Metastatic tumors in oral mucosa and jawbones: Unusual primary origins and unusual oral locations.

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.

Markers of the pre-metastatic niche "knock on the door" of metastasis-free cervical lymph nodes in patients with oral cancer.

AIM: To assess expression of some markers of the pre-metastatic niche (PMN) in lymph nodes (LNs) of oral cancer patients. MATERIALS: LNs from metastatic-free neck dissections (LN0/N0, N = 43) and metastatic-free LNs in the vicinity of metastasis-containing LNs (LN0/N+, N = 30) were immuno-histochemically stained for lysyl oxidase (LOX), fibronectin (FN), vascular-endothelial growth factor receptor (VEGFR)-1 and matrix metalloproteinase (MMP)-9. Staining was assessed as 0 (no or weak staining), 1 (strong stain in 25% cells or extracellular area), 2 (same as 1 but in up to 50%) and 3 (same as 1 but in > than 50% of cells/area). Assessment was performed in the lymph node capsule (CAP), sub-capsular sinus (SCS) and medullary sinus (MS). In addition, sections were stained with picrosirius red and examined with polarized microscopy for assessing the distribution of polarization colors of the collagen fibers in the LN capsular area. RESULTS: All examined LNs were positive for markers of the PMN. In general, the distribution and intensity of the immunoreactivity was similar between the LN0/N0 and LN0/N+, with only a few differences regarding expression of LOX in the capsule (p = 0.002) and VEGFR1 and MMP9 in the SCS (p = 0.023 and p < 0.001, respectively). Picrosirius red stain and polarized microscopy revealed a disrupted arrangement and distribution of the collagen fibers in both LN0/N0 and LN0/N + . CONCLUSION: Markers for PMN were shown for the first time to be expressed in cervical LN0/N0 from patients with oral cancer, suggesting the increased permissive pathway remotely paved by the primary oral tumor for the incoming metastatic cells.

Cancer-associated fibroblasts in the tumor microenvironment of tongue carcinoma is a heterogeneous cell population.

OBJECTIVES: To examine different immunophenotypes of cancer-associated fibroblasts (CAFs) in tongue squamous cell carcinoma (TSCC) and to investigate how they related to clinical outcomes. METHODS: Serial sections from 54 cases of TSCC were immunohistochemically stained with α-smooth muscle actin (αSMA, CAF marker) to determine CAF density, and double-immunostained with αSMA combined with CD80 and CD86 (myeloid/monocytic-derived cell markers), Nanog (mesenchymal stem cell marker) and CD133 (hematopoietic/endothelial stem cell marker). Density of cells co-expressing these marker combinations was semi-quantitatively assessed in 5 randomly selected high power fields within the tumor area and scored as 1 - one-to-five stained cells in each field, 2 - more than 5 stained cells in each field; any finding less than score 1, was allocated a score of 0. RESULTS: There were 26 CAF-poor, 16 CAF-rich and 12 CAF-intermediated cases. CD86+αSMA+ cells were the most frequent (80.4%) followed by CD80+αSMA+ (72%) and Nanog+αSMA+ cells (56%). The CD133+αSMA+ phenotype was found only in association with blood vessels. High density of αSMA+ CAFs was associated with disease recurrence and poor survival (p < 0.05). Increased density of CD86+αSMA+ cells was significantly associated with CAF-rich tumors and with poor survival (p < 0.05). CONCLUSION: In TSCC, CAFs demonstrate heterogeneous and overlapping phenotypes with the myeloid/monocytic type being the most frequent and having an impact on the clinical outcomes. Further studies are needed in order to further characterize CAF phenotypes in carcinomas of various oral sites, as this may open new frontiers for personalized medicine.

Histopathological spectrum of bone lesions associated with dental implant failure: osteomyelitis and beyond.

Early or late post-implant placement complications are usually localized infectious/inflammatory processes and treated accordingly. If the healing process does not take place within a reasonable timeframe, the possibility of a pathologic process beyond localized infection/inflammation should be suspected. We describe a radiological/histopathological spectrum of bony lesions ranging from inflammatory to malignant lesions surrounding failed dental implants. Five cases of mandibular dental implant failure that clinically, radiologically and histopathologically appeared to be inflammatory processes are presented. The failure of the dental implants was immediate in two cases and late in the remaining three. The radiological features were essentially similar for all five, and they included radiolucent or mixed radiolucent-radiopaque lesions with poorly defined borders. Three lesions were limited to the area of the failed implant, while the other two extended to a large part of the mandible. The histopathological findings ranged from acute osteomyelitis and chronic osteomyelitis with features of a fibro-osseous-like lesion and occasional rimming of atypical osteoblasts to osteogenic sarcoma that was admixed with a component of osteomyelitis (diagnosis of the latter was achieved only after a series of biopsies). In-depth investigative procedures are imperative in order to establish an accurate diagnosis whenever the histopathological diagnosis is inconsistent with persisting clinical signs and symptoms in bone lesions associated with failed dental implants.

Mutational analysis of PTEN/PIK3CA/AKT pathway in oral squamous cell carcinoma.

The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma (AKT) viral oncogene pathway is involved in regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth. Mutations in the genes associated with the PI3K/AKT pathway including PI3K, AKT, RAS and PTEN, are infrequently found within head and neck squamous cell carcinoma and more specifically are rarely reported in oral squamous cell carcinoma (OSCC) cases. We aimed to investigate the frequency of mutations in AKT1, PTEN, PIK3CA, and RAS (K-RAS, N-RAS, H-RAS) genes in 37 cases of oral squamous cell carcinoma (OSCC). Mutational analysis of PTEN, RAS, PIK3CA and AKT genes was performed using chip-based matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry and by direct sequencing. The only gene mutated in our series was the PIK3CA. Missense mutations of the PIK3CA gene were found in 4 of our cases (10.8%); no correlation has been found with oral location, stage and survival. The absence of mutations in AKT1, PTEN, and RAS genes in the present study is in accordance with previous studies confirming that these genes are rarely mutated in OSCC. Our data confirm that PIK3CA is important to OSCC tumorigenesis and can contribute to oncogene activation of the PIK3CA/AKT pathway in OSCC. The knowledge of the PIK3CA's involvement in OSCC is important because a specific kinase inhibitor could be considered as a future therapeutic option for OSCC patients with PIK3CA mutations.

Relative frequency of localized reactive hyperplastic lesions of the gingiva: a retrospective study of 1675 cases from Israel.

BACKGROUND: The gingiva reacts to chronic irritation or trauma with localized reactive hyperplastic lesions (LRHL) that can be classified into four groups: focal fibrous hyperplasia (FFH), pyogenic granuloma (PG), peripheral ossifying fibroma (POF), and peripheral giant cell granuloma (PGCG). This study determined the frequency of LRHL in an oral pathology biopsy service and compared these data with reports from other countries. METHODS: The material included the biopsies of all consecutive LRHL of the gingiva stored in the departmental database (1989-2008). Lesions were analyzed according to their location and to the patients' age and gender. The findings were compared with those published in studies from other countries. RESULTS: There were 1675 LRHL that comprised 6.7% of the 25,106 accessed biopsies. FFH was the most common (31.8%), followed by PG (29.1%), POF (20.4%), and PGCG (18.7%). POF tended to affect younger patients than did FFH, PG, and PGCG. FFH, PG, and POF were more common in women, while PGCG showed no gender predilection. PG and POF were more common in the maxilla, PGCG more common in the mandible and FFH was distributed equally between the jaws. The anterior region of the maxilla was the most prevalent site for FFH, PG, and POF. CONCLUSION: The results of this study differ somewhat from those of other countries. There is a need for further investigation to answer the question whether the differences can be attributed to geographic or ethnic factors and/or to small sample sizes of the reported studies.

Metastatic tumours to the oral cavity - pathogenesis and analysis of 673 cases.

The oral region is an uncommon site for metastatic tumour cell colonization and is usually evidence of a wide spread disease. In 25% of cases, oral metastases were found to be the first sign of the metastatic spread and in 23% it was the first indication of an undiscovered malignancy at a distant site. The jawbones, particularly the mandible, were more frequently affected than the oral soft tissues (2:1). In the oral soft tissues, the attached gingiva was the most commonly affected site (54%). The major primary sites presenting oral metastases were the lung, kidney, liver, and prostate for men, breast, female genital organs (FGO), kidney, and colo-rectum for women. The primary site differs according to oral site colonization, in men the lung was the most common primary site affecting both the jawbones and oral mucosa (22% and 31.3%, respectively) followed by the prostate gland in the jawbones (11%) and kidney in the oral soft tissues (14%). In women, the breast was the most common primary tumour affecting the jawbones and soft tissues (41% and 24.3%, respectively), followed by the adrenal and female genital organs (FGO) in the jawbones (7.7%) and FGO in the soft tissues (14.8%). The clinical presentation of the metastatic lesions differ between the various sites in the oral region. In the jawbones most patients complain of swelling, pain and paresthesia which developed in a relative short period. Early manifestation of the gingival metastases resembled a hyperplastic or reactive lesion, such as pyogenic granuloma, peripheral giant cell granuloma, or fibrous epulis. Because of its rarity, the diagnosis of a metastatic lesion in the oral region is challenging, both to the clinician and to the pathologist, in recognizing that a lesion is metastatic and in determining the site of origin. The clinical presentation of a metastatic lesion in the oral cavity can be deceiving leading to a misdiagnosis of a benign process, therefore, in any case where the clinical presentation is unusual especially in patients with a known malignant disease a biopsy is mandatory.