6018
Background: PD-1 inhibition using nivolumab (nivo) monotherapy is modestly effective in metastatic HNSCC. Neoadjuvant trials using nivo may permit development of more effective combinations in ...surgically resectable HNSCC. We evaluated combinations with nivo plus additional immune checkpoints, CTLA-4 (ipilimumab, ipi) and LAG-3 (relatlimab, rela). Methods: Phase II randomized trial of neoadjuvant nivo alone (240 mg q2 weeks), or with ipi (1 mg/kg q3 weeks) or rela (160 mg q4 weeks) for 4 weeks prior to surgery. Response was scored using RECIST and standard pathologic response criteria. Patients were stratified by p16, PD-L1, and LAG-3, with staining assessed by immunohistochemistry. Freshly digested tumors were subjected to single cell RNA sequencing (scRNAseq) for T cell receptors and gene pathways to identify biomarkers of response or progression. The Cochran-Armitage trend test was used to explore associations with increasing pathological response efficacy. Results: 41 patients (pts) have been enrolled, with 33 evaluable for this analysis. Of these 33, median age is 63 (32-81), primary site oral cavity (n=25), oropharynx (n=5, 3 HPV), larynx (n=3), clinical T2 (n = 5), T3 (n = 12), T4 (n = 13), and cN0/1 (n = 22), cN2 (n = 9), and PD-L1 CPS > 1 (n=25). There were no serious study drug-related AEs or unexpected surgical delays/complications. Pathologic response (Table) was more frequent with nivo/rela (11/13) vs. nivo/ipi (6/10) or nivo (4/10). Partial (>50%) or major (>90%) pathologic responses were more frequent and deeper in the combination arms. Minor (<50%) pathologic responses were more frequent with nivo/rela, and similar between nivo/ipi and nivo. There was no association between RECIST response, PD-L1, or LAG3 and pathologic response. Combined PD-L1 and LAG3 expression was not associated with pathologic response in the nivo/rela arm, however more patients with combined positivity had a >50% response (4 vs. 0). Expansion of CD8
+
T cells, as well as expanded proportion of CD8
+
CXCL13
+
T cells in responder tumors were identified in post-treatment specimens using scRNAseq. Conclusions: Neoadjuvant nivo/ipi or nivo/rela combinations were safe and associated with promising pathologic responses compared to nivo monotherapy. Anti-tumor CD8
+
T cell populations and targetable pathways are emerging in responder patients. The trial continues to enroll and further evaluation of this strategy is warranted. Clinical trial information: NCT04080804 . Table: see text
Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no ...known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Schneiderian papilloma (SP) are uncommon tumors with malignant transformation even less common. The histologic criteria to define malignant transformation are not well developed nor is the ...immunohistochemical profile reported in a large series of carcinomas. 20 cases of malignant transformation of SP included 7 females and 13 males, aged 38–86 years (mean 60.7 years). Patients presented most frequently with a mass (n = 11) and obstructive symptoms (n = 7), present for 38.7 months (mean). Most patients had no previous history of SP (n = 13); metachronous carcinoma was identified in 7 patients an average of 34.4 months after the first diagnosis of SP, with 1–4 recurrences of SP. With a mean size of 4.1 cm, the majority of tumors involved a combination of more than one anatomic site (n = 10), followed by the maxillary sinus only (n = 5) or nasal cavity only (n = 3). Histologically, 17 were inverted and 3 exophytic type SP. There were 17 squamous cell carcinomas, 2 mucoepidermoid carcinomas and 1 sinonasal undifferentiated carcinoma, comprising from 10 to 95 % of the tumor volume. Malignant histologic features included atypical mitoses, necrosis, bone invasion, lymphovascular invasion, decreased transmigrating neutrophils, paradoxical maturation, dyskeratosis and/or perineural invasion (n = 3). Patients tended to present with advanced stage (n = 14, Stage III and IV). Immunohistochemical studies showed positive reactions in the malignancies for CK5/6 (86 %), p63 (86 %), CK7 (luminal, 50 %), p53 (83 %), and p16 (25 %). In situ hybridization detected human papillomavirus in 26 %. Surgery was often accompanied by radiation therapy (n = 13), with a mean of 2.4 years of follow-up. Five patients developed a recurrence between 0.8 and 3.3 years. Carcinomas ex-SP are less common and are associated with better outcome than previously reported. Patients tend to present with a synchronous carcinoma, developing in an inverted type SP, with squamous cell carcinoma the most common malignancy. Development of metachronous carcinomas ex-SP was always preceded by SP recurrence in this series.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Somatostatin receptor 2 (SSTR2) expression has previously been documented in olfactory neuroblastoma (ONB). Here, we fully characterize SSTR2 expression in ONB and correlate staining results with ...clinicopathologic parameters including Hyams grade. We also assess SSTR2 immunohistochemistry expression in various histologic mimics of ONB to assess its diagnostic functionality. 78 ONBs (51 primary biopsies/excisions and 27 recurrences/metastases) from 58 patients were stained for SSTR2. H-scores based on intensity (0–3 +) and percentage of tumor cells staining were assigned to all cases. 51 histologic mimics were stained and scored in an identical fashion. 77/78 (99%) ONB cases demonstrated SSTR2 staining (mean H-score: 189, range: 0–290). There were no significant differences in staining between primary tumors and recurrences/metastases (mean H-score: 185 vs 198). Primary low-grade ONB had somewhat stronger staining than high-grade tumors (mean H-score: 200 vs 174). SSTR2 expression had no prognostic value when considering disease-free or disease-specific survival. SSTR2 staining is significantly higher in ONB than its histologic mimics (mean H-score: 189 vs 12.9, p < 0.001) suggesting a potential use of the marker in diagnosis of ONB. In conclusion, SSTR2 is consistently expressed in ONB suggesting a role for somatostatin-analog based imaging and therapy in this disease. More generally, SSTR2 may be another marker of neuroendocrine differentiation in ONB.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract only
6546
Background: Anti-PD-1 mAbs have changed the landscape of R/M HNSCC treatment, but physical, immunologic, and metabolic barriers present in the tumor microenvironment are likely ...drivers of low response rates. Hypoxia is a well-established feature of the tumor microenvironment and may act as a barrier to T cell infiltration and function. We evaluated the effect of hypoxia on the efficacy of anti-PD-1 mAb treatment in R/M HNSCC patients. Methods: We conducted a retrospective analysis of R/M patients treated with anti-PD-1 mAb that had consented to the UPMC Hillman tissue banking protocol (HCC 99-069). Pre-treatment archival FFPE samples were analyzed via immunofluorescent imaging for number of CD8+ T cells (CD8), Tregs, and the percent area (% CAIX) and mean intensity (Int) of carbonic anhydrase IX, a well-described marker of hypoxia. Tissue sections stained with PanCK, CAIX, CD8, Foxp3, and DAPI were imaged with an Olympus IX 83 microscope. ImageJ software and custom software plugins were used to determine %CAIX, Int, CD8, and Treg. PD-L1 by IHC was reported as a combined positive score (CPS) defining positive as CPS > 1. We compared non-responders (NR) i.e. PD to responders (R) i.e. PR or SD, and analyzed OS, PFS. All data were analyzed using GraphPad Prism software. Two-tailed unpaired t test was used when comparing 2 groups, 1-way ANOVA was used for multiple comparisons, and log-rank test was used for survival analysis. Results: The 36 patients included were 69% male, median age 59, 58% smokers. 61% were platinum failure. Primary site included 39% OC, 22% OPC (38% HPV positive), 17% Larynx, 17% other, 5% hypopharynx. Low %CAIX/Int, high CD8, and high CD8/Treg were all significantly associated with R. Patients with low %CAIX/Int (12 month OS Low: 75% vs. Mid: 17% vs. High:8%, p = 0.02) and high CD8/Treg had a significant increase in OS. Only high CD8 was associated with significantly higher PFS. Low %CAIX alone showed a non-significant trend towards increased R and no difference in PFS/OS. There was no difference in CD8, CD8/Treg, PD-L1 and Treg between %CAIX/Int groups. Conclusions: To our knowledge this is the first evaluation of tumor hypoxia as a predictive biomarker in anti-PD-1 mAb treated R/M HNSCC patients. Lower hypoxia by %CAIX/Int was associated with significantly increased response and OS. While further analysis in a larger dataset is needed to confirm, the lack of significant difference in CD8, Treg, PD-L1, and CD8/Treg between %CAIX/Int groups (Low, Mid, High) suggests that hypoxia may be an independent predictive marker.
Aims
Accurate classification of salivary gland neoplasms may be challenging, owing to morphological overlap, particularly in small biopsies. Recurrent translocations involving the high‐mobility group
...AT
‐hook 2 (
HMGA
2) gene are present in a subset of pleomorphic adenomas (
PA
s) and carcinoma ex‐pleomorphic adenomas (
CA
ex‐
PA
s). The aim of this study was to evaluate immunohistochemical
HMGA
2 expression in 225 salivary gland tumours, including 56
PA
s, 37
CA
ex‐
PA
s, and 132 potential histological mimics, to determine its diagnostic utility.
Methods and results
HMGA
2 expression was identified in 19
PA
s (33.9%) and nine
CA
ex‐
PA
s (24.3%). Expression was strong and diffuse throughout all
PA
s, and in four of nine positive
CA
ex‐
PA
s. In five
CA
ex‐
PA
s,
HMGA
2 showed weak‐to‐strong multifocal staining within the carcinomatous component, and strong diffuse
HMGA
2 expression in the residual
PA
. Among histological mimics, six
de‐novo
salivary duct carcinomas (28.5%), three epithelial–myoepithelial carcinomas (33.3%) and one case each of myoepithelioma and basal cell adenoma expressed
HMGA
2. Fluorescence
in‐situ
hybridization for
HMGA
2
rearrangement performed on a subset of tumours that showed diffuse
HMGA
2 expression in
PA
s and
CA
ex‐
PA
s was frequently associated with rearrangement of the
HMGA
2
locus, whereas cases of
de‐novo
salivary duct carcinoma, or
CA
ex‐
PA
with limited or no
HMGA
2 expression, had an intact
HMGA
2
locus.
Conclusions
HMGA
2 expression is a highly specific (96.2%), but low‐sensitivity (29.8%), marker for
PA
and
CA
ex‐
PA
when compared with histological mimics, and is frequently associated with rearrangement of the
HMGA
2
locus.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Abstract only
e18014
Background: Data on the efficacy of including definitive local therapy to the primary head and neck disease (PHN) for non-nasopharyngeal head and neck squamous cell carcinoma ...(HNSCC) patients with synchronous distant metastasis are lacking. Methods: In this single institution retrospective study, we evaluated the outcomes of patients treated from 2000-2020 at UPMC for non-nasopharyngeal HNSCC with synchronous distant metastasis whose therapy included definitive therapy to the PHN. We evaluated overall survival (OS), calculated as date of diagnosis to date of death and progression free survival (PFS), calculated as date of diagnosis to date of death or progression. Based on an initial univariate analysis, the potential significant predictors were evaluated further in the multiple covariates Cox model via stepwise procedures. The relative mortality rates were summarized with hazard ratio (HR), with HR > 1.0 corresponding to increased mortality. Results: A total of 40 patients met inclusion criteria. The median age was 61, primary sites included 52.5% oropharynx (48% HPV +), 40% larynx/hypopharynx, 7.5% oral cavity, and 85% had a solitary metastatic lesion, most commonly in the lung. Definitive treatment of the PHN was with surgery (55%) or chemoradiation (45%), and 45% also underwent local treatment for all distant disease. The median PFS was 8.6 months (95% CI, 6.4-11.6), and OS was 14.2 months (95% CI, 10.9-27.5). In the 28% of patients that received induction therapy, there was a two-fold increase in median OS to 27.5 vs. 13.7 months, p = 0.06. In the 33% of patients that received anti-PD-1 mAb immunotherapy (IO), the median OS was significantly increased to 41.7 months (95% CI, 8.7-NR) vs. 12.1 months (95% CI, 8.4-14.4), p = 0.01, with a numeric increase in PFS as well (11.3 vs. 8.2 months respectively, p = 0.07). Notably no difference in PFS or OS was seen with type of local therapy to the PHN, receipt of local treatment to all distant disease, by HPV status, or year of diagnosis. In multivariate analysis including induction and other variables significant in univariate analysis (age, number of metastatic sites), IO was independently associated with improved OS (HR 3.123 (No IO vs. IO) (95% CI, 1.198-8.137), p = 0.02), as was age and number of metastatic sites. In the patients that received IO started as part of induction the median PFS and OS were 19.5 and 45.5 months respectively. Conclusions: We observed impressive survival in select non-nasopharyngeal HNSCC patients with synchronous distant metastasis treated with definitive local therapy to the primary head and neck disease in addition to induction and/or IO, with IO independently associated with improved OS. To our knowledge this is the first evaluation of the efficacy of definitive local therapy and IO in this population. Prospective evaluation is warranted.
Abstract only
e19043
Background: As cancer centers expand, evaluation of potential disparities in outcomes amongst the catchment area is critically important. We examined the effect of LOR and SES on ...overall survival (OS) in HNSCC patients treated at HCC, which spans 29 counties in western Pennsylvania with diverse socioeconomic profiles across urban and rural localities. Methods: Retrospective review included patients with primary HNSCC (excluding M1 and recurrent disease) treated at HCC 1997-2018. Using Rural-Urban Commuting Area codes, LOR was classified as urban/suburban or rural according to ZIP code. SES was defined by medium income level (low, moderate (Mod), middle (Mid), Upper) via Federal Financial Institutions Examination Council geocoded census tract data. Kaplan-Meier methods and Cox regression models were used to evaluate OS. Results: 3512 patients were identified. Median age was 61, 72.7% male, 93.2% White, 18% HPV +, 75.5% urban/suburban, and by SES: 4% Low, 21% Mod, 46% Mid, and 19% Upper. Primary site included 35.2% oral cavity, 28.4% oropharynx, 28.1% larynx, 8.3% other, stage was majority III/IVa (61%), 66% had surgery and 54% received multimodality treatment (tx). While median OS differed significantly by race (Black: 5.8 vs. White: 7.3 years, p = 0.0457) and SES (Low: 4.1 vs. Mod: 5.3 vs. Mid: 7.3 vs. Upper: 9.1 years, p < 0.0001), there was no difference by LOR (rural: 7.7 vs. urban/suburban: 7.2 years, p = 0.99). Multivariable Cox Regression showed lower SES was associated with a higher risk of death (Low vs. Upper, HR: 1.416, 95% CI: 1.023-1.959) (Mod vs. Upper, HR:1.443, 95% CI: 1.214 – 1.716), p = 0.0004, adjusting for LOR and factors associated with OS in univariate analysis (age, smoking status, primary site, staging, tx, HPV status, race, and enrollment on clinical trial). The effect of LOR, race, and enrollment on clinical trial were not significant in multivariate analysis. Conclusions: SES was independently associated with OS in HNSCC patients treated at HCC, while LOR was not associated with OS. The lack of difference by LOR may be partially explained by HCC’s efforts to increase access to care throughout the catchment area by establishing community sites. However, a focus on improving outcomes for lower SES HNSCC patients is needed.
Acinic cell carcinoma (AiCC) with high-grade transformation is a rare variant of AiCC composed of both a conventional low-grade (LG) AiCC and a separate high-grade (HG) component. We describe here, ...the clinicopathologic and immunohistochemical features of 25 cases diagnosed between 1990 and 2015. Available tissue was analyzed and compared with a cohort of pure LG AiCC for the morphologic and immunophenotypic profile. Incidence was higher in females (1.8:1) than males with an overall mean age at presentation of 63.2 years. All tumors occurred in the parotid gland including 76 % with facial nerve trunk and branches involvement. Most patients were treated with extensive resection and adjuvant therapy. Local recurrence or distant metastasis occurred in most patients, with 72.7 % dead with disease (mean 2.9 years) and 3 patients alive with disease (mean 2.4 years). The majority of the tumors were composed of a LG microcystic AiCC and a HG component consisting of invasive lobules of undifferentiated cells with predominantly solid, cribriform, and glandular patterns. Acinic differentiation was still present in HG areas but aggressive features such as perineural invasion (76 %), lymphovascular invasion (62 %), positive margins (72 %), high mitotic rate, atypical mitoses and/or comedonecrosis (86 %) were easily identified. Compared to the pure LG AiCC, the cases with HG transformation showed significantly increased expression of cyclin-D1, p53 and Ki-67. Most HG areas of AiCC expressed membranous β-catenin (92 %) and were negative for p63 (three cases were focally positive), S100, SMA, androgen, and estrogen receptors. DOG1 expression was present in all LG AiCC tested with retained expression in 91 % of cases with HG transformation, supporting acinic differentiation in the HG foci. Recognition of AiCC with high-grade transformation is imperative as more aggressive clinical management is warranted.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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