CXC ligand 13 orchestrates an immunoactive microenvironment and enhances immunotherapy response in head and neck squamous cell carcinoma.

Objectives: This study aims to systematically explore the role of chemokine CXC ligand 13 (CXCL13) in head and neck squamous cell carcinoma (HNSCC). Methods: The Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases provided the RNA-seq data for cancer and normal tissues, respectively. Gene set enrichment analysis was applied to search the cancer hallmarks associated with CXCL13 expression. TIMER2.0 was the main platform used to investigate the immune cell infiltration related to CXCL13. Immunohistochemistry was applied to explore the relationship between CXCL13 and patients' prognosis and the relationship between CXCL13 and tertiary lymphoid structures (TLSs). Results: The expression of CXCL13 was upregulated in most tumors, including HNSCC. The higher expression of CXCL13 was closely related to the positive prognosis of HNSCC. CXCL13 was mainly expressed in B cells and CD8 + T cells, revealing the relationship between its expression and immune activation in the tumor microenvironment. Furthermore, immunohistochemistry and multiple fluorescence staining analysis of HNSCC samples showed a powerful correlation between CXCL13 expression, TLSs formation, and positive prognosis. Finally, CXCL13 significantly increased the response to cancer immunotherapy. Conclusions: CXCL13 may function as a potential biomarker for predicting prognosis and immunotherapy response and associate with TLSs in HNSCC.

Immunohistochemical comparison of p63 and p40 in head and neck Spindle Cell Carcinoma.

BACKGROUND: Spindle Cell Carcinoma (SpCC) is a rare type of squamous cell carcinoma (SCC) with prominent malignant spindle cell component. This unique biphasic feature on histopathological examination makes its diagnosis problematic. Detection of p63 antigens in SpCC can be helpful however its expression in variousb proliferating soft tissue lesions demands for better marker. METHODS: In this study, histopathologically diagnosed SpCC of head and neck region were considered as cases, and 22 soft tissue sarcomas, reactive lesions and spindle cell lesions of the body were taken as controls. Immunohistochemistry (IHC) was done using Anti-p63 and p40 clone and the results were compared. CK was done for negative cases to prove their epithelial origin. P. value < 0.05 considered statistically significant. RESULTS: Among 22 cases of SpCC, 19 cases showed positive immunoreactivity to p63, and 18 cases for p40. IHC of controls showed no immunoreactivity in any of the sarcomas, reactive lesions or spindle cell lesions. The sensitivity of p63 is 86% while that of p40 is 82%. Specificity of both the markers was 100% CONCLUSION: Though p63 is a slightly (4%) more sensitive marker than p40, percentage of cell positivity for p40 is higher compared to p63. Both of these markers are 100% specific for SpCC.

Prognostic Role of Tumoral PD-L1 and IDO1 Expression, and Intratumoral CD8+ and FoxP3+ Lymphocyte Infiltrates in 132 Primary Cutaneous Merkel Cell Carcinomas.

The association of immune markers and clinicopathologic features and patient outcome has not been extensively studied in Merkel cell carcinoma (MCC). We correlated tumoral PD-L1 and IDO1 expression, and intratumoral CD8+ and FoxP3+ lymphocytes count with clinicopathologic variables, Merkel cell polyomavirus (MCPyV) status, and patient outcomes in a series of 132 MCC. By univariate analyses, tumoral PD-L1 expression >1% and combined tumoral PD-L1 >1% and high intratumoral FoxP3+ lymphocyte count correlated with improved overall survival (OS) (p = 0.016, 0.0072), MCC-specific survival (MSS) (p = 0.019, 0.017), and progression-free survival (PFS) (p = 0.043, 0.004, respectively). High intratumoral CD8+ and FoxP3+ lymphocyte count correlated with longer MSS (p = 0.036) and improved PFS (p = 0.047), respectively. Ulceration correlated with worse OS and worse MSS. Age, male gender, and higher stage (3 and 4) significantly correlated with worse survival. MCPyV positivity correlated with immune response. By multivariate analyses, only ulceration and age remained as independent predictors of worse OS; gender and stage remained for shorter PFS. Tumoral PD-L1 expression and increased density of intratumoral CD8+ lymphocytes and FoxP+ lymphocytes may represent favorable prognosticators in a subset of MCCs. Tumoral PD-L1 expression correlated with intratumoral CD8+ and FoxP3+ lymphocytes, which is supportive of an adaptive immune response.

Evaluation of UV-C Decontamination of Clinical Tissue Sections for Spatially Resolved Analysis by Mass Spectrometry Imaging (MSI).

Clinical tissue specimens are often unscreened, and preparation of tissue sections for analysis by mass spectrometry imaging (MSI) can cause aerosolization of particles potentially carrying an infectious load. We here present a decontamination approach based on ultraviolet-C (UV-C) light to inactivate clinically relevant pathogens such as herpesviridae, papovaviridae human immunodeficiency virus, or SARS-CoV-2, which may be present in human tissue samples while preserving the biodistributions of analytes within the tissue. High doses of UV-C required for high-level disinfection were found to cause oxidation and photodegradation of endogenous species. Lower UV-C doses maintaining inactivation of clinically relevant pathogens to a level of increased operator safety were found to be less destructive to the tissue metabolome and xenobiotics. These doses caused less alterations of the tissue metabolome and allowed elucidation of the biodistribution of the endogenous metabolites. Additionally, we were able to determine the spatially integrated abundances of the ATR inhibitor ceralasertib from decontaminated human biopsies using desorption electrospray ionization-MSI (DESI-MSI).

Systematic Review of Second Primary Oropharyngeal Cancers in Patients With p16+ Oropharyngeal Cancer.

OBJECTIVE: To systematically review the literature to determine the prevalence and clinical outcomes of second primary oropharyngeal squamous cell carcinoma (OPSCC). DATA SOURCES: Search strategies created with a medical librarian were implemented using multiple databases in October 2019. REVIEW METHODS: The population of interest included adults age >18 years with a p16+ or human papillomavirus-positive OPSCC. The outcome was a synchronous or metachronous second primary OPSCC. Inclusion and exclusion criteria were designed to capture all study designs. In total, 685 records were identified by the search strategy. Two reviewers independently performed the review, extracted data, and performed a quality assessment. Primary Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. A random-effects model was used for the meta-analysis. RESULTS: A total of 2470 patients with 35 second primary OPSCCs from 15 studies were identified. The pooled prevalence of second primary OPSCC was 1.4% (range, 0%-14.3%). In the random-effects model, the prevalence was estimated at 1.3% (95% CI, 0.7%-2.3%; P = .51, I2 = 52%). Of the 30 patients with treatment information, 26 (86.7%) received surgical treatment, while 4 (13.3%) underwent nonsurgical therapy. Of the 29 patients with available survival information, 22 (75.9%) had no evidence of disease at last follow-up, 5 (17.2%) ultimately died of disease, and 2 (6.9%) were alive with disease. CONCLUSION: Overall, the rate of second primary OPSCC in patients with an index p16+ OPSCC is low, and most patients are successfully treated. Insufficient evidence currently exists to recommend routine elective tonsillectomy during surgical treatment of p16+ OPSCC.

Folliculocystic and Collagen Hamartoma: A Distinct Hamartoma Associated With Tuberous Sclerosis Complex.

ABSTRACT: Tuberous sclerosis complex (TSC) is a neurocutaneous disease characterized by cutaneous and extracutaneous hamartomas. Dermatologic evaluation is critical for early diagnosis because mucocutaneous manifestations account for 4 of 11 major and 3 of 6 minor diagnostic criteria. Folliculocystic and collagen hamartoma (FCCH) is a recently described entity associated with TSC. We herein describe the case of a 28-year-old woman with a history of TSC who presented with a scalp lesion present since childhood. Physical examination revealed a solitary, well-circumscribed exophytic tumor over the occipital scalp measuring 9 × 8 cm and covered with comedones and cyst-like structures. Biopsy of the lesion demonstrated thickening of the collagen bundles throughout the dermis, concentric perifollicular and perivascular fibrosis, an increased number of dilated vessels, and keratin-filled cysts lined by the infundibular epithelium. Clinicopathologic correlation was diagnostic for FCCH. The patient was referred for surgical excision. In addition, we review 11 other cases of FCCH previously reported in the literature.

Primary Cutaneous Myxoid Spindle Cell Squamous Cell Carcinoma of the Scalp: A Case Report.

Cutaneous squamous cell carcinomas are the second most frequent type of non-melanoma skin cancer. A 78-year-old man with a slow-growing but large nodular lesion on his scalp presented to the hospital. The nodular lesion was excised. Histologically, the lesion was diagnosed as a primary cutaneous myxoid spindle cell squamous cell carcinoma, which is the subject of this case report. Extracellular mucin production is an even less common finding in SCC. We also aim to discuss the histological and immunohistochemical findings for distinguishing MSC SCC from other primary cutaneous and metastatic spindle cell neoplasms with myxoid stroma.

Metastatic Epithelial-Myoepithelial Carcinoma in a Female Presenting with Neck Mass and Lytic Lesion in Acetabulum: A Diagnostic Challenge on Cytology.

Epithelial-myoepithelial carcinoma (EMC) is a rare, low-grade, malignant salivary neoplasm. Establishing an accurate cytological diagnosis is often challenging owing to its rarity, bland cytologic appearance and variable representation of cell populations in the smears. The diagnostic struggle is more so when the aspiration is from a metastatic site with an unknown primary, as in such cases the list of differential diagnoses expands further. A 58-year-old female presented with a low-back pain from last one month. On examination, she also had a level III, right cervical swelling for the last 20 years. Radiology revealed a lytic lesion in the left acetabulum. She had undergone surgery 35 years ago for a right-sided upper neck swelling, the medical records of which were not available. Fine needle aspiration (FNA) from the cervical swelling was performed. The smears were cellular and showed predominantly dispersed, round to polygonal tumor cells with mild pleomorphism, eccentric nuclei, coarse chromatin, occasional nucleoli and moderate cytoplasm with some showing vacuolations. The cell-block section revealed tumor cells arranged in the form of tubules lined by dual layer of tumor cells without any chondromyxoid stroma. On immunocytochemistry, the luminal cells showed positivity for CK7 (epithelial marker) and the abluminal cells showed positivity for p63 (myoepithelial marker). Based on these features, a final diagnosis of metastatic epithelial-myoepithelial carcinoma was rendered. The present report highlights the characteristic cytomorphological and immunocytochemical features of EMC and reiterates the diagnostic accuracy of FNAC for diagnosis of such challenging cases.

Clear Cell Hidradenoma-Basal Cell Carcinoma Collision.

ABSTRACT: A 91-year-old man presented with a tumor on the left temporal area, clinically suspicious of basal cell carcinoma. The histopathologic study showed a central solid-cystic tumor composed by 3 different types of cells (clear or finely granular cells, polygonal cells, and squamoid cells). It had a sclerotic stroma. At the periphery, another tumor composed by smaller interconnected nests was evident. Some nests were separated from the stroma by clefts. The stroma of this second tumor was highly cellular. There was a sharp delimitation between both tumors, with no transitional area. Immunochemistry demonstrated they are different tumor. A diagnosis of clear cell hidradenoma-basal cell carcinoma collision was performed. To the best of our knowledge, this is the first description of this challenging association.

Cutaneous Adenosquamous Carcinoma of the Scalp With Intestinal Phenotype.

Cutaneous adenosquamous carcinoma is a mixed, squamous and glandular, rare malignant tumor of the skin characterized by a mixed, squamous, and glandular differentiation. Few cases of this tumor have been so far reported, and even fewer have been thoroughly studied by immunohistochemistry. We report here an exceptional case of cutaneous adenosquamous carcinoma which showed immunohistochemically features of intestinal differentiation, namely because of the expression of keratin 20 and CDX2, a marker of gastrointestinal tumors.

Solitary fibrous tumors of the head and neck region revisited: a single-institution study of 20 cases and review of the literature.

A solitary fibrous tumor (SFT) is a rare, NAB2-STAT6 fusion gene-associated mesenchymal neoplasm. It most commonly arises in the pleural site, but it can occur at many other sites, and rarely also in the head and neck (H&N) region. STFs may show many growth patterns and therefore can be easily mistaken for other more common H&N spindle cell or epithelial lesions. In this study, we present our experience in the diagnosis of 20 cases of SFT in the H&N region and discuss their most notable mimickers. In all cases, STAT6 expression was found positive by immunohistochemistry, and the NAB2-STAT6 fusion was confirmed by next-generation sequencing. Three major fusion variants were detected: NAB2ex2-STAT6int1 (5/20, 25%), NAB2ex6-STAT6ex16 (4/20, 20%), and NAB2ex4-STAT6ex2 (3/20, 15%). Clinical follow-up was available for 16 patients (median follow-up time: 84 months). One patient with a morphologically malignant SFT experienced multiple local recurrences, followed by dissemination into the lungs and meninges. This malignant SFT also displayed an aberrant FLI1 expression, which was not previously reported in SFT cases. We also summarize findings from 200 cases of SFT of the H&N region, which included cases from our study, and from previous studies that reported on the fusion status of the STAT6 gene. The results suggest that metastatic disease developed only in cases with STAT6 variants that included the DNA-binding domain (STAT6-full variants), which contradicts expectations from previous reports and deserves further investigation.

Peripheral Palisading in Melanoma Mimicking Basal Cell Carcinoma: A Case Report.

The incidence of melanoma has been increasing over the past few decades. Because of its phenotypic diversity, melanoma may present in various clinical and histopathological manifestations, and it can mimic varieties of skin lesions from benign to malignant and from epithelial to nonepithelial. Accurate diagnosis of melanoma is crucial because delayed treatment leads to worse prognoses. Here, we describe a case of melanoma in an 82-year-old man with an unusual histopathologic presentation, namely, the presence of neoplastic aggregates with a palisaded periphery resembling basal cell carcinoma.

SOX-10 and S100 Negative Desmoplastic Melanoma: Apropos a Diagnostically Challenging Case.

An 83-year-old man presented with a tumor of the neck, clinically consistent with an epidermal inclusion cyst. Excisional biopsy revealed a deeply infiltrating spindled cell tumor. Immunohistochemical markers for S100, SOX-10, Melan-A, HMB-45, and NK1/C3 were negative. Based on the presence of an area of lentigo maligna and the histologic pattern of the spindle cell component, a diagnosis of desmoplastic melanoma was made despite the absence of immunophenotypic evidence for melanocytic differentiation. To the best of our knowledge, the complete lack of both S100 and SOX-10 makes this tumor an unprecedented case. To avoid ruling out the diagnosis of desmoplastic melanoma prematurely, physicians should be made aware of this possible immunohistochemical profile.

Don't stop the champions of research now: a brief history of head and neck pathology developments.

The field of head and neck pathology was just developing 50 years ago but has certainly come a long way in a relatively short time. Thousands of developments in diagnostic criteria, tumor classification, malignancy staging, immunohistochemistry application, and molecular testing have been made during this time, with an exponential increase in literature on the topics over the past few decades: There were 3506 articles published on head and neck topics in the decade between 1969 and 1978 (PubMed source), with a staggering 89266 manuscripts published in the most recent decade. It is daunting and impossible to narrow the more than 162000 publications in this field and suggest only a few topics of significance. However, the breakthrough in this anatomic discipline has been achieved in 3 major sites: oropharyngeal carcinoma, salivary gland neoplasms, and sinonasal tract tumors. This review will highlight selected topics in these anatomic sites in which the most profound changes in diagnosis have occurred, focusing on the information that helps to guide daily routine practice of surgical pathology.

Predictive and prognostic significance of telomerase levels/telomere length in tissues and peripheral blood in head and neck squamous cell carcinoma.

A growing body of evidence indicates that the expression of TERT, the catalytic subunit of telomerase, is a biological marker of progression in several cancers. We investigated the predictive and prognostic role of TERT levels and telomere length in tissues and peripheral blood in patients with head and neck squamous cell carcinoma (HNSCC). High TERT levels in cancer tissues were independently associated with worse response to therapy (odds ratio [OR]:6.26), regional failure (hazard ratio [HR]:5.75), progression (HR:2.12), and death (HR:3.53). Longer telomeres in the mucosa surrounding the tumor (SM) were independently associated with a lower risk of mucosal failure (HR:0.39). While telomere length in peripheral blood mononuclear cells (PBMC) significantly decreased with age, no correlation was found between age and telomere length in SM. No associations were found between TERT levels in plasma and telomere length in PBMC and the prognostic variables. High levels of TERT transcripts in cancer cells represent a reliable prognostic marker for identifying HNSCC patients with risk of progression. The altered relationship of telomere length to age in SM compared with PBMC suggests that in a subset of cases the phenotypically normal SM constitutes an acquired telomere-shortened epithelial field prone to genetic instability.

Primary intrafascial desmoplastic melanoma with pseudoglandular differentiation and aberrant cytokeratins expression: An exceptional presentation.

Desmoplastic melanoma (DM) is an uncommon variant of malignant melanoma (MM), histologically characterized by a mainly dermal proliferation of spindled cells within a desmoplastic stroma. Normally, involvement of deeper tissues by DM is the result of direct extension down from the overlying dermis. MM is widely known to harbor a striking potential for morphological and phenotypic variability; among MM morphological variants, pseudoglandular MM is characterized by extensive discohesion within cords and nests of malignant cells and ensuing formation of so-called pseudolumina, thus mimicking adenocarcinoma. We present an exceptional case of DM characterized by intrafascial origin, partly pseudoglandular differentiation, and aberrant experession of cytokeratins in the pseudoglandular component; genetic data from next-generation sequencing supported the final diagnosis of DM, as well as the ontogenetic identity of the pseudoglandular component. Prior to this report, pseudoglandular features had never been described in DM. Additionally, our case is unusual because of the deep origin of the tumor, arising below the subcutaneous fat of the scalp, as well as the aberrant experession of cytokeratins in the pseudoglandular component, thus posing a challenging differential diagnosis with several soft tissue tumors.

AlloDriver: a method for the identification and analysis of cancer driver targets.

Identifying the variants that alter protein function is a promising strategy for deciphering the biological consequences of somatic mutations during tumorigenesis, which could provide novel targets for the development of cancer therapies. Here, based on our previously developed method, we present a strategy called AlloDriver that identifies cancer driver genes/proteins as possible targets from mutations. AlloDriver utilizes structural and dynamic features to prioritize potentially functional genes/proteins in individual cancers via mapping mutations generated from clinical cancer samples to allosteric/orthosteric sites derived from three-dimensional protein structures. This strategy exhibits desirable performance in the reemergence of known cancer driver mutations and genes/proteins from clinical samples. Significantly, the practicability of AlloDriver to discover novel cancer driver proteins in head and neck squamous cell carcinoma (HNSC) was tested in a real case of human protein tyrosine phosphatase, receptor type K (PTPRK) through a L1143F driver mutation located at the allosteric site of PTPRK, which was experimentally validated by cell proliferation assay. AlloDriver is expected to help to uncover innovative molecular mechanisms of tumorigenesis by perturbing proteins and to discover novel targets based on cancer driver mutations. The AlloDriver is freely available to all users at http://mdl.shsmu.edu.cn/ALD.

Functional imaging early during (chemo)radiotherapy for response prediction in head and neck squamous cell carcinoma; a systematic review.

This systematic review gives an extensive overview of the current state of functional imaging during (chemo)radiotherapy to predict locoregional control (LRC) and overall survival (OS) for head and neck squamous cell carcinoma. MEDLINE and EMBASE were searched for literature until April 2018 assessing the predictive performance of functional imaging (computed tomography perfusion (CTp), MRI and positron-emission tomography (PET)) within 4 weeks after (chemo)radiotherapy initiation. Fifty-two studies (CTp: n = 4, MRI: n = 19, PET: n = 26, MRI/PET: n = 3) were included involving 1623 patients. Prognostic information was extracted according the PRISMA protocol. Pooled estimation and subgroup analyses were performed for comparable parameters and outcome. However, the heterogeneity of included studies limited the possibility for comparison. Early tumoral changes from (chemo)radiotherapy can be captured by functional MRI and 18F-FDG-PET and could allow for personalized treatment adaptation. Lesions showed potentially prognostic intratreatment changes in perfusion, diffusion and metabolic activity. Intratreatment ADCmean increase (decrease of diffusion restriction) and low SUVmax (persistent low or decrease of 18F-FDG uptake) were most predictive of LRC. Intratreatment persistent high or increase of perfusion on CT/MRI (i.e. blood flow, volume, permeability) also predicted LRC. Low SUVmax and total lesion glycolysis (TLG) predicted favorable OS. The optimal timing to perform functional imaging to predict LRC or OS was 2-3 weeks after treatment initiation.