Standardised definitions and diagnostic criteria for extranodal extension detected on histopathological examination in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Detection of extranodal extension on histopathology in surgically treated head and neck squamous cell carcinoma indicates poor prognosis. However, there is no consensus on the diagnostic criteria, interpretation, and reporting of histology detected extranodal extension, which has contributed to conflicting evidence in the literature, and likely clinical inconsistency. The Head and Neck Cancer International Group conducted a three-round modified Delphi process with a group of 19 international pathology experts representing 15 national clinical research groups to generate consensus recommendations for histology detected extranodal extension diagnostic criteria. The expert panel strongly agreed on terminology and diagnostic features for histology detected extranodal extension and soft tissue metastasis. Moreover, the panel reached consensus on reporting of histology detected extranodal extension and on nodal sampling. These consensus recommendations, endorsed by 19 organisations representing 34 countries, are a crucial development towards standardised diagnosis and reporting of histology detected extranodal extension, and more accurate data collection and analysis.

Recurrence Patterns and Clinical Management after a Positive Sentinel Node Biopsy in Melanoma Patients.

Introduction melanoma patients who become stage III after a positive sentinel node biopsy (SNB) may have several patterns of recurrence patients and methods retrospective analysis of melanoma patients who have undergone SNB in a single institution from 2000 to 2015. Results There were 111 recurrences (45.1%) among 246 (20.3%) SNB positive patients and median DRFS was 77.7 months. After initial treatment, further recurrences occurred in 68 (77.3%) patients, regardless the site of initial recurrence conclusions multimodal strategies are recommended to achieve better results when managing stage III melanoma patients after a positive SNB.

Differences in Placental Histology Between Zika Virus-infected Teenagers and Older Women.

In pregnant women, Zika virus (ZIKV) is associated with a congenital syndrome, most frequently involving damage to embryo brain formation and the development of microcephaly. The mechanism(s) by which ZIKV enters the maternal-fetal interface and is transmitted to the fetus remains incompletely determined. We sought to evaluate histologic changes in the placenta of ZIKV-infected pregnant women and to determine if this varied by maternal age. Placental samples were obtained from 66 women, 33 of whom were positive for ZIKV. Histologic evaluations were performed on 4 areas of the placenta: fetal surface, maternal surface, umbilical cord, and membranes. Samples were analyzed by the tissue microarray technique and tested for CD4, CD8, CD20, CD68, FOXP3, and cyclooxygenase-2 expression. Data were evaluated using Fisher exact test. ZIKV infection was more frequent in women less than 18 yr of age (9/11, 81.8%) than in women above 18 yr old (24/55, 43.6%) (P=0.0440). ZIKV detection was associated with neutrophilic chorioamnionitis (P=0.0332) and with septal (P=0.0244) and villous (P=0.0534) calcification. Hofbauer cell hyperplasia (P=0.0260) and cyclooxygenase-2 expression (P=0.0346) were more prevalent in ZIKV-positive women aged 18 yr and below than in the older ZIKV-positive women. ZIKV infection during pregnancy occurs more frequently in adolescents and induces higher rates of damage at the maternal-fetal interface than in older women.

PD-L1 expression patterns in oral cancer as an integrated approach for further prognostic classification.

BACKGROUND: Despite the well-known role of programmed cell death ligand 1 (PD-L1) in promoting immune resistance in oral squamous cell carcinoma (OSCC), its potential utility as a prognostic biomarker is undetermined. We evaluated PD-L1 expression as predictor of survival in patients with OSCC and explored PD-L1 expression patterns. METHODS: We conducted a retrospective cohort study that assessed PD-L1 expression through immunohistochemistry in 123 surgical specimens of OSCC. A first approach evaluated tumor proportion scores (TPS) and combined proportion scores (CPS). Next, expression patterns were examined by evaluating PD-L1 localization in tumor nests, as well as the interfaces of tumor cells (TC) and immune cells (IC) in the tumor microenvironment. RESULTS: High-level PD-L1 expression determined by TPS and CPS using variable cutoffs was not associated with survival. Immunohistochemistry revealed that TC expressed PD-L1 in either patchy or diffuse patterns. The patchy pattern was an independent risk factor for overall survival. Furthermore, expression patterns in the tumor immune microenvironment showed that most cases expressed PD-L1 on both TC and IC, while PD-L1 non-expressors had the lowest overall survival. CONCLUSION: PD-L1 expression patterns in the context of localization in tumor nests and TC-IC interactions represent antitumor immune responses better than either TPS or CPS. Our suggested classification system may have important implications for the characterization of OSCC and for the use of PD-L1 as a prognostic biomarker.

Functional and metabolic imaging in transthoracic biopsies guided by computed tomography.

OBJECTIVES: CT-guided biopsy of indeterminate lung lesions sometimes provides insufficient histological results due to tumor necrosis. Functional and metabolic methods such as DWI-MR and PET-CT may help by directing sample collection to a lesion area of greater biological representativeness. The objective is to evaluate the histopathological results based on findings on ADC and SUV levels in lung lesions suspected for primary cancer. METHODS: Tissue samples were evaluated after undergoing biopsies guided by either DWI-MR or PET-CT findings. In each patient, sample collection from two lesion areas was guided by local ADC and SUV. Values were used to define areas of low vs. high suspicion for cancer. RESULTS: Patients who underwent DWI-MR had median lesion size of 78.0 mm. Areas of higher suspicion (HSA) had a median ADC of 1.1 × 10-3 mm2/s, while areas of lower suspicion (LSA) had median ADC of 1.8 × 10-3 mm2/s (p = 0.0001). All HSA samples and 71.43% of LSA samples were positive for cancer (p = 0.0184). Patients who performed PET-CT had median lesion size of 61.0 mm. Median SUV was 7.1 for HSA and 3.9 for LSA (p = 0.0002). Positivity for cancer was observed in 76.9% of samples for both HSA and LSA (p = 0.0522). CONCLUSION: Use of DWI-MR and PET-CT showed that tumors are functional and metabolically heterogeneous and that this heterogeneity has implications for histopathological diagnosis. KEY POINTS: • Lung cancer is heterogeneous regarding functional and metabolic imaging. • Tumor heterogeneity may have implications in histopathological diagnosis. • Intralesional lower levels of ADC target highly suspected areas with a significant improvement in lung cancer diagnosis.

Histopathologic Changes in Placental Tissue Associated With Vertical Transmission of Zika Virus.

Zika virus (ZIKV) is highly neurotropic after crossing the placenta, inducing teratogenic effects that result in delayed development and microcephaly in infants. The available evidence for vertical transmission of this infection is based on placental studies showing alterations in trophoblastic tissue. However, complete characterization of ZIKV-infected placenta and involved pathways has yet to be fully clarified. This case report of placental ZIKV infection describes morphologic and molecular changes in the placenta. Hyperplasia of placental Hofbauer cells in chorionic villi and numerous histiocyte-like cells in the decidua were observed. The decidua, fibroblasts, and chorion, as well as circulating cells in the intravascular compartment stained positive for ZIKV envelop protein. Deciduitis was present on the maternal surface of the placenta, with a prevalence of lymphocytes associated with vasculitis. A high level of uncommitted CD3 T lymphocytes were present, in addition to CD4 and CD8 cells. Elevated expression of the apoptosis inhibitor, Bcl-2, was observed in syncytiotrophoblasts. These parameters may promote the persistence of ZIKV in placental tissue and transmission to the fetus.

A decreased peritumoral CD1a+ cell number predicts a worse prognosis in oral squamous cell carcinoma.

AIMS: Dendritic cells (DCs) are known to play a central role in the regulation of both innate and adaptive immunological responses, including antitumour immunity. The aim of this study was to evaluate the prognostic impact of intratumoral and peritumoral DCs in oral squamous cell carcinoma (OSCC) affecting the tongue and floor of the mouth. METHODS AND RESULTS: Immunohistochemistry for CD1a and CD83 was performed in 53 patients with OSCC in the tongue and floor of the mouth. The markers were evaluated by automated examination in intratumoral and peritumoral compartments, and the results were expressed as density of cells/mm2 . Correlations between these data and clinicopathological and survival outcomes were investigated. Depletion of peritumoral CD1a+ cells was associated with lymph node metastasis (P = 0.05), whereas depletion of peritumoral CD83+ cells was correlated with smoking history (P = 0.04), lymph node metastasis (P = 0.015), and extracapsular spread of lymph nodes (P = 0.018). Peritumoral CD1a+ was correlated with recurrence (P = 0.007) and overall survival (P = 0.03). The results of the survival analysis with the Cox proportional hazard model showed that depletion of peritumoral CD1a+ cells is an independent factor associated with overall survival and disease-free survival. CONCLUSION: Our results suggest that depletion of peritumoral CD1a+ cells is a strong independent prognostic factor, predicting a higher recurrence rates and worse survival outcomes.

In transit sentinel node drainage as a prognostic factor for patients with cutaneous melanoma.

BACKGROUND: Minor basin or in transit node drainage can be found in patients with cutaneous melanoma who undergo sentinel node biopsy. Its clinical impact is still unclear. Our objective is to evaluate clinical outcomes in patients who presented with in transit sentinel node (ITN) drainage. MATERIAL AND METHODS: Retrospective analysis of patients who underwent sentinel node biopsy (SNB) in a single Brazilian institution between 2000 and 2015. RESULTS: Our cohort comprised 1223 SNB. There were 64 patients (5.2%) with ITN. Melanoma of the limbs (OR 10.61, P < 0.0001) and acral subtype (OR 3.49, P < 0.0001) were associated with ITN drainage. Among these 64 patients, 14 (21.9%) had a positive SNB. The ITN was positive for metastases in five patients, four in a popliteal basin and one on the trunk. Regarding completion node dissection (CND), two patients had positive non-sentinel nodes (NSN), both in major basins. In patients who developed recurrence, time to recurrence was shorter (mean time 18 vs 31.4 months, P = 0.001) and time to death was shorter (mean time 31.6 vs 40 months, P = 0.039) in those who had ITN drainage. CONCLUSION: ITN drainage was associated with earlier recurrences and deaths from melanoma.

Different patterns of expression of cell cycle control and local invasion-related proteins in oral squamous cell carcinoma affecting young patients.

OBJECTIVES: Oral squamous cell carcinoma (OSCC) predominantly affects males in the fifth decade of life; nevertheless, an increased incidence in young patients has been reported worldwide, and the clinical and behavioral characteristics of tumors in this group are controversial, and the literature shows divergent results. PURPOSE: To investigate the clinicopathological features and prognostic significance of the immunoexpression of cell cycle and local invasion proteins in OSCC affecting young patients (≤40 years old). METHODS: A tissue microarray was performed with 132 OSCC samples (61 cases of young patients vs 71 cases of elderly patients) and submitted to immunohistochemical reactions with Ki67, p53, p16, Bcl-2, Cyclin D1, C-ErbB2, p21, Myc, EGFR, MMP-9, SMA, Cathepsin K and FGF-2 antibodies. RESULTS: Clinicopathological features and survival rates were similar in both groups. Although overexpression of EGFR (P=.042) and MMP-9 (P=.001) was more frequent in young patients, only C-ErbB-2 (P=.048) and SMA (P=.048) expression correlated with lower disease-free survival (DFS) in this group of patients. CONCLUSION: Clinicopathological features and survival rates are similar between younger and older patients with OSCC. The different patterns of C-ErbB2, EGFR, MMP-9, and SMA expression between the groups merits further investigation to understand their role in the early tumor onset in young patients.

Osteogenic Melanoma With Desmin Expression.

BACKGROUND: Osteogenic differentiation is rarely seen in melanomas, when it occurs it is mainly in acral lesions. METHODS: We report a case of an osteogenic melanoma in a 49-year-old woman who presented with a pigmented lesion in the subungueal region of her left hallux. The lesion was ulcerated and infiltrated until the deep dermis without bone involvement. RESULTS: The tumor was composed of pleomorphic atypical epithelioid and fusiform cells disposed in nests or cords, with vesicular nuclei and prominent central nucleoli. Focal lentiginous proliferation of large atypical melanocytes was present along the dermoepidermal junction. Areas of osteoid matrix focally mineralized were disposed in trabeculae, and there were islands of neoplastic cells. Immunohistochemistry revealed strong expression of S-100 protein and, unexpectedly, of desmin. Focal expression of Melan-A, microphthalmia transcription factor, and HMB-45 is also revealed. Mutations in BRAF and NRAS genes were not present. The patient was submitted to an amputation of the left hallux with negative sentinel lymph node. CONCLUSION: The importance of recognizing osteogenic melanoma is based on difficulties for histologic recognition and its differentials diagnosis.

Artificial dermis (Matriderm®) followed by skin graft as an option in dermatofibrosarcoma protuberans with complete circumferential and peripheral deep margin assessment.

Dermatofibrosarcoma protuberans (DFSP) is a locally invasive neoplasia with a pattern of infiltrative growth that leads to extended resections. To avoid unnecessary resections and spare tissues, its treatment requires an adequate assessment of the margins. We present a case where artificial dermis (Matriderm®) was used followed by skin graft for reconstruction. We present a 50-year-old woman with a DFSP in the occipital region. She was referred to us after a first surgery with positive margins. A wide local excision with a 2-cm margin was performed and periosteal tissue was also removed, which led to exposure of the skull. Matriderm was placed on the bone surface and dressings were changed every other day. Meanwhile, margins were evaluated by the complete circumferential and peripheral deep margin assessment (CCPDMA) and were positive for DFSP in the superior margin. After 4 weeks the area was completely covered by granulation tissue and a new resection followed by reconstruction with a skin graft was performed. With regard to the difficulties in the margin assessment in DFSP, we present artificial dermis (Matriderm) as an option for reconstructive surgery in these patients, especially when a skin graft cannot be performed as a first option.

CD24 and CD44 in salivary gland pleomorphic adenoma and in human salivary gland morphogenesis: differential markers of glandular structure or stem cell indicators?

AIMS: Salivary gland neoplasms originate from salivary gland compartments, to which they are histologically related. Pleomorphic adenoma (PA) is a benign salivary gland neoplasm that comprises epithelial and myoepithelial cells and a complex stroma, whose structure, architecture and origin (from intercalated ducts) suggest stem cell participation. We compared the expression of CD24 and CD44 in PA and in developing human salivary glands to investigate whether these markers can be considered as cancer stem cell markers. METHODS AND RESULTS: One hundred and one cases of PA and salivary gland specimens from 20 human fetuses were examined by immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR). All PAs were positive for CD24 and CD44 by immunohistochemistry: neoplastic luminal structures were positive for CD24; modified myoepithelial cells were positive for CD44. In fetal salivary glands, these markers were restricted to the intercalated duct region. Real-time RT-PCR assays detected increased expression of CD44, but not CD24, in PA specimens in comparison with normal salivary gland controls. CONCLUSIONS: PA and stem cells share the expression of CD24 and CD44; their value as markers of neoplastic cell multipotency and the implications of their expression for tumour behaviour are yet to be determined.

New Insights into the Impact of Human Papillomavirus on Oral Cancer in Young Patients: Proteomic Approach Reveals a Novel Role for S100A8.

Human papillomavirus (HPV) infection has recently been linked to a subset of cancers affecting the oral cavity. However, the molecular mechanisms underlying HPV-driven oral squamous cell carcinoma (OSCC) onset and progression are poorly understood. METHODS: We performed MS-based proteomics profiling based on HPV status in OSCC in young patients, following biological characterization and cell assays to explore the proteome functional landscape. RESULTS: Thirty-nine proteins are differentially abundant between HPV (+) and HPV (-) OSCC. Among them, COPS3, DYHC1, and S100A8 are unfavorable for tumor recurrence and survival, in contrast to A2M and Serpine1, low levels of which show an association with better DFS. Remarkably, S100A8 is considered an independent prognostic factor for lower survival rates, and at high levels, it alters tumor-associated immune profiling, showing a lower proportion of M1 macrophages and dendritic cells. HPV (+) OSCC also displayed the pathogen-associated patterns receptor that, when activated, triggered the S100A8 and NFκB inflammatory responses. CONCLUSION: HPV (+) OSCC has a peculiar microenvironment pattern distinctive from HPV (-), involving the expression of pathogen-associated pattern receptors, S100A8 overexpression, and NFκB activation and responses, which has important consequences in prognosis and may guide therapeutic decisions.

Oral Manifestations of Coronavirus Disease 2019 (COVID-19): A Comprehensive Clinicopathologic and Immunohistochemical Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents rapid transmission and significant mortality worldwide. It is responsible for coronavirus disease 2019 (COVID-19). The disease presents diverse clinical symptoms, including fever, cough, dyspnea, and pneumonia. However, other manifestations associated with COVID-19 need to be clarified, leading specialists to an early diagnosis and better prognosis. We describe the spectrum of clinicopathologic COVID-19-related oral lesions that can be the first and/or the unique manifestation of the disease. Fourteen patients with a mean age of 58 years (range: 23 to 88 y) with oral lesions were included. All patients were confirmed to be infected with SARS-CoV-2 by reverse transcription polymerase chain reaction testing. Patients demonstrated mild symptoms, including dysgeusia, anosmia, fever, and headache. The lesions were recognized and classified into 2 groups: (1) lesions caused by ischemia and/or hemorrhage and (2) lesions secondary to inflammatory events associated with viral load. The palate was most affected (n=8), followed by the tongue (n=4), and both the lip and palate (n=2). Histologic analysis demonstrated thrombosis of small arteries and capillaries, associated with areas of hemorrhage and chronic inflammatory infiltrate. Immunohistochemistry showed positive staining for spike protein (SARS-CoV and SARS-CoV-2) and angiotensin-converting enzyme 2 in the surface epithelium, salivary glands, inflammatory cells, and endothelial cells. Although the incidence of oral lesions among patients infected with SARS-CoV-2 appears to be uncommon, these findings suggest that the oral mucosa can also be a target organ for SARS-CoV-2.

Development and validation of a Brazilian nomogram to assess sentinel node biopsy positivity in melanoma.

BACKGROUND: Although well-established, sentinel node biopsy (SNB) for melanoma is not free from controversies and sometimes it can be questionable if SNB should be considered even for patients who meet the criteria for the procedure. Mathematical tools such as nomograms can be helpful and give more precise answers for both clinicians and patients. We present a nomogram for SNB positivity that has been internally validated. METHODS: Retrospective analysis of patients who underwent SNB from 2000 to 2015 in a single institution. Single logistic regressions were used to identify variables that were associated to SNB positivity. All variables with a p value < 0.05 were included in the final model. Overall performance, calibration, and discriminatory power of the final multiple logistic regression model were all assessed. Internal validation of the multiple logistic regression model was performed via bootstrap analysis based on 1000 replications. RESULTS: Site of primary lesion, Breslow thickness, mitotic rate, histologic regression, lymphatic invasion, and Clark level were statistically related to SNB positivity. After internal validation, a good performance was observed as well as an adequate power of discrimination (area under the curve 0.751). CONCLUSIONS: We have presented a nomogram that can be helpful and easily used in daily practice for assessing SNB positivity.

The Role of Radiation Therapy as an Adjuvant Treatment in Nodal Metastasis of Malignant Chondroid Syringoma.

Malignant chondroid syringomas (MCSs) are extremely rare and aggressive skin tumors, and wide surgical excision is the main treatment. They can progress with local recurrence and nodal and distant metastasis. The role of radiotherapy is uncertain, but may enhance local control after surgical approach. We report a case of a 60-year-old female with this disease that, four years after surgical resection, presented with nodal metastasis and was managed with surgery and adjuvant radiotherapy.

Impact of human papillomavirus status on survival and recurrence in a geographic region with a low prevalence of HPV-related cancer: A retrospective cohort study.

BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is associated with better tumor-response rates and survival outcomes. However, in some geographic regions, the impact of HPV infection on prognosis remains unclear. The aim of this study was to describe the patterns of recurrence and survival among patients treated for OPSCC in a geographic region with a reported low prevalence of HPV-related OPSCC. METHODS: We retrospectively evaluated 215 patients diagnosed with American Joint Committee on Cancer (AJCC) stages I to IV OPSCC who were treated with upfront surgery or radiation therapy with or without chemotherapy in a tertiary Cancer Center in Brazil. The collected data included demographic information, HPV status, tobacco and alcohol consumption, and pathologic and treatment variables. The patterns of recurrence were recorded according to HPV status. Disease-specific survival and recurrence-free survival were calculated. RESULTS: One hundred twenty-seven (59.1%) patients were diagnosed with HPV-positive OPSCC. According to the AJCC eighth edition, 34 (15.8%), 71 (33%), 47 (21.9%), and 60 (27.9%) patients had stage I, II, III, and IV disease, respectively. Surgery was performed in 109 (50.7%) cases, and upfront chemoradiation regimens were provided in 104 (48.4%, P = .69) patients. Overall, the 5-year cancer-specific survival was 73.5% and 68.1% for patients positive and negative to HPV, respectively. Tobacco status was considered the only independent prognostic factor for survival. Furthermore, HPV status was not associated with differences in recurrence rates (P = .68). While all distant relapses were found to be lung metastases in the HPV-negative group, we observed unusual sites of distant metastases in the HPV-positive group. CONCLUSIONS: HPV status was not associated with higher rates of survival among the investigated population. Moreover, smoking status was considered the only independent prognostic factor for survival. Furthermore, patients with HPV-positive tumors were more likely than patients with HPV-negative OPSCC to have unusual distant metastases.

GADD45B Transcript Is a Prognostic Marker in Papillary Thyroid Carcinoma Patients Treated With Total Thyroidectomy and Radioiodine Therapy.

Currently, there is a lack of efficient recurrence prediction methods for papillary thyroid carcinoma (PTC). In this study, we enrolled 202 PTC patients submitted to total thyroidectomy and radioiodine therapy with long-term follow-up (median = 10.7 years). The patients were classified as having favorable clinical outcome (PTC-FCO, no disease in the follow-up) or recurrence (PTC-RE). Alterations in BRAF, RAS, RET, and TERT were investigated (n = 202) and the transcriptome of 48 PTC (>10 years of follow-up) samples was profiled. Although no mutation was associated with the recurrence risk, 68 genes were found as differentially expressed in PTC-RE compared to PTC-FCO. Pathway analysis highlighted a potential role of cancer-related pathways, including signal transduction and FoxO signaling. Among the eight selected genes evaluated by RT-qPCR, SLC2A4 and GADD45B showed down-expression exclusively in the PTC-FCO group compared to non-neoplastic tissues (NT). Increased expression of GADD45B was an independent marker of shorter disease-free survival [hazard ratio (HR) 2.9; 95% confidence interval (CI95) 1.2-7.0] in our cohort and with overall survival in the TCGA dataset (HR = 4.38, CI95 1.2-15.5). In conclusion, GADD45B transcript was identified as a novel prognostic marker candidate in PTC patients treated with total thyroidectomy and radioiodine therapy.

ErbB2 and fatty acid synthase (FAS) expression in 102 squamous cell carcinomas of the tongue: correlation with clinical outcomes.

The oncoprotein ErbB2 (HER-2/neu) is a tyrosine kinase cell surface receptor overexpressed in several human malignancies, including oral squamous cell carcinoma (OSCC). ErbB2 was recently shown to regulate the expression of fatty acid synthase (FAS), a multifunctional enzyme complex responsible for the de novo biosynthesis of saturated fatty acids. Here we evaluated the relationship between the immunohistochemical expression of ErbB2, FAS, and Ki-67 with the clinicopathologic characteristics of tongue squamous cell carcinoma (SCC). One hundred and two patients with tongue SCC treated from 1990 to 1995 were studied. Clinical and treatment data were obtained from the medical records and histopathological features revised. Paraffin-embedded tissues were submitted to standard immunohistochemical reactions for ErbB2, FAS and Ki-67. A strong positive correlation between ErbB2 labeling at the cell membrane and FAS expression was found in the tongue SCC samples (p<0.0001). The intracytoplasmatic expression of ErbB2 as well as Ki-67 nuclear staining were significantly associated with a high risk of recurrence by predicting both disease free survival (log-rank test, p=0.0096 and p=0.0047, respectively) and overall survival (log-rank test, p=0.0029 and p=0.0001, respectively). Taken together, our results suggest that the immunolocalization of ErbB2 at the cell surface of malignant oral keratinocytes is linked to FAS expression whereas the intracytoplasmatic ErbB2 or Ki-67 staining predict high risk of recurrence of tongue SCC.