Cancer Stem Cell Markers in Squamous Cell Carcinomas of the Salivary Glands.

BACKGROUND: Cancer stem cells (CSC) are cells that exhibit stem cell properties and are pivotal in tumor biology. CSC markers have been described for many tumorous entities. However, to this date, there is no data on CSC markers in respect to squamous cell carcinomas (SCC) of the salivary glands. METHODS: Histologic samples from patients with salivary gland SCCs were stained for CSC markers (ALDH-1/BMI-1/SOX-2/CD-44/vimentin) and divided into high and low expression subgroups. These were then correlated with tumor and patient characteristics as well as overall survival (OS), disease-specific survival, recurrence-free survival and local control rates (LCR) after 3 and 5 years. RESULTS: Overall, 31 samples were included. CD-44 and ALDH-1 expression were associated with tumor origin (metastatic/primary disease, p = 0.048 and p = 0.011, respectively). Strong BMI-1 expression was associated with poorer OS (62.9 vs. 27.3%, p = 0.029), strong SOX-2 expression was associated with poorer LCR (62.5 vs. 21.9%, p = 0.007). CONCLUSION: CD-44 and ALDH-1 may be useful in differentiating between primary SCCs and metastatic disease. BMI-1 and SOX-2 are correlated with poorer prognosis.

MCM3 proliferative index is worthier over Ki-67 in the characterization of salivary gland tumors.

BACKGROUND: Salivary gland tumors bear uncanny characteristics of being different based on their morphological aspects rather than the presence of clear demarcation. This ambiguity in the spectrum from benign to malignant salivary gland neoplasms while categorizing the neoplasm is having inherent pitfalls. The present study was, therefore, designed to characterize benign and malignant salivary gland tumors based on their proliferative indices. MATERIALS AND METHOD: Study samples comprised of 97 cases of histopathologically confirmed benign and malignant salivary gland tumors. The cases were immunohistochemically assessed for MCM3 and Ki-67 expressions and the molecular characterization was performed based on the findings. RESULTS: The majority of benign and malignant salivary gland tumors were from the parotid gland, (51.2%) and (42.4%), respectively. Overall mean labeling index of MCM3 was higher i.e., (5.60 ± 3.99) in comparison to Ki-67 i.e., (2.82 ± 3.14) with P = 0.05 using paired t-test. Besides, malignant salivary gland neoplasms represented a higher mean score of MCM3 and Ki-67 than benign neoplasms. CONCLUSION: The requirement of a novel marker has led to the use of MCM3 which has a characteristic role in the entire spectrum of the cell cycle. The present study highlighted the extrapolation of MCM3 over Ki-67 for diagnosis and for true characterization of biologic behavior of salivary gland pathologies which may, in turn, influence the treatment modality employed for such lesions.

Coexistence of the BRCA1 and KRAS mutations in a patient with salivary gland carcinoma arising in mediastinal mature teratoma.

Teratoma with malignant transformation is a rare type of malignant teratoma. In the present case, we describe a patient with salivary gland carcinoma (SGC) generating in mediastinal mature teratoma. Next-generation sequencing showed BRCA1 and KRAS somatic mutations, which might be associated with malignant transformation of the mediastinal mature teratomas. To our knowledge, the present case is the first report of coexistence of BRCA1 and KRAS mutations in mature cystic teratoma with malignant transformation to SGC. And the tumor showed a good response to chemotherapy with cisplatin and paclitaxel according to the transformed histology.

Metastasis of small cell bronchopulmonary cancer in the submandibular gland: a new case.

The metastases of bronchopulmonary cancer in the submandibular gland are infrequent. We report a case of metastasis in the submandibular gland in a patient with small cell lung cancer who had chemotherapy with disease stability.

Immunohistochemical Reactivity of Prostate-Specific Markers for Salivary Duct Carcinoma.

OBJECTIVES: NKX3.1, a transcription factor related to androgen expression, has recently been introduced as a diagnostic marker of prostate adenocarcinoma. Salivary duct carcinoma (SDC) is typically positive for androgen receptor (AR). Therefore, we hypothesized that NKX3.1 is a new immunohistochemical marker for SDC and aimed to investigate whether NKX3.1 staining in combination with other immunomarkers of prostate carcinoma could have a diagnostic or prognostic value in SDC. METHODS: Materials obtained from 42 resected SDCs were examined by immunohistochemistry using antibodies against AR, NKX3.1, α-methylacyl-CoA racemase (AMACR), prostatic acid phosphatase (PAP), and prostate-specific antigen (PSA). RESULTS: In immunoreactivity among SDC cases, 81.0, 35.7, 58.5, 33.3, and 0% were positive for AR, NKX3.1, AMACR, PAP, and PSA, respectively. AMACR and PAP immunoreactivity rates were higher in recurrence cases than in cases with no recurrence. CONCLUSIONS: NKX3.1 expression is useful for SDC diagnosis, but decreased NKX3.1 expression was not correlated with SDC progression. The immunoreactivity of AMACR and PAP could be useful for assessing prognosis in SDC, but immunohistochemical staining of prostate-specific markers should be interpreted with caution when determining whether a metastatic tumor is of prostate origin, especially when patients have a history of SDC.

Metastatic hepatocellular carcinoma to the parotid gland: A diagnostic dilemma with review of the literature.

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy and is a leading cause of cancer-related death worldwide. It has a very aggressive clinical course, with a mean survival rate of much less than a year if left untreated. Here, we present a case of a 68-year-old male with progressively enlarging painful right facial swelling, involving the ramus and condyle of mandible on contrast-enhanced computed tomography mimicking an osteosarcoma. Eventually, the final diagnosis of HCC metastatic to the right parotid gland was made. We report a case of a rare metastasis of HCC to the parotid gland. Furthermore, the present case demonstrates the importance of tissue biopsy and immunohistochemistry for obtaining an accurate final diagnosis.

First description of basaloid carcinoma of the canine mammary gland: case report / Primeira descrição do carcinoma basaloide da glândula mamária canina: relato de caso

The objective of this case report was to describe histopathological and immunohistochemical characteristics of the first reported basaloid carcinomas in the canine mammary gland. Two bitches were treated for tumors in the mammary gland and underwent mastectomy. Microscopic evaluation of these tumors revealed epithelial cells arranged in a predominantly solid pattern with hyperchromatic peripheral cells arranged in a palisade pattern. Metastases in regional lymph nodes were found in both animals, and one bitch exhibited pulmonary metastasis. Immunohistochemistry revealed positive labeling for the basal cell markers cytokeratin 14 and p63. Histopathological and immunohistochemical findings led to diagnoses of basaloid carcinoma of the canine mammary gland with regional and distant metastasis.(AU)

O objetivo deste relato de caso é descrever as características histopatológicas e imuno-histoquímicas do primeiro relato de carcinoma basaloide na glândula mamária canina. Duas cadelas foram atendidas com tumores na glândula mamária e foram submetidas à mastectomia. A avaliação microscópica demonstrou células epiteliais arranjadas em um padrão predominantemente sólido, com células periféricas hipercromáticas, dispostas em paliçada. As duas apresentaram metástase em linfonodos regionais e uma delas metástase pulmonar. A imuno-histoquímica revelou marcação positiva para citoqueratina 14 e p63, marcadores de células basais. Achados histopatológicos e imuno-histoquímicos levaram ao diagnóstico de carcinoma basaloide da glândula mamária canina com metástase regional e a distância.(AU)

Prognostic value of programed death ligand-1 and ligand-2 co-expression in salivary gland carcinomas.

OBJECTIVES: The aim of the present study was to investigate the molecular basis for the use of immune checkpoint inhibitors to treat salivary gland carcinomas (SGC). MATERIALS AND METHODS: We examined the clinical and prognostic significance of programed death ligands 1 and 2 (PD-L1 and -L2) expression using immunohistochemistry and in situ hybridization, as well as microsatellite instability (MSI) status using polymerase chain reaction, along with tumor-infiltrating lymphocytes (TILs) in 30 cases of SGC. RESULTS: The SGC cases studied included adenoid cystic carcinoma (AdCC, 36.7%), salivary duct carcinoma (SDC, 26.7%), mucoepidermoid carcinoma (MEC, 23.3%), and carcinoma ex pleomorphic adenoma (CxPA, 13.3%). Either PD-L1 or PD-L2 overexpression was observed in 36.7% patients. PD-L2 expression was associated with reduced disease-specific survival (DSS) and disease-free survival (DFS) (P = 0.0266 and P = 0.0209, respectively). Simultaneous PD-L1 and PD-L2 overexpression was detected in 13.3% of cases, and was correlated with reduced DSS (P = 0.0113). Among non-AdCCs, all cases that developed distant metastasis were positive for PD-L2 (P = 0.001). Cases showing low-TILs that were positive for either PD-L1 or L2 were associated with poor DFS. No MSI was detected in the SGC cases studied. CONCLUSION: To our knowledge, this is the first comprehensive study examining PD-L1 and PD-L2 status, MSI status, and TILs in SGC. Our results indicate that the PD-1/PD-L1 or PD-L2 pathway, which is associated with poor clinical outcomes, may provide promising therapeutic targets against SGC in selected patients. Further experimental and clinical studies are encouraged.

Intraocular metastasis of medullary thyroid carcinoma investigated by transscleral fine-needle aspiration. A case report and review of the literature.

Medullary thyroid carcinoma occurs in a sporadic setting and may also be inherited in an autosomal dominant fashion, which is related with germline mutations of the RET gene. Metastases are often present at the time of a diagnosis-most frequently within the cervical lymph nodes, followed by the liver, lungs, and bones. Intraocular metastases are extremely rare. We present a case of choroidal metastasis as a first presentation of disease progression in a patient with Multiple Endocrine Neoplasia type 2A syndrome (MEN2A) who had undergone thyroidectomy 33 years earlier for medullary thyroid carcinoma. Transscleral aspirate smears showed necrotic malignant cells suggesting amelanotic malignant melanoma or metastatic neuroendocrine tumor. The similar cells were found on parotid fine-needle aspiration. The diagnosis of metastatic medullary thyroid carcinoma was definitely established on the parotidectomy specimen based on its characteristic morphological and immunohistochemical features. This is the only case of ocular metastasis from medullary thyroid carcinoma found in the English literature that was investigated by pathological examination using transscleral fine-needle aspiration biopsy.

Report of a unique case of myoepithelial carcinoma of left parotid gland with metachronous bilateral cavernous sinus metastasis.

Myoepithelial carcinoma (MC) is a rare, locally aggressive malignant neoplasm of the salivary glands. Only few evidences on its metastatic behavior are available in the literature. We herein present a unique case of MC of left parotid gland which metastasized to bilateral cavernous sinuses. The patient was successfully treated with palliative radiotherapy and chemotherapy.

Multiple clear-cell sarcomas of small intestine with parotid gland metastasis: A case report.

Clear-cell sarcoma is a rare, malignant soft tissue tumor that displays melanocytic differentiation with a distinct molecular profile. It is rarely localized in the gastrointestinal tract. Herein we reported a case of multiple synchronous clear-cell sarcomas of the gastrointestinal tract with parotid gland metastasis. A 51-year-old male patient presented with a growing painless mass under the right ear. A preoperative positron emission tomography/computed tomography showed multiple intestinal masses and a mass in the right parotid with increased glucose uptake, and he underwent operative treatment with resection of three tumors in the jejunum and ileum and then received a right parotidectomy. Postoperative pathological examination showed that cells in the intestinal tumor were consistent with clear-cell sarcoma of the gastrointestinal tract, and the malignant cells in the parotid gland were similar to the intestinal tumor. Immunohistochemical studies revealed positive expression of HMB-45, Melan-A, and S-100. EWSR1 gene fusion transcripts were undetectable by fluorescence in situ hybridization.

Successful multimodal treatment of intraoral salivary duct carcinoma in a patient with multiple lymph node metastases: a case report.

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary gland malignancy that is associated with an aggressive clinical behavior and poor prognosis. Herein, we report on a long surviving case of SDC of the minor salivary gland with multiple lymph node metastases (LNMs). CASE PRESENTATION: An 83-year-old woman presented with a history of lymphadenopathy in the right side of the neck and recent onset and rapid growth of a mass in the right buccal region. Clinical examinations and biopsy findings were suggestive of a salivary gland malignant tumor with regional LNMs. The patient was treated with neoadjuvant chemotherapy. Tumor excision and ipsilateral radical neck dissection were performed, followed by adjuvant chemoradiotherapy. Postoperative histological examination revealed a tumor with irregular nests of atypical ductal epithelial cells, a cribriform growth pattern, and comedo-like central necrosis that lead to a final diagnosis of SDC. LNMs were observed in six lymph nodes of the right side of the neck. The patient underwent postoperative chemotherapy using single-agent cisplatin that was administered concurrently with radiotherapy (total, 65 Gy). There was no evidence of local recurrence or distant metastasis for >6 years. CONCLUSIONS: Although available data on treatment modalities for SDC remain limited, multimodal therapy may contribute to improved clinical outcomes in patients with advanced intraoral SDC.

Cisplatin+Vinorelbine Treatment of Recurrent or Metastatic Salivary Gland Malignancies (RMSGM): A Final Report on 60 Cases.

OBJECTIVES: Recurrent or metastatic salivary gland malignancies (RMSGM) are not suitable for conventional treatment. We report the clinical outcomes of 60 patients affected by RMSGM who were treated with DDP+VNB as a first-line or second-line scheme. MATERIALS AND METHODS: Sixty patients between 2001 and 2008, affected by RMSGM were enrolled in this cohort prospective study; they received the following first-line or second-line chemotherapy (CT), for a maximum of 6 cycles: DDP at 80 mg/m on day 1+VNB at 25 mg/m on day 1 and 8, at 3-week intervals. RESULTS: Seventy percent of the patients received DDP+VNB as the first-line CT and 30% of them received it as the second-line CT. After 5 cycles (median) of first-line DDP+VNB, 7% of the patients achieved a complete response, 24% achieved a partial response, 33% achieved an no change, and 36% achieved a PD. After 4 cycles (median) of second-line CT, 0 patients achieved a CR, 5% achieved a PR, 33% achieved an NC, and 62% achieved a PD. The median overall survival period was 10 months for those who received the first-line CT and 4 months for those who received the second-line CT. The best ORR (54%) and median survival were observed, during first-line treatment, in adenocarcinomas, whereas undifferentiated tumours were unresponsive with a poor median survival (4.6 mo). CONCLUSIONS: Adenocarcinomas show the best response and prognosis with DDP+VNB scheme that seems to be an effective and well-tolerated first-line CT for RMSGM, whereas it has only low palliative activity as a second-line CT.

Metastatic HER-2-positive salivary gland carcinoma treated with trastuzumab and a taxane: a series of six patients.

Metastatic salivary gland carcinoma is a rare malignancy. A subset of these tumors overexpresses the human epidermal growth factor receptor 2 (HER-2), which is considered a poor prognostic marker. Targeted therapy with the monoclonal antibody trastuzumab can be a treatment option in these patients. We describe six cases of metastatic salivary gland carcinoma treated with trastuzumab in combination with a taxane. Three of these patients had salivary duct cancer, two had mucoepidermoid carcinoma and one patient was treated for acinic cell carcinoma. The therapy was well tolerated. We observed five partial responses and a median progression free survival of 10.8 months, which compares favorably with the reported outcome of combination chemotherapy. One patient achieved a complete and durable remission. When HER-2 and androgen receptor were co-expressed, trastuzumab-based treatment appeared to be more active than androgen deprivation in our experience.

Sustained response of HER2-positive metastatic salivary adenocarcinoma, not otherwise specified, treated with trastuzumab.

OBJECTIVE: Adenocarcinoma-not otherwise specified (AD-NOS) is an aggressive salivary gland carcinoma subtype with poor prognosis. Her2/neu-targeted therapy may be beneficial in cases of overexpression (20% of AD-NOS). Here, a case of metastatic AD-NOS of the submandibular gland showing sustained complete response to trastuzumab is reported, and the existing literature is reviewed. STUDY DESIGN AND RESULTS: A 68-year-old male with poorly differentiated AD-NOS of the submandibular gland with multiple metastases (T3 N2 bM1) underwent radical surgery and adjuvant radiation. The primary lesion demonstrated Her2/neu overexpression, and treatment with trastuzumab was initiated. The patient remains alive without evidence of disease at 36-months after treatment (three cycles of trastuzumab). Literature review of all published trastuzumab-based therapy studies (1990-2015) for salivary gland carcinoma is included. CONCLUSIONS: Definitive clinical trials of trastuzumab-based interventions are challenging to undertake in rare tumors. This report adds to increasing evidence for trastuzumab-based therapy in salivary carcinomas, where sustained partial response at 36-months is achievable.

Renal clear cell carcinoma metastasis to salivary glands - a series of 9 cases: clinico-pathological study.

Metastatic tumors involving salivary glands arising from the non-head and neck area are very rare. Renal cell carcinoma (RCC) is known for its high propensity for metastasis to unusual localizations. RCC metastasis to the maxillofacial area is an uncommon event (16%), but metastasis to salivary glands is extremely rare. We report a series of 9 such cases retrieved from two institutions. The group included 6 females and 3 males. The age at diagnosis ranged from 60 to 97 years (mean 72.6 years). The tumors involved the parotid gland in 7 cases, and the submandibular and small salivary gland of the oral cavity in 1 case each. The size of tumors ranged from 0.4 to 5 cm. Total parotidectomy with selective neck dissection was performed in 4 cases, while superficial parotidectomy was performed in 1 case and simple resection in 3 cases. Histologically, all the tumors were clear cell renal cell carcinomas, and therefore the differential diagnosis mainly included clear cell variants of salivary gland carcinomas. The parotid gland was the initial manifestation of renal malignancy in 4 of the cases, while in the remaining 5 cases a history of RCC had been known. The salivary gland involvement developed from 11 months to 13 years after the time of diagnosis of the primary tumor. In 2 cases it was the first site of dissemination. Pathologists need to maintain a high index of suspicion for the possibility of metastasis when confronted with oncocytic or clear cell neoplasms developing in salivary glands. RCC, although rare, should be included in this differential diagnosis.

Distant Metastases and Palliative Care.

Salivary gland neoplasms are rare and diverse tumors with variable disease courses, making it difficult to concisely summarize the management of distant metastases (DM). Nonetheless, there are trends of DM in salivary gland cancer that can be contextualized and reviewed. In general, the primary tumor characteristics that predict DM include the primary tumor site, tumor stage and grade, perineural spread, cervical nodal status, and genomic signatures. The most common site of DM is the lung, followed by the bone, liver, and brain. Depending on the clinical presentation, DM can be treated with watchful waiting, local therapies (surgery and/or radiation), or systemic therapy (cytotoxic or targeted chemotherapy). In general, DM confer a poor prognosis, and any cancer-directed treatment options should be carefully considered in the context of specific goals of care, symptom burden, and patient preference.

Management of Regional Metastases of Malignant Salivary Gland Neoplasms.

Metastases from salivary gland carcinomas to the cervical lymph nodes are relatively uncommon. However, their impact on prognosis is significant and, thus, it is important to manage them appropriately. Treatment of clinically evident metastases consists primarily of surgery, frequently followed by radiation. Management of the N0 neck, on the other hand, remains controversial. While there seems to be agreement regarding the tumor and patient factors that make it more likely for a patient to harbor subclinical metastases in the lymph nodes, some clinicians prefer to treat those patients with surgery, i.e. a neck dissection, and others prefer to use elective radiation. These different approaches and their rationale will be discussed in detail.

Metastatic Salivary Gland Tumors: A Single-Center Study Demonstrating the Feasibility and Potential Clinical Benefit of Molecular-Profiling-Guided Therapy.

We evaluated the use of molecular profiling (MP) for metastatic salivary gland adenoid cystic carcinoma (SACC), for which there is no standard treatment. MP (Caris Molecular Intelligence) was performed on biopsy samples from all metastatic SACC patients attending a tertiary medical center between 2010 and 2013 (n = 14). Treatment was selected according to the biomarkers identified. Findings were compared with all similarly diagnosed patients treated in the same center between 1996 and 2009 (n = 9). For each patient, MP identified 1-13 biomarkers associated with clinical benefit for specific therapies (most commonly low/negative TS, low ERCC1). Eleven patients (79%) received MP-guided treatment (2 died prior to treatment initiation, 1 opted not to be treated), with complete response in 1, partial response (PR) in 3, and stable disease in 4. In the historical controls, 2 patients (22%) were treated (1 had PR). Median (range) progression-free survival in the first line after MP was 8.2 months (1.4-49.5+). Median (range) overall survival from diagnosis of metastatic disease was 31.3 (1.4-71.1+) versus 14.0 (1.5-116) months in the historical controls. In conclusion, MP expands treatment options and may improve clinical outcomes for metastatic SACC. In orphan diseases where randomized trials cannot be performed, MP could become a standard clinical tool.

[Clinical investigation on distant metastases of salivary gland carcinoma after being treated by surgery combined with 125I internal brachytherapy].

OBJECTIVE: To investigate clinical features of distant metastases (DM) and analyze clinicopathologic risk factors associated with DM from salivary gland carcinomas after being treated by surgery combined with 125I internal brachytherapy. METHODS: Between October 2001 and March 2010, 197 patients with salivary gland carcinoma were treated by surgery combined with 125I internal brachytherapy and had follow-up for 2 years or more. Univariate and multivariate analyses were performed to evaluate clinicopathologic risk factors that might influence the risk of distant metastases. RESULTS: DM occurred in 28 of 197 patients (14.2%). The commonest site of distant metastases overall was the lung 89.3% (25/28), followed by bones 17.9% (5/28) and liver (4/28). DM developed after an average interval of (44.2±45.8) months from the time of initial diagnosis, and the mean interval was 64 months. The average time to death after the diagnosis of DM was only (9.7±13.4) months, and the mean time was 12 months. The 3-year locoregional control rate and survival rate were 90.8%, and 87.8% respectively,and the 5-year ones 84.0% and 81.0%, respectively. Univariate analyses revealed that the risk of distant metastases was significantly influenced by locoregional tumor failure (F=26.997, P<0.01) and histologic differentiation (F=1.592, P<0.01). Multivariate analysis of freedom from distant metastases revealed that locoregional control (F=29.332, P<0.01) significantly influenced this end point. CONCLUSION: Salivary gland carcinoma could achieve high local control rate after being treated by surgery combined with 125I internal brachytherapy, and the average interval from diagnosis to DM was prolonged, DM was significantly influenced bylocoregional control.