Parotid squamous cell carcinoma metastases: Application of human papillomavirus-DNA test on liquid-based cytology to recognize oropharyngeal origin of the neoplasm.

Malignancies of the parotid gland are relatively uncommon and in most cases are primary neoplasms; intraparotid metastases are rare. Oral and oropharyngeal squamous cell carcinoma (O- and OP-SCC) can potentially metastasize to the parotid gland or intraparotid lymph nodes. Fine-needle aspiration cytology (FNAC) serves as the initial diagnostic approach for this purpose. HPV status in FNAC specimens is relevant and can guide the diagnostic workup, indicating a potential oropharyngeal origin of the primary tumor. A small series of occult SCC metastases is presented below, in which HPV-DNA testing of FNAC specimens helped identify primary neoplasms located in the oropharynx. US-guided FNAC of parotid nodules was conducted by an experienced interventional cytopathologist in three cases. Each patient underwent assessment of direct smears, cell blocks, and liquid-based samples for HPV testing. The morphological and immunocytochemical features of SCC were documented, and real-time PCR was employed for the detection and genotyping of HPV. The role of HPV testing on FNAC specimens in pinpointing the primary neoplasms in the oropharynx is highlighted. Consequently, FNAC samples emerge as valuable diagnostic and prognostic tools in this context, providing essential insights for patient management.

Composite Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma and Epstein-Barr virus-negative diffuse large B-cell lymphoma in the parotid salivary gland of a patient with Sjögren's syndrome and rheumatoid arthritis: a case report.

BACKGROUND: Epstein-Barr virus is associated with many human hematopoietic neoplasms; however, Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma is extremely rare. In routine clinical practice, detection of mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma in a tissue sample presumes a clonal relation between these neoplasms and that diffuse large B-cell lymphoma developed by transformation of the mucosa-associated lymphoid tissue lymphoma. However, evidence to support this presumption is sparse and controversial. Assessment of the clonal relationship of the lymphoid components of a composite lymphoma is important for understanding its pathogenesis and correct diagnosis. CASE PRESENTATION: We present an unusual case of composite lymphoma (Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma/Epstein-Barr virus-negative diffuse large B-cell lymphoma) in the parotid salivary gland of a 62-year-old Caucasian woman with Sjögren's syndrome and rheumatoid arthritis. Simultaneous occurrence of mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma in the parotid salivary gland led us to initially assume a clonal relationship between diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma. Epstein-Barr virus was detected by in situ hybridization and polymerase chain reaction in the mucosa-associated lymphoid tissue lymphoma, but not in diffuse large B-cell lymphoma, suggesting that these lymphomas were not clonally related. Fragment analysis of frame region 3 polymerase chain reaction products from microdissected mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma components revealed different clonal pattern rearrangements of the immunoglobulin heavy chain gene. CONCLUSIONS: Our patient's case highlights the importance of assessing the clonal relationships of the lymphoid components of a composite lymphoma and Epstein-Barr virus screening in mucosa-associated lymphoid tissue lymphoma in patients with autoimmune disease.

No evidence for human papillomavirus having a causal role in salivary gland tumors.

BACKGROUND: Salivary gland malignancies are a very heterogeneous group of cancers, with histologically > 20 different subtypes, and prognosis varies greatly. Their etiology is unknown, however, a few small studies show presence of human papillomavirus (HPV) in some subtypes, although the evidence for HPV having a causal role is weak. The aim of this study was to investigate if HPV plays a causal role in the development of different parotid salivary gland tumor subtypes. METHODS: DNA was extracted from 107 parotid salivary gland formalin fixed paraffin embedded tumors and 10 corresponding metastases, and tested for 27 different HPV types using a multiplex bead based assay. HPV DNA positive tumors were stained for p16INK4a overexpression by immunohistochemistry. RESULTS: One of the 107 malignant parotid salivary gland tumors (0.93%) and its corresponding metastasis on the neck were positive for HPV16 DNA, and both also overexpressed p16INK4a. The HPV positive primary tumor was a squamous cell carcinoma; neither mucoepidermoid nor adenoid cystic tumors were found HPV positive. CONCLUSIONS: In conclusion, HPV DNA analysis in a large number of malignant parotid salivary gland tumors, including 12 different subtypes, did not show any strong indications that tested HPV types have a causal role in the studied salivary gland tumor types.

Lymphoepithelial carcinoma in parotid gland related to EBV infection: A case report.

Lymphoepithelial carcinoma commonly occurs at the nasopharynx and rarely occurs at other sites in the head and neck region. It is well known to occur at limited patients of local area as Asia or Arctic Circle. Related to this point, it is pointed out that this tumor has strong relation with Epstein-Barr Virus (EBV) infection. In this time, we experienced to treat lymphoepithelial carcinoma with metastatic cervical lymph nodes occurring at parotid gland. The morbidity ratio of this tumor is less than one percent of all parotid gland tumors. Moreover, we proved the infection of EBV to tumor cell by in situ hybridization (ISH). Incidentally, because it is considered that this tumor has well sensitivity against irradiation or anti-tumor drugs, prognosis of this tumor is better than that of other head and neck tumors with different pathological type. Actually, we tried to perform chemotherapy twice in (Nedaplatin (CDGP) 60mg/m2×day 2 and 5-FU 600mg/m2×day 5) and to irradiate about 70Gy dose against parotid gland and cervical lymph nodes. It could not find local recurrence or metastasis as of now after five years from treatment.

Oncogenic DNA viruses found in salivary gland tumors.

BACKGROUND: Previous investigations studying the association of DNA viruses with salivary gland tumors (SGTs) have led to conflicting results. The aim of this study was to determine the prevalence of different DNA viruses by using a highly sensitive assay in a multi-center series of over 100 fresh frozen salivary gland samples. METHODS: DNA was isolated from 84 SGTs (80 parotid tumors and 4 submandibular gland tumors) and 28 normal salivary tissue samples from 85 patients in Northeast Italy. Using a highly sensitive type-specific multiplex genotyping assay, we analyzed the samples for the presence of DNA from 62 different viruses including 47 papillomaviruses, 10 polyomaviruses, and 5 herpesviruses. RESULTS: We observed a high prevalence of beta human papillomavirus DNA in malignant tumors. In contrast, polyomavirus DNA was present in benign, malignant, and non-tumor control samples. Most striking was the significant distribution of herpesvirus DNA in the SGT samples, in particular the high prevalence of Epstein-Barr type 1 and type 2 DNA in Warthin's tumor samples. CONCLUSION: Our data provides evidence for the presence of DNA viruses in SGTs. Mechanistic studies are needed to further attribute tumor formation to these viruses.

Coexistence of Lymphoepithelial Carcinoma of the Parotid Gland and Submandibular Gland Pleomorphic Adenoma.

Lymphoepithelial carcinoma is a variant of undifferentiated carcinoma with characteristic dense lymphoid stroma in which nasopharynx is site of predilection. Racial and geographic association and Epstein-Barr virus positivity in endemic areas are other characteristics of this rare neoplasm. Lymphoepithelial carcinoma accounts for only 0.4% of malignant salivary gland tumors. The authors present a patient with Epstein-Barr virus positive lymphoepithelial carcinoma of the parotid gland in a nonendemic region. Besides this, synchronous pleomorphic adenoma in the contralateral submandibular gland caused a challenge in making initial therapeutic decision.

A proportion of primary squamous cell carcinomas of the parotid gland harbour high-risk human papillomavirus.

AIMS: In the current study, we aimed to examine primary parotid squamous cell carcinoma (ParSCC) for the presence of high-risk human papillomavirus (HR-HPV) and associated molecular alterations. METHODS AND RESULTS: Eight cases of ParSCC were retrieved after a detailed clinicopathological review to exclude the possibility of metastasis and/or extension from another primary site. HR-HPV status was determined on the basis of immunohistochemistry (IHC) for p16 expression and chromogenic in-situ hybridization (CISH) for HR-HPV. All cases were genotyped with a multiplexed mass spectrometry assay interrogating 91 hotspot mutations in eight cancer-related genes (EGFR, KRAS, NRAS, BRAF, PIK3CA, AKT1, MEK1 and ERBB2), and studied by fluorescence in-situ hybridization for PTEN copy number alteration. Three of eight cases (37.5%) were positive for the presence of HR-HPV by CISH and p16 IHC. One of three (33%) HR-HPV-positive cases harboured a PTEN hemizygous deletion, and one (33%) HR-HPV-positive case harboured a PIK3CA E545K somatic mutation. No alteration of the PTEN-PI3K pathway was detected in HR-HPV-negative tumours. Over a median follow-up period of 66.2 months, only the patient with the HR-HPV-positive PIK3CA-mutated tumour died of his disease, the remaining seven patients being disease-free. CONCLUSIONS: Given the established aetiological role of HR-HPV in other head and neck squamous cell carcinomas, it is likely that HR-HPV represents an oncogenic driver in the pathogenesis of more than one-third of ParSCCs. The presence of HR-HPV in ParSCC may be coupled with alterations in the PTEN-PI3K pathway. Further studies on HR-HPV and the molecular characterization of a larger number of ParSCCs are needed to determine the clinical significance of these findings.

Small cell carcinoma in the parotid harboring Merkel cell polyomavirus.

OBJECTIVE: This study aimed to document three new cases of primary small cell carcinoma (SmCC) of the parotid and examine immunohistochemical and quantitative real-time polymerase chain reaction (qPCR) data of the recently developed Merkel cell polyomavirus (MCPyV) within these tumors. STUDY DESIGN: Immunohistochemistry for neuroendocrine markers (chromogranin A, CD56, CD57, neuron-specific enolase [NSE], thyroid transcription factor 1 [TTF-1]), epithelial markers (CK20, CK7, CAM 5.2), and MCPyV large T antigen (LTAg) were examined. qPCR and Sanger sequencing were performed to confirm the presence of the MCPyV LTAg gene. RESULTS: Two males and one female, average age 76 years, presented with left parotid masses. Clinical examinations, histories, and imaging studies were negative for cutaneous Merkel cell carcinoma (MCC), pulmonary and extrapulmonary SmCC, or any other malignancy. Immunohistochemical analysis demonstrated positive immunoreactivity for CK20 in a perinuclear dotlike pattern (3/3), CAM 5.2 (3/3), (2/3), NSE (3/3), CD56 (2/3), and CD57 (3/3). Two cases stained positive for MCPyV, showing moderate to strong, diffuse positivity, confirmed with qPCR. PCR-Sanger sequencing of LTAg exon 2 showed greater than 97% similarity to the MCPyV reference genome in both cases. CONCLUSION: Our findings expand the number of reported cases classified as primary parotid SmCC that harbors MCPyV and underscore the similarity between cutaneous MCC and parotid SmCC. Further investigation is needed to determine whether immune-based therapeutic strategies targeting MCPyV in MCC are also effective in the setting of parotid SmCC harboring MCPyV.

Ludwik Gross, Sarah Stewart, and the 1950s discoveries of Gross murine leukemia virus and polyoma virus.

The Polish-American scientist Ludwik Gross made two important discoveries in the early 1950s. He showed that two viruses - murine leukemia virus and parotid tumor virus - could cause cancer when they were injected into susceptible animals. At first, Gross's discoveries were greeted with skepticism: it seemed implausible that viruses could cause a disease as complex as cancer. Inspired by Gross's initial experiments, similar results were obtained by Sarah Stewart and Bernice Eddy who later renamed the parotid tumor virus SE polyoma virus after finding it could cause many different types of tumors in mice, hamsters, and rats. Eventually the "SE" was dropped and virologists adopted the name "polyoma virus." After Gross's work was published, additional viruses capable of causing solid tumors or blood-borne tumors in mice were described by Arnold Graffi, Charlotte Friend, John Moloney and others. By 1961, sufficient data had been accumulated for Gross to confidently publish an extensive monograph--Oncogenic Viruses--the first history of tumor virology, which became a standard reference work and marked the emergence of tumor virology as a distinct, legitimate field of study.

Primary lymphoepithelioma-like carcinoma of salivary glands: a clinicopathological study of 21 cases.

Lymphoepithelioma-like carcinoma (LELC) of salivary glands is a rare kind tumor. In this study, the authors evaluated 21 patients with LELC of salivary glands who had long-term follow-up. Clinical characteristics, Epstein-Barr virus (EBV) infection, immunohistochemical features, oncoprotein expression, treatments, and outcomes were analyzed. All patients were Chinese. Their ages ranged from 20 to 73 years. All tumors showed the typical syncytial growth pattern of undifferentiated epithelial cells with a significant lymphocyte reaction. All of patients were found by in situ hybridization to have the EBV genome. All tumors showed positive immunostaining of AE1/AE3, CK5/6 and p63. Nearly all cases had bcl-2 oncoprotein expression, but the detection rate of p53, and c-erb B-2 expression was extremely low. LELC of salivary glands is a distinct entity of salivary cancer. LELC of salivary glands can receive multimodality treatment and has a better prognosis similar to that of nasopharyngeal carcinoma.

Human papilloma virus (HPV) is not implicated in the etiology of Warthin's tumor of the parotid gland.

CONCLUSION: The lack of human papilloma virus (HPV) sequences as well as potential HPV-activated cells such as cells that would be p16- and Ki-67 positive does not support a role of HPV in the pathogenesis of this lesion. OBJECTIVE: The exact etiopathogenesis of Warthin's tumor of the parotid gland is still unclear. The aim of the present study was to evaluate if HPV could play a role in the development of this parotid lesion. METHODS: Tissue samples from 40 Warthin's tumors of the parotid gland were investigated by PCR followed by in situ hybridization. The immunohistochemical expression of p16 and the dual immunostaining of p16 and Ki-67 were evaluated in all samples. RESULTS: Strong and diffuse p16 immunoreactivity was found in 7 of the 40 cases (17.5%). In situ hybridization showed a diffuse episomal signal in those samples. However, PCR could not reliably detect the presence of HPV genes. Furthermore, p16-expressing epithelial cells were mostly negative for the proliferation marker Ki-67.

Lymphoepithelial-like carcinoma of the parotid gland: a case report and a brief review of the western literature.

BACKGROUND: Primary lymphoepithelial-like carcinoma of the parotid gland is a rare tumour with an increased incidence among Eskimos and Orientals. In these populations, it is usually associated with Epstein-Barr virus. In Western countries, salivary gland lymphoepithelial-like carcinomas are uncommon and only 14 cases have been described so far; among these, only five cases showed Epstein-Barr virus positivity. CASE REPORT: A 45-year-old woman was admitted to Siena Hospital for evaluation of a pre-existent (2 years) painless and tender submandibular mass, rapidly enlarging since two months. On physical examination, a 2.5-cm mass was found in the right parotid. It was firm, mobile and non-tender. Laboratory data were within reference range. Nuclear magnetic resonance detected a 2,5×1,5×1-cm well-circumscribed mass in the deep lobe of the right parotid. A total right paroditectomy with dissection of a satellite lymph node was performed. On the basis of morphological, immunohistochemical and molecular biology findings, a diagnosis of stage II (according to TNM7) Epstein Barr-virus positive, undifferentiated lymphoepithelial-like carcinoma of the parotid gland was made. Twenty months after surgery the patient was free of disease. CONCLUSIONS: Further studies seem to be necessary to completely elucidate the oncogenic role of Epstein Barr-virus in these tumors, which have identical morphology but different prognosis and variable presence of the virus. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1260381551000616.

Lymphoepithelial carcinoma: a case of a rare parotid gland tumor.

A 29-year-old woman presented from another hospital with a 10-month history of an enlarging left-sided facial mass. Computed tomographic scan revealed a mass in the superficial lobe of the left parotid gland with left-sided cervical lymphadenopathy. The patient received a total left parotidectomy and a selective neck dissection. Histopathologic slides revealed lymphoepithelial carcinoma (LEC) that stained positive for cytokeratin, as well as Epstein-Barr virus (EBV). An LEC of the parotid is a rare salivary gland tumor accounting for less than 1% of all salivary gland tumors. As reaffirmed in our case, LEC is more common in women, occurs primarily in the parotid gland, and has an ethnic predilection. Histologic analysis reveals an infiltrative, poorly differentiated tumor nestled in a lymphoid stroma, with near 100% positivity for EBV in endemic areas. Complete resection of this poorly differentiated carcinoma followed by postoperative radiation is essential for local control.

Detection and quantification of human papillomavirus in benign and malignant parotid lesions.

BACKGROUND/AIM: Human papillomavirus (HPV) is implicated in head and neck squamous cell carcinomas. However, the causal role of HPV in carcinomas of the parotid gland remains uncertain and less documented. This study aimed to determine the potential implication of HPV in the development of benign and malignant lesions of the parotid gland. MATERIALS AND METHODS: Paraffin-embedded biopsies were obtained from 40 patients with benign parotid gland tumors and from 39 patients with parotid gland carcinomas. The 79 samples were evaluated for the presence of HPV DNA using both GP5+/GP6+ consensus Polymerase Chain Reaction (PCR) and type-specific E6/E7 PCR to detect 18 HPV types. RESULTS: Our results showed a low prevalence of HPV, with only three HPV-positive cases among the 40 benign tumors and one infected carcinoma in the malignant population. CONCLUSION: No association between the presence of HPV DNA and the development of parotid gland tumors was found in our study.

Extracutaneous Merkel cell carcinomas harbor polyomavirus DNA.

Merkel cell carcinoma is a neuroendocrine tumor, with characteristic morphological and immunohistochemical features. Originally reported as primary carcinoma of skin, it has been described in numerous other sites such as lymph nodes, oral cavity, breast, vaginal walls, and salivary glands. Recent studies have revealed in cutaneous Merkel cell carcinomas a clonally integrated polyomavirus, named Merkel cell polyomavirus. The aim of the present study was to verify the presence of Merkel cell polyomavirus in 5 cases of primary Merkel cell carcinomas of lymph nodes and 1 case of parotid gland to investigate similarities or differences among Merkel cell carcinomas from various sites. Cases studied were 5 primary Merkel cell carcinomas in lymph nodes, 1 in the parotid gland, and 12 in the skin. Twelve cases of primary and metastatic small cell carcinoma of the lung were also investigated. Immunohistochemistry for keratin 20, chromogranin, synaptophysin, and thyroid transcription factor 1 was performed in all cases. Viral DNA was studied using polymerase chain reaction assay and the products evaluated in agarose gel and sequenced. Cytokeratin 20 and Merkel cell polyomavirus were detected in all cases of primary Merkel cell carcinoma irrespective of their site of origin. On the contrary, all cases of pulmonary small cell carcinoma were negative for both Merkel cell polyomavirus and cytokeratin 20. It appears that cutaneous and extracutaneous Merkel cell carcinomas share similar histologic, immunohistochemical, and molecular features. This is further evidence that Merkel cell carcinomas are a multiorgan carcinoma and that Merkel cell polyomavirus might play a role in the pathogenesis of this neoplasm.

Absence of Merkel cell polyomavirus in primary parotid high-grade neuroendocrine carcinomas regardless of cytokeratin 20 immunophenotype.

High-grade neuroendocrine carcinoma of the salivary glands is a rare malignancy that can be difficult to distinguish from metastatic neuroendocrine (Merkel cell) carcinoma of the skin, which often occurs on the head and neck and may metastasize to lymph nodes in or adjacent to salivary glands, particularly the parotid gland. As the 2 tumors have morphologic and immunophenotypic overlap, additional diagnostic tools may be clinically useful. Merkel cell carcinoma is known to harbor Merkel cell polyomavirus in up to 80% of cases. However, the presence or absence of this virus in salivary gland neuroendocrine carcinomas has not been investigated. We evaluated 7 primary salivary gland high-grade neuroendocrine carcinomas (all from the parotid) for the virus by both immunohistochemistry (CM2B4 clone) and real-time polymerase chain reaction directed against the conserved small T antigen. Five of the tumors had small cell morphology, and 2 had large cell morphology. All were either chromogranin and/or synaptophysin positive. Four of the 5 small cell (80%) and 1 of the 2 large cell (50%) carcinomas were cytokeratin 20 positive. All but 1 case had cervical lymph node metastases at presentation. Merkel cell polyomavirus T antigen was not detected in any of the 7 tumors, either by immunohistochemistry or by polymerase chain reaction with adequate controls. These observations suggest that primary parotid high-grade neuroendocrine carcinoma arises from a biological pathway that is different from that of cutaneous Merkel cell carcinomas. Furthermore, viral testing may aid in distinguishing the 2 tumor types, as a positive result would favor a metastasis.