common primary sites in China were liver and intrahepatic bile duct, and in decreasing frequency lung, thyroid, breast and kidney. In the USA, the most frequent primary sites were breast, lung, colon, kidney and prostate; in Canada, prostate, lung and breast were the most common origins, followed by squamous cell carcinoma of skin, while kidney was among the least common (Daley and Darling, 2011; Zhang et al., 2011). While in the present Israeli series kidney is the most frequent primary origin for both oral soft tissue and jaws, it was the least frequent or among the
Yamaguchi et al., 2004). On the other hand, angiosarcoma, leiomyosarcoma and liposarcoma in the oral soft tissues or jawbones should be highly suspicious to be metastatic deposition from a distant origin; these are typically tumors of advanced age (Sandhu et al., 2014). The differences between the frequency of tumor types in the general population and the relative frequency of origin of metastasis to oral mucosa and jawbones support past suggestions that the distribution of metastases to different organs is not random, but rather is driven by some biological properties that control the specific homing of metastases from different tumor types to specific target organs. It is now assumed that site-specific metastatic growth is determined by establishment of a viable pre-metastatic niche within the target organ that would enable the initial survival of extravasated tumor cells in a nonreceptive target organ (Psaila and Lyden, 2009). This process involves mobilization of hematopoietic progenitors from the bone marrow into the target sites in response to molecular signals emitted by the primary tumors (Psaila and Lyden, 2009; Peinado et al., 2011). The bone marrow tissue within the body of the mandible, albeit in small amounts, 5
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Table 1 Distribution (number) of the metastatic tumors to the oral cavity (site of primary tumor, gender and location in oral cavity). Primary sites of origin
Breast Kidney Skin (melanoma, SCCa) Lung Colon/rectum UADTb (including stomach) Thyroid Soft tissue (sarcomas) Liver Prostate Bone Diagnosis with differentialc Unknown primary Total a b c
Females
Males
Soft tissues
Jawbones
Total
Soft tissues
Jawbones
Total
2 3 4 3 2 – – 2 – – – – – 16
7 (1 socket) 3 2 (1 socket) 1 1 2 2 – – – 1 – – 19
9 6 6 4 3 2 2 2 – – 1 – – 35
– 3 2 (1 SCC) 2 1 –
– 3 – 1
– 6 2 3 1 2
2 – – – 1 3 (1 sarcoma, 2 adenocarcinomas) 14
2 (socket) – 1 1 2 – – 1 (high grade sarcoma) 11
3 1 2 – 1 4 25
Squamous cell carcinoma. Upper aerodigestive tract. Diagnosis narrowed down to short differential list.
Fig. 7. Flow chart for the immunohistochemical workup of metastatic deposits for the determination of the origin of the primary tumor. CK – cytokeratin; LCA – leukocyte common antigen; SMA – smooth muscle actin; EMA – epithelial membrane antigen; TTF – thyroid transcription factor; ER – estrogen receptor; PR – progesterone receptor; GI – gastro intestinal; RCC – renal cell carcinoma; MGB – mammoglobin
malignant melanoma was not reported as a source for oral metastases, as opposed to 11.7% of cases in the present series. Thus, both ethnic and geographic factors probably play an important role in this complex issue. To be better prepared to recognize and identify oral metastases, both clinicians and pathologists need to be familiar with the specific information for each population, and keep a high level of awareness for the specific cancer types relevant in their population base, as there seem to be significant differences across the world. Further analysis of the characteristics of the present series revealed
least frequent sites in reports from China and Canada. In contrast, liver is the most frequent origin in China and is the least common in the present series. In comparison to the Canadian report, where prostate was the most common organ of origin, it was one of the least frequent in the present series. A report from India included a pediatric age group with metastases from brain and adrenal glands, which are reported neither in the present series nor from other countries (Muttagi et al., 2011). The results from Israel are closer to those reported from the USA than any of the other series. However, in all of these countries skin 6
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patients, metastasis from a distant site needs to be included in the differential diagnosis of oral masses at any oral location, whether the existence of a primary tumor is reported or not.
that although the gingiva and jawbones were the most frequent locations for metastatic deposition from distant organs, as would be expected from the literature, some cases presented as tissue masses in unusual locations, such as the posterior dorsal tongue in a case of RCC (Fig. 3C), the mandibular vestibule in a cases of malignant melanoma (Fig. 3E), or the lower lip in a carcinoma of unknown origin. The metastatic lesions in many of the cases exhibited clinical characteristics which mimic reactive lesions, and no specific sign to induce high suspicion for malignancy or to suggest a metastasis. In some of the cases the oral surgeon was not aware of the history of past malignancy at the time the biopsy was obtained, thus metastasis was not anticipated. For example, the patient with the RCC presenting as a bleeding mass in the posterior dorsal tongue, had RCC 10 years previously, with no relevant findings in the oncological follow-up visits since. The case of metastatic melanoma which presented as a mass in the mandibular vestibule occurred in a patient that had a melanoma removed from her shoulder area 7 years previously. She did not comply with the recommended follow-up and failed to report it to the oral surgeon, and ultimately she presented with a painful, rapidly progressing oral vestibular mass. Thus, we conclude that in adult/older patients, metastasis from a distant site needs to be included in the differential diagnosis of oral masses in any oral location, whether the existence of a primary tumor is reported or not. Furthermore, clinicians need to have an increased level of suspicion for oral metastasis in patients with RCC, breast, skin, lung, and soft tissue cancers, as most of the metastases in the present series originated in these organs. Moreover, this is true for female patients (58.3% in the present series) in the sixth decade of life, while in males metastatic disease would be expected in a more advanced age group. For the pathologist, faced with a suspected metastatic tumor, thorough immunohistochemical workup, occasionally supplemented by other molecular tests, are required to define the origin of the primary tumor (Fig. 7), especially in those cases in which there is no information of a known malignancy at the time the biopsy is submitted. In the majority of cases a battery of stains is required, and the results allow in most cases to confirm the site of origin, but in some cases only a narrowed down list of possible origins can be suggested from the histopathological workup, and in some cases the origin may remain unknown (both options accounted for 8.4% in the present series). Thus, occasionally, cytogenetic analyses and further systemic workup with different imaging modalities are required in addition to histopathology to identify the primary origin. This process is a routine procedure in the management of oncologic patients.
Declaration of Competing Interest The authors declare no conflict of interests References Allon, I., Pessing, A., Kaplan, I., Allon, D.M., Hirshberg, A., 2014. Metastatic tumors to the gingiva and the presence of teeth as a contributing factor: a literature analysis. J. Periodontol. 85, 132–139. Daley, T., Darling, M.R., 2011. Metastases to the mouth and jaws: a contemporary Canadian experience. J. Can. Dent. Assoc. 77, 1–7. Gorsky, M., Epstein, J.B., 1998. Head and neck and intra-oral soft tissue sarcomas. Oral Oncol. 34, 292–296. Hirshberg, A., 2016. Metastatic Neoplasms to the Oral Cavity. (accessed 11.14.16). http://emedicine.medscape.com/article/1079102-overview. Hirshberg, A., Berger, R., Allon, I., Kaplan, I., 2014. Metastatic tumors to the jaws and mouth. Head Neck Pathol. 8, 463–474. Hirshberg, A., Buchner, A., 1995. Metastatic tumours to the oral region. An overview. Oral Oncol. Eur. J. Cancer 31B, 355–360. Hirshberg, A., Leibovich, P., Buchner, A., 1993. Metastases to the oral mucosa: analysis of 157 cases. J. Oral Pathol. Med. 22, 385–390. Hirshberg, A., Leibovich, P., Buchner, A., 1994. Metastatic tumors to the jawbones: analysis of 390 cases. J. Oral Pathol. Med. 23, 337–341. Hirshberg, A., Shnaiderman-Shapiro, A., Kaplan, I., Berger, R., 2008. Pathogenesis and analysis of 673 cases. Oral Oncol. 44, 743–752. Israel National Cancer Registry 2013; available at: https://www.health.gov.il/English/ MinistryUnits/HealthDivision/Icdc/Icr/Pages/default.aspx. Ketabchi, A., Kalavrezos, N., Newman, L., 2011. Sarcomas of the head and neck: a 10-year retrospective of 25 patients to evaluate treatment modalities, function and survival. Brit. J. Oral Maxillofac. Surg. 49, 116–120. Kumar, G.S., Manjunatha, B.S., 2013. Metastatic tumors to the jaws and oral cavity. J. Oral Maxillofac. Pathol. 17, 71–75. Lo Muzio, L., Favia, G., Farronato, G., Piattelli, A., Maiorano, E., 2002. Primary gingival leiomyosarcoma. A clinicopathological study of 1 case with prolonged survival. J. Clin. Periodontol. 29, 182–187. McElderry, J., McKenney, J.K., Stack, B.C., 2008. High-grade liposarcoma metastatic to the gingival mucosa: case report and literature review. Am. J. Otolaryngol. 29, 130–134. Muttagi, S.S., Chaturvedi, P., D’Cruz, A., Kane, S., Chaukar, D., Pai, P., Singh, B., Pawar, P., 2011. Metastatic tumors to the jaw bones: Retrospective analysis from an Indian tertiary referral center. Indian J. Cancer 48, 234–239. Peinado, H., Lavotshkin, S., Lyden, D., 2011. The secreted factors responsible for premetastatic niche formation: old sayings and new thoughts. Semin. Cancer Biol. 21, 139–146. Pesis, A., Taicher, S., Greenberg, G., Hirshberg, A., 2014. Metastasis to the jaws as a first manifestation of hepatocellular carcinoma: report of a case and analysis of 41 cases. J. Craniomaxillofac. Surg. 42, 1997–2001. Psaila, B., Lyden, D., 2009. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293. Sandhu, S.V., Sodhi, S.P., Rai, S., Bansal, H., 2014. Primary leiomyosarcoma of the maxilla: an investigative loom-report of a challenging case and review of literature. J. Oral Maxillofac. Pathol. 18, 453–459. Taicher, S., Mazar, A., Hirshberg, A., Dayan, D., 1991. Metastatic chondrosarcoma of the gingiva mimicking a reactive exophytic lesion: a case report. J. Periodontol. 62, 223–226. Williams, S.B., Foss, R.B., Fanburg-Smith, J.C., 2007. Oral and maxillofacial sclerosing epithelioid fibrosarcoma: report of five cases. Head Neck Pathol. 1, 13–20. Yamaguchi, S., Nagasawa, H., Suzuki, T., Fujii, E., Iwaki, H., Takagi, M., Amagasa, T., 2004. Sarcomas of the oral and maxillofacial region: a review of 32 cases in 25 years. Clin. Oral Invest. 8, 52–55. Zhang, F.G., Hua, C.G., Shen, M.L., Tang, X.F., 2011. Primary tumor prevalence has an impact on the constituent ratio of metastases to the jaw but not on metastatic sites. Int. J. Oral Sci. 3, 141–152.
5. Conclusions The majority of metastases to the oral cavity and jaws occurred in this study in adults in the 5th-9th decades. The most frequent primary tumors of origin were kidney, breast skin, lung and soft tissue sarcomas, not necessarily corresponding to the relative frequency of the primary tumors in the general population. Thorough immunohistochemical workup is required to identify the origin of the primary tumor. Although the majority of metastasis involves the gingiva and jawbones, any oral mucosal location might be involved. Thus, in adult/ older
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Metastatic tumors in oral mucosa and jawbones: Unusual primary origins and unusual oral locations ⁎
Ilana Kaplana,b,c, , Vadim Raiserd, Amir Shusterc,d, Benjamin Shlomic,d, Eli Rosenfelde, Adi Greenberge, Avraham Hirshbergc, Ran Yahalomf, Anna Shnaiderman-Shapirog, Marilena Veredc,g a
Institute of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel Institute of Pathology, Rabin Medical Center, Petah-Tikva, Israel c Department of Oral Pathology and Oral Medicine, Goldschleger School of Dental Medicine, Tel-Aviv University, Israel d Oral and Maxillofacial Surgery Unit, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel e Department of Oral and Maxillofacial Surgery, Rabin Medical Center, Petah-Tikva, Israel f Department of Oral and Maxillofacial Surgery, The Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel g Institute of Pathology, The Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel b
A R T I C LE I N FO
A B S T R A C T
Keywords: Metastases Oral metastases Jawbone metastases
Aim: To perform clinico-pathological characterization of a large series of oral metastases, collected from 3 main medical centers in Israel and compare findings to data on frequency of primary cancer types in the population. Materials: Pathology archives were searched for cases of metastatic tumors to the oral soft tissues and jawbones, 1990 – 2016. Metastases to the skin of face or to major salivary glands have been excluded. Demographic data and histopathological features were analyzed. Results: Study population included 60 patients, 35 females and 25 males (ratio of 1.4:1). The age range was 17–87 years, mean 67.7 + 14.36 years. Only 3 (5%) patients were under 40 years, the remaining clustered predominantly in the 60–80 year age group. The mean age of females (59 + 13.84) was significantly lower than that of males (67.44 + 14) (p = 0.03). There was an almost equal distribution between the oral soft tissue and the jawbones (48.3% and 51.7%, respectively). The five most common organs from which metastases were distributed to the oral cavity and jawbones combined were kidney (20%), breast (15%), cutaneous (predominately melanoma, 13%), lung (11.7%) and soft tissue-sarcomas (8.3%). For comparison, Israel National Cancer Registry 2013 reported that the most frequent malignancies were breast (25.8%), colorectal cancer (16.3%), lung (12%) and prostate (10%). Malignant melanoma was 6th (5.4%), kidney malignancy was only 9th in frequency (4.2%). Although the gingiva and jawbones were the most frequent locations, some cases presented in unusual locations, (mandibular vestibule, lower lip, posterior dorsal tongue), without any specific clinical feature to suggest metastasis. Conclusions: The most frequent primary origins for oral metastasis do not correspond to the relative frequency of the primary tumors in the population, indicating that metastatic spread is not a random process. Although the majority of metastasis involves the gingiva and jawbones, any other oral mucosal location might be involved. Thus, in adult/older patients, metastasis from a distant site should be included in the differential diagnosis of oral masses at any oral location, whether the existence of a primary tumor is reported or not.
1. Introduction Metastases to the oral cavity are rare and account for only 1%–1.5% of all malignant tumors in this region (Hirshberg, 2016; Kumar and Manjunatha, 2013). It is assumed that oral metastases represent secondary spread from other primary metastatic deposits, most frequently
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the lungs (Kumar and Manjunatha, 2013). Yet, oral metastases were reported to be the first sign of metastatic spread of a malignancy in about 30% of the cases (Hirshberg, 2016). In this setting, it is assumed that the metastatic tumor bypasses the lung filtration, spreading to the oral cavity via the vertebral valveless venous plexus, which supplies the axial skeleton as well as the head and neck region.
Corresponding author at: Institute of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. E-mail address: [email protected] (I. Kaplan).
https://doi.org/10.1016/j.acthis.2019.151448
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Please cite this article as: Ilana Kaplan, et al., Acta Histochemica, https://doi.org/10.1016/j.acthis.2019.151448
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cavity and jawbones combined were kidney (20%), breast (15%), skin (13%; malignant melanoma alone - 11.7%), lung (11.7%) and soft tissue sarcoma (8.3%) (Fig. 2). Fig. 3 presents the clinical features of selected cases, Figs. 4–6 present examples of immunohistochemical stains that aided in the identification of the origin of the metastatic disease. Some differences were observed in the distribution of the primary sites of origin between genders, as well as distribution between oral soft tissues and jawbones; the most common primary sites for soft tissue metastases in females were skin (4, 25%), lung and kidney (3, 18.8%, each), while in males, it was kidney and unknown primaries (3, 23%, each). The most common primary sites to send metastases to the jawbones were breast (7, 36.8%) and kidney (3, 15.8%) in females and kidney (3, 25%) and upper aerodigestive tract and prostate (2, 16.7%, each) in males (Table 1). In the patients with soft tissue metastases, there were 16 females and 13 males with a mean age of 63.7 + 13.9 years (range 19–86 years). The most common oral soft tissue location involved with metastasis was the gingiva/alveolar mucosa (19, 65.5%), followed by the buccal mucosa (5, 17.2%). Several lesions occurred in unusual locations for metastatic deposits, such as vestibule (2, 6.9%), lower lip, floor of the mouth, and dorsal aspect of tongue (1 case, 3.4%, each). The present series included four cases of metastatic sarcoma to the oral soft tissues Sarcomas are rare as primary tumors and even less so as oral metastases; two cases were metastases from angiosarcoma and one each liposarcoma and chondrosarcoma, (the latter has been previously published, Taicher et al., 1991). In the group of jawbone metastases, there were 19 females and 12 males, with a mean age of 61.6 + 14.9 years (age range 17–87 years). The vast majority of the tumors involved the mandible (26, 83.9%) and only 5 (16%) the maxilla. Three mandibular metastases (11% of jaw metastasis) became clinically evident at an extraction site. The case of liver metastasis has been previously published (Pesis et al., 2014). There were three cases of metastatic sarcomas: osteogenic sarcoma, rhabdomyosarcoma and a high grade sarcoma of unknown origin. For comparison, the cancer statistics of the Israel National Cancer Registry (last available data is for, 2013) were searched for information regarding the incidence of cancer in different organs in the Israeli population. The most frequent was breast cancer (4768 cases, 25.8%), followed by colorectal cancer (3335 cases, 16.3%), lung (2485 cases, 12%) and prostate (2060 cases, 10%). Malignant melanoma was 6th (1121 cases, 5.4%) and kidney malignancy was only 9th in frequency (861 cases, 4.2%), soft tissue malignancy (217 cases, 1%) (Fig. 2).
The primary sites from which metastases to the oral cavity have been reported include lung, breast, kidney, bone and colorectal regions. The majority of primary tumors, which metastasize to the oral cavity and jaws, have been of epithelial origin (∼70%) and only a minority has been sarcomas (Hirshberg et al., 1994). Some differences have been noted regarding gender and location of metastatic deposits (Hirshberg, 2016; Hirshberg and Buchner, 1995; Hirshberg et al., 2008). In male patients lung is the most common primary site with metastases to the jawbones (22%) and soft tissues (31%), followed by prostate metastasizing to jawbones (11%) and kidney to soft tissues (14%). In female patients, breast is the main primary source for oral metastases to both jawbones (41%) and soft tissues (23.3%), followed by the adrenal gland and genitalia with metastases to jawbones (7.7%) and primary tumors of genital region metastasizing to oral soft tissues (14.8%) (Hirshberg et al., 2008). Patients with oral metastases are usually in the 4th and 7th decades of life. Jawbone metastases have been observed in a younger age group than those with soft tissue metastases (mean 45 years and 54 years, respectively). This difference is mainly related to metastasis from neuroblastoma, a tumor of the pediatric age group (Hirshberg and Buchner, 1995; Hirshberg et al., 2008). The present study has been undertaken to characterize a large series of oral metastases, collected from 3 main medical centers in the central area of Israel. Analysis of clinical and histopathological features, with emphasis on unusual cases of oral metastases will be presented, and compared to data on frequency of primary cancer types in the population. 2. Material and methods The files of 3 principal medical centers that serve the central area of Israel were searched for cases of metastatic tumors to the oral soft tissues and jawbones, between January 1990 and December 2016. Inclusion criteria included adequate demographic data, clinical information on the location and clinical presentation of the metastatic deposit, information on primary tumor of origin if known and detailed histopathological description. Cases of metastases to the skin of the face or to the major salivary glands have been excluded from the study. Statistical analysis was performed by t-test using SPSS package, version 22 (Chicago, IL, USA). Statistical significance was set at p < 0.05. Study was conducted in accordance with the ethical requirements (Israeli and International Conference on Harmonization Good Clinical Practice standards) of clinical trials.
4. Discussion
3. Results
The process of metastatic spread is complex, involving both characteristics of each individual tumor and qualities relating to the host response. For these reasons, there is a wide variety between tumor types regarding the frequency of metastasis and the particular distribution of metastases in distant organs. However, some patterns have been observed and reported in the past in relation to metastasis to the oral soft tissues and bone. Metastasis from carcinomas of prostate were reported to have a predisposition to the jawbones and those from the breast were twice as frequent in the jawbones than in the soft tissue; in contrast, those from lung and kidney were more frequent in the soft tissues (Hirshberg and Buchner, 1995; Hirshberg et al., 1993, 1994, 2008, 2014; Allon et al., 2014). In the present comprehensive series of cases, an unexpected finding was that renal cell carcinoma (RCC) was the most frequent metastasis in both oral soft tissues and jawbones (20%), while kidney malignancy was only 9th in the order of cancer types in Israel comprising only 4.2% of cancer cases. Thus, there is a significantly increased proportion of metastasis from kidney to oral cavity and jawbones than could be expected if metastasis distribution was random. Breast cancer was second in frequency in the metastases group and
A total of 60 cases of metastases have been retrieved. The study population included 35 females and 25 males (ratio of 1.4:1). The age range was 17–87 years, with a mean of 67.7 + 14.36 years. Only 3 (5%) patients were under 40 years (17, 19 and 39 years respectively), the remaining clustered were predominantly in the 60–80 years age group (Fig. 1). The mean age of the female patients (59 + 13.84 years, range 19–87 years) was significantly lower than that of the male patients (67.4 + 14 years, range 17–86 years) (p = 0.03). There was an almost equal distribution between the oral soft tissue and the jawbones (28, 48.3% and 30, 51.7%, respectively). Some of the cases, mainly those from the more recent years, had detailed and updated panels of immunohistochemical stains that aided in identifying the primary tumor or confirmed a metastasis from a known primary tumor. Older cases had less comprehensive immunohistochemical workup; diagnosis also relied on the morphological similarity to the primary tumor (in those cases when the primary tumor was known). The five most common organs from which metastases to the oral 2
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Fig. 1. Age and gender distribution of patients with oral metastatic tumors. Fig. 2. Relative frequency (%) of primary cancers in the Israeli population in 2013 versus relative frequency of origin for metastatic tumors to the oral cavity and jawbones. MET – metastasis according to present study; NHL - Non Hodgkin Lymphoma; Connective tissue – in regard to metastasis, the term referred to sarcomas; Unclassified - in regard to metastasis, the term referred to combined entities of "origin unknown" and "narrowed down differential" from Table 1; UADT - upper aerodigestive tracts; Skin – primary malignant melanoma excluded
first in order in the general population in Israel, thus representing a relatively good correlation in frequency between the incidence in general population and oral metastasis. Oral metastases from skin, (malignant melanoma and squamous cell carcinoma combined), were third in frequency (13.3%), out of which malignant melanoma accounted for the vast majority of these cases (11.7%), although melanoma was only 8th in frequency in the general population (5.4%). Lung was fourth in frequency of oral metastases (11.7%) and the third most frequent malignancy in the general population. The fraction of metastases from skin melanoma was almost identical to that of metastases from the lungs, although the number of annual cases was approximately half that of lung cancer. Thus, similar to metastasis from the kidneys, there were remarkably more metastases from skin melanoma to the oral cavity and jaws than would be expected from the number of cases in the population. Metastases from colorectal cancer were present only in 6.7% of the cases, far less than expected from the incidence in the general population, where colorectal cancer is second in frequency after breast cancer (16.3%), with at least 4 times as many primary cases than kidney cancer, which as mentioned above was the primary cancer with the most frequent oral metastasis. A similar discordance was found regarding prostate cancer, which was among the least frequent origins
in the present series with only 3.3% of the oral metastases, while in the general population it was one of the leading types of cancer (10%), 4th in frequency, with only a slightly lower annual number of cases in comparison to lung or colorectal cancers. Four cases (6.7%) were metastases from soft tissue sarcomas, which are generally rare neoplasms, but the frequency of these metastases was higher than expected, since the number of cases of malignancy from connective tissue in the general population was small (1%). Interestingly, metastases from soft tissue sarcomas to the oral cavity (either soft tissues or jawbones) are extremely rare and account for ∼1% of all metastases in previous reports in the literature (Hirshberg et al., 1993, 1994), far less than the present results (total 7 cases, 11.7%). Angiosarcoma and leiomyosarcoma are the most frequently reported sarcomas metastasizing to oral location (Lo Muzio et al., 2002). Two of the cases in the present series were also angiosarcomas, which is in agreement with the previous literature. However, only one previous report of oral metastasis from liposarcoma had been found (McElderry et al., 2008). Primary oral sarcomas are generally rare. Rhabdomyosarcoma, Ewing's sarcoma and osteogenic sarcoma are among the types of sarcoma that may be encountered as primary oral tumors, and in most cases develop in children and young adults (Gorsky and Epstein, 1998; Ketabchi et al., 2011; Williams et al., 2007;
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Fig. 3. A. Gingival metastasis from carcinoma of breast - rapidly growing erythematous gingival mass. The patient had previous metastasis in lung and brain. B. This rapidly growing erythematous gingival mass was a metastasis from a poorly differentiated liposarcoma, originating in the leg. Several other metastases in various organs were present. C. A bleeding mass in the posterior dorsal tongue was the clinical presentation of a metastasis from renal cell carcinoma, clear cell type, developing approximately 10 years after the primary tumor had been diagnosed. D. Metastasis from renal cell carcinoma, clear cell type, presenting as multiple ulcerated and easily bleeding gingival masses. The patient had been first diagnosed about 20 years, and developed multiple metastases in several organs in recent years. E. A painful and rapidly growing purple mass in the buccal vestibule was the clinical presentation of a metastatic malignant melanoma, originating in the skin of shoulder. Primary tumor had been diagnosed 7 years prior to oral metastasis. Vestibule is an unusual location for metastasis in oral mucosa (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.). Fig. 4. Metastatic angiosarcoma. A. Atypical hyperchromatic endothelial cells lining irregular spaces (hematoxylin and eosin). B. The neoplastic endothelial cells were positively stained by CD34. C. Non-neoplastic endothelial cells were positively stained by CD31. D. Ki67 proliferative marker was positive in ∼20% of the neoplastic endothelial cells. A - scale bar 100μ; B–D – scale bar 200μ.
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Fig. 5. Metastasis from clear cell variant of renal cell carcinoma. A. Clusters of clear cells are seen in a vascular stroma (hematoxylin and eosin). B. PAS stain was positive in the tumor cells. Tumor cells were positive for vimentin (C), pan-cytokeratin (D), CD 10 (E), PAX8 (F). G. Ki67 proliferation marker was positive in about 5–10 % of the cells. A, B - scale bar 100μ; C–G – scale bar 200μ. Fig. 6. Metastatic dedifferentiated liposarcoma. A. bundles of spindle cells lacking any characteristic features, with a high mitotic rate and diffuse hyperchromasia. Inset: single cells exhibited a somewhat vacuolar cytoplasm (hematoxylin and eosin). B. Positive nuclear MDM2 staining was consistent with previously diagnosed liposarcoma of thigh. C. Ki67 proliferation marker was very high, at about 80% of the cells, which correlated with the aggressive clinical behavior. A, B - scale bar 100μ; C – scale bar 200μ.
could provide an adequate microenvironment for the establishment of the pre-metastatic niche and effective chemo-attraction of the circulating metastatic cells (Hirshberg et al., 2014). In addition, the gingivae that are constantly inflamed and has a rich vascular network, is again an appropriate site for initiation of the premetastatic niche (Hirshberg et al., 2014). There also seems to be ethnic or geographic differences in the variability and frequency of oral metastasis. Comparison of the present series and reports from other countries, such as China, the USA, Canada and others revealed significant differences. The most common primary sites in China were liver and intrahepatic bile duct, and in decreasing frequency lung, thyroid, breast and kidney. In the USA, the most frequent primary sites were breast, lung, colon, kidney and prostate; in Canada, prostate, lung and breast were the most common origins, followed by squamous cell carcinoma of skin, while kidney was among the least common (Daley and Darling, 2011; Zhang et al., 2011). While in the present Israeli series kidney is the most frequent primary origin for both oral soft tissue and jaws, it was the least frequent or among the
Yamaguchi et al., 2004). On the other hand, angiosarcoma, leiomyosarcoma and liposarcoma in the oral soft tissues or jawbones should be highly suspicious to be metastatic deposition from a distant origin; these are typically tumors of advanced age (Sandhu et al., 2014). The differences between the frequency of tumor types in the general population and the relative frequency of origin of metastasis to oral mucosa and jawbones support past suggestions that the distribution of metastases to different organs is not random, but rather is driven by some biological properties that control the specific homing of metastases from different tumor types to specific target organs. It is now assumed that site-specific metastatic growth is determined by establishment of a viable pre-metastatic niche within the target organ that would enable the initial survival of extravasated tumor cells in a nonreceptive target organ (Psaila and Lyden, 2009). This process involves mobilization of hematopoietic progenitors from the bone marrow into the target sites in response to molecular signals emitted by the primary tumors (Psaila and Lyden, 2009; Peinado et al., 2011). The bone marrow tissue within the body of the mandible, albeit in small amounts, 5
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Table 1 Distribution (number) of the metastatic tumors to the oral cavity (site of primary tumor, gender and location in oral cavity). Primary sites of origin
Breast Kidney Skin (melanoma, SCCa) Lung Colon/rectum UADTb (including stomach) Thyroid Soft tissue (sarcomas) Liver Prostate Bone Diagnosis with differentialc Unknown primary Total a b c
Females
Males
Soft tissues
Jawbones
Total
Soft tissues
Jawbones
Total
2 3 4 3 2 – – 2 – – – – – 16
7 (1 socket) 3 2 (1 socket) 1 1 2 2 – – – 1 – – 19
9 6 6 4 3 2 2 2 – – 1 – – 35
– 3 2 (1 SCC) 2 1 –
– 3 – 1
– 6 2 3 1 2
2 – – – 1 3 (1 sarcoma, 2 adenocarcinomas) 14
2 (socket) – 1 1 2 – – 1 (high grade sarcoma) 11
3 1 2 – 1 4 25
Squamous cell carcinoma. Upper aerodigestive tract. Diagnosis narrowed down to short differential list.
Fig. 7. Flow chart for the immunohistochemical workup of metastatic deposits for the determination of the origin of the primary tumor. CK – cytokeratin; LCA – leukocyte common antigen; SMA – smooth muscle actin; EMA – epithelial membrane antigen; TTF – thyroid transcription factor; ER – estrogen receptor; PR – progesterone receptor; GI – gastro intestinal; RCC – renal cell carcinoma; MGB – mammoglobin
malignant melanoma was not reported as a source for oral metastases, as opposed to 11.7% of cases in the present series. Thus, both ethnic and geographic factors probably play an important role in this complex issue. To be better prepared to recognize and identify oral metastases, both clinicians and pathologists need to be familiar with the specific information for each population, and keep a high level of awareness for the specific cancer types relevant in their population base, as there seem to be significant differences across the world. Further analysis of the characteristics of the present series revealed
least frequent sites in reports from China and Canada. In contrast, liver is the most frequent origin in China and is the least common in the present series. In comparison to the Canadian report, where prostate was the most common organ of origin, it was one of the least frequent in the present series. A report from India included a pediatric age group with metastases from brain and adrenal glands, which are reported neither in the present series nor from other countries (Muttagi et al., 2011). The results from Israel are closer to those reported from the USA than any of the other series. However, in all of these countries skin 6
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patients, metastasis from a distant site needs to be included in the differential diagnosis of oral masses at any oral location, whether the existence of a primary tumor is reported or not.
that although the gingiva and jawbones were the most frequent locations for metastatic deposition from distant organs, as would be expected from the literature, some cases presented as tissue masses in unusual locations, such as the posterior dorsal tongue in a case of RCC (Fig. 3C), the mandibular vestibule in a cases of malignant melanoma (Fig. 3E), or the lower lip in a carcinoma of unknown origin. The metastatic lesions in many of the cases exhibited clinical characteristics which mimic reactive lesions, and no specific sign to induce high suspicion for malignancy or to suggest a metastasis. In some of the cases the oral surgeon was not aware of the history of past malignancy at the time the biopsy was obtained, thus metastasis was not anticipated. For example, the patient with the RCC presenting as a bleeding mass in the posterior dorsal tongue, had RCC 10 years previously, with no relevant findings in the oncological follow-up visits since. The case of metastatic melanoma which presented as a mass in the mandibular vestibule occurred in a patient that had a melanoma removed from her shoulder area 7 years previously. She did not comply with the recommended follow-up and failed to report it to the oral surgeon, and ultimately she presented with a painful, rapidly progressing oral vestibular mass. Thus, we conclude that in adult/older patients, metastasis from a distant site needs to be included in the differential diagnosis of oral masses in any oral location, whether the existence of a primary tumor is reported or not. Furthermore, clinicians need to have an increased level of suspicion for oral metastasis in patients with RCC, breast, skin, lung, and soft tissue cancers, as most of the metastases in the present series originated in these organs. Moreover, this is true for female patients (58.3% in the present series) in the sixth decade of life, while in males metastatic disease would be expected in a more advanced age group. For the pathologist, faced with a suspected metastatic tumor, thorough immunohistochemical workup, occasionally supplemented by other molecular tests, are required to define the origin of the primary tumor (Fig. 7), especially in those cases in which there is no information of a known malignancy at the time the biopsy is submitted. In the majority of cases a battery of stains is required, and the results allow in most cases to confirm the site of origin, but in some cases only a narrowed down list of possible origins can be suggested from the histopathological workup, and in some cases the origin may remain unknown (both options accounted for 8.4% in the present series). Thus, occasionally, cytogenetic analyses and further systemic workup with different imaging modalities are required in addition to histopathology to identify the primary origin. This process is a routine procedure in the management of oncologic patients.
Declaration of Competing Interest The authors declare no conflict of interests References Allon, I., Pessing, A., Kaplan, I., Allon, D.M., Hirshberg, A., 2014. Metastatic tumors to the gingiva and the presence of teeth as a contributing factor: a literature analysis. J. Periodontol. 85, 132–139. Daley, T., Darling, M.R., 2011. Metastases to the mouth and jaws: a contemporary Canadian experience. J. Can. Dent. Assoc. 77, 1–7. Gorsky, M., Epstein, J.B., 1998. Head and neck and intra-oral soft tissue sarcomas. Oral Oncol. 34, 292–296. Hirshberg, A., 2016. Metastatic Neoplasms to the Oral Cavity. (accessed 11.14.16). http://emedicine.medscape.com/article/1079102-overview. Hirshberg, A., Berger, R., Allon, I., Kaplan, I., 2014. Metastatic tumors to the jaws and mouth. Head Neck Pathol. 8, 463–474. Hirshberg, A., Buchner, A., 1995. Metastatic tumours to the oral region. An overview. Oral Oncol. Eur. J. Cancer 31B, 355–360. Hirshberg, A., Leibovich, P., Buchner, A., 1993. Metastases to the oral mucosa: analysis of 157 cases. J. Oral Pathol. Med. 22, 385–390. Hirshberg, A., Leibovich, P., Buchner, A., 1994. Metastatic tumors to the jawbones: analysis of 390 cases. J. Oral Pathol. Med. 23, 337–341. Hirshberg, A., Shnaiderman-Shapiro, A., Kaplan, I., Berger, R., 2008. Pathogenesis and analysis of 673 cases. Oral Oncol. 44, 743–752. Israel National Cancer Registry 2013; available at: https://www.health.gov.il/English/ MinistryUnits/HealthDivision/Icdc/Icr/Pages/default.aspx. Ketabchi, A., Kalavrezos, N., Newman, L., 2011. Sarcomas of the head and neck: a 10-year retrospective of 25 patients to evaluate treatment modalities, function and survival. Brit. J. Oral Maxillofac. Surg. 49, 116–120. Kumar, G.S., Manjunatha, B.S., 2013. Metastatic tumors to the jaws and oral cavity. J. Oral Maxillofac. Pathol. 17, 71–75. Lo Muzio, L., Favia, G., Farronato, G., Piattelli, A., Maiorano, E., 2002. Primary gingival leiomyosarcoma. A clinicopathological study of 1 case with prolonged survival. J. Clin. Periodontol. 29, 182–187. McElderry, J., McKenney, J.K., Stack, B.C., 2008. High-grade liposarcoma metastatic to the gingival mucosa: case report and literature review. Am. J. Otolaryngol. 29, 130–134. Muttagi, S.S., Chaturvedi, P., D’Cruz, A., Kane, S., Chaukar, D., Pai, P., Singh, B., Pawar, P., 2011. Metastatic tumors to the jaw bones: Retrospective analysis from an Indian tertiary referral center. Indian J. Cancer 48, 234–239. Peinado, H., Lavotshkin, S., Lyden, D., 2011. The secreted factors responsible for premetastatic niche formation: old sayings and new thoughts. Semin. Cancer Biol. 21, 139–146. Pesis, A., Taicher, S., Greenberg, G., Hirshberg, A., 2014. Metastasis to the jaws as a first manifestation of hepatocellular carcinoma: report of a case and analysis of 41 cases. J. Craniomaxillofac. Surg. 42, 1997–2001. Psaila, B., Lyden, D., 2009. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293. Sandhu, S.V., Sodhi, S.P., Rai, S., Bansal, H., 2014. Primary leiomyosarcoma of the maxilla: an investigative loom-report of a challenging case and review of literature. J. Oral Maxillofac. Pathol. 18, 453–459. Taicher, S., Mazar, A., Hirshberg, A., Dayan, D., 1991. Metastatic chondrosarcoma of the gingiva mimicking a reactive exophytic lesion: a case report. J. Periodontol. 62, 223–226. Williams, S.B., Foss, R.B., Fanburg-Smith, J.C., 2007. Oral and maxillofacial sclerosing epithelioid fibrosarcoma: report of five cases. Head Neck Pathol. 1, 13–20. Yamaguchi, S., Nagasawa, H., Suzuki, T., Fujii, E., Iwaki, H., Takagi, M., Amagasa, T., 2004. Sarcomas of the oral and maxillofacial region: a review of 32 cases in 25 years. Clin. Oral Invest. 8, 52–55. Zhang, F.G., Hua, C.G., Shen, M.L., Tang, X.F., 2011. Primary tumor prevalence has an impact on the constituent ratio of metastases to the jaw but not on metastatic sites. Int. J. Oral Sci. 3, 141–152.
5. Conclusions The majority of metastases to the oral cavity and jaws occurred in this study in adults in the 5th-9th decades. The most frequent primary tumors of origin were kidney, breast skin, lung and soft tissue sarcomas, not necessarily corresponding to the relative frequency of the primary tumors in the general population. Thorough immunohistochemical workup is required to identify the origin of the primary tumor. Although the majority of metastasis involves the gingiva and jawbones, any oral mucosal location might be involved. Thus, in adult/ older
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