Michael G. Keeney

Clinicopathologic factors and adjuvant treatment effects on survival in adult head and neck synovial cell sarcoma

Synovial cell sarcoma is a rare soft tissue sarcoma. The purpose of this study was to investigate clinicopathologic factors and management on survival in primary synovial sarcoma of the head and neck.

Transcriptional Activity of HPV in Inverted Papilloma Demonstrated by In Situ Hybridization for E6/E7 mRNA

Objective Assess human papilloma virus (HPV) transcriptional activity in inverted Schneiderian papillomas (IPs). Study Design Case series with chart review. Setting Academic tertiary care center. Subjects and Methods Retrospective clinicopathologic review of 19 cases of IP in patients undergoing surgical excision from 1995 to 2013 at Mayo Clinic in Rochester, Minnesota. Surgical pathology archival material was histopathologically reviewed using hematoxylin and eosin–stained slides. Formalin-fixed, paraffin-embedded material from each case was evaluated for p16 expression using immunohistochemistry as well as HPV DNA and E6/E7 messenger RNA (mRNA) transcription using polymerase chain reaction (PCR) and in situ hybridization (via RNAscope technology), respectively. Results Eight patients were female (42%), with an average age of 53 years (range, 23-82 years). Three demonstrated malignancy, and 5 subsequently recurred. Average follow-up was 49 months (range, 0-200 months), and 1 patient died from squamous cell carcinoma arising from the IP. RNAscope detected HPV mRNA transcripts exclusively within IP in 100% of cases; however, in 11 patients (58%), less than 1% of cells exhibited transcriptional activity. Only 2 of 19 cases (11%) demonstrated mRNA activity in 50% or more cells. HPV DNA was detected in only 2 specimens by PCR. Conclusions This study reveals wide prevalence but limited transcriptional activity of HPV in IP. No correlation between HPV transcriptional activity and progression, recurrence, or malignant transformation was identified. These data suggest that transcription of HPV may contribute to the pathogenesis of IP, but prospective data are needed to definitively demonstrate this connection. These results also suggest that RNAscope may be more sensitive than PCR in detecting HPV activity in IP.

High-grade transformation of acinic cell carcinoma: an inadequately treated entity?

OBJECTIVE Acinic cell carcinoma (AcCC) is an uncommon salivary gland malignancy. We aim to characterize the clinical and pathologic characteristics of AcCC with and without high-grade transformation (HGT). Importantly, cases of mammary analogue secretory carcinoma, a recently described histologic mimic of AcCC, have been excluded by using cytogenetics and molecular studies. STUDY DESIGN Archival surgical pathology material was obtained for patients diagnosed with AcCC at Mayo Clinic Rochester between 1990 and 2010. Tumors harboring the ETV6-NTRK3 fusion transcript were excluded from analysis by using cytogenetics and molecular studies. Tumors with HGT were characterized by areas with an infiltrative growth pattern, nuclear anaplasia, prominent nucleoli, brisk mitotic activity, geographic necrosis, and stromal desmoplasia. Demographic and clinical data were extracted from the medical records. RESULTS AcCC with HGT was seen in 8 of 48 cases (17%). Patients with AcCC with HGT were significantly older than patients without HGT (median 69 vs 54 years; P = .04). Angiolymphatic invasion was more common in AcCC with HGT (P = .02). Relapse-free survival and overall survival were significantly worse for cases of AcCC with HGT (hazard ratio 10.4 and 9.3, respectively; P < .0001 for both comparisons). Locoregional recurrence-free survival was not significantly different (P = .12), but distant metastases-free survival was significantly worse in patients with HGT compared with non-HGT patients (P < .0001). CONCLUSIONS Prognosis for overall survival and distant relapse for AcCC patients with HGT is significantly worse than that for patients without HGT.

Detection of human papillomavirus in non-small cell carcinoma of the lung.

High-risk human papillomavirus (hrHPV) is an etiologic agent in squamous cell carcinoma (SqCC) arising in the oropharynx and cervix, and a proven prognostic factor in oropharyngeal SqCC. Many studies have found HPV in non-small cell lung carcinoma (NSCLC). Recent studies advocate the detection of messenger RNA transcripts of E6/E7 as more reliable evidence of transcriptively active HPV in tumor cells. The clinical significance of finding HPV remains unclear in NSCLC. This study sought to determine the prevalence of biologically active HPV infection in NSCLC comparing different methodologies. Surgical pathology material from resected primary lung adenocarcinoma (ADC; n=100) and SqCC (n=96) were retrieved to construct tissue microarrays. In situ hybridization (ISH) for hrHPV DNA (DNA-ISH), hrHPV E6/E7 RNA (RNA-ISH), and p16 immunohistochemistry were performed. Cases of oropharyngeal SqCC with known HPV infection were used as positive controls. Expression of p16 was scored as positive if at least 70% of tumor cells showed diffuse and strong nuclear and cytoplasmic staining. Punctate nuclear hybridization signals by DNA-ISH in the malignant cells defined an HPV-positive carcinoma. Of the 196 patients (range, 33-87 years; 108 men), p16 was positive in 19 ADCs and 9 SqCCs, but HPV DNA-ISH and RNA-ISH were negative in all cases. Our study did not detect HPV infection by DNA-ISH or RNA-ISH in any cases of primary NSCLC despite positive p16 expression in a portion of ADC and SqCC. p16 should therefore not be used as a surrogate marker for HPV infection in NSCLC.

Identifying a subset of patients with DCIS who have a low likelihood of residual disease at surgical excision following a core needle biopsy

Current randomized controlled trials are investigating the outcomes of non‐surgical treatment for patients with ductal carcinoma in situ (DCIS). We sought to evaluate pre‐operative factors associated with no residual disease at definitive resection following a core needle biopsy (CNB) diagnosis of DCIS.

A Validated Nomogram to Predict Upstaging of Ductal Carcinoma in Situ to Invasive Disease

BackgroundApproximately 8–56% of patients with a core needle biopsy (CNB) diagnosis of ductal carcinoma in situ (DCIS) will be upstaged to invasive disease at the time of excision. Patients with invasive disease are recommended to undergo axillary nodal staging, most often requiring a second operation. We developed and validated a nomogram to preoperatively predict percentage of risk for upstaging to invasive cancer.MethodsWe reviewed 834 cases of DCIS on CNB between January 2004 and October 2014. Multivariable analysis was used to evaluate CNB and imaging factors to develop a nomogram to predict the risk of upstaging from DCIS to invasive cancer. This nomogram was validated with an external dataset of 579 similar patients between November 1998 and September 2016. An area under the receiver operating characteristic curve was constructed to evaluate nomogram discrimination.ResultsThe rate of upstaging to invasive disease was 118/834 (14.1%). On multivariable analysis, grade on CNB and imaging factors, including mass lesion, multicentric disease, and largest linear dimension, were associated with upstage to invasive disease, and was used to develop a nomogram (c-statistic 0.71). In the external validation dataset, 62/579 (10.7%) patients were upstaged to invasive disease. Our nomogram was validated in this dataset with a c-statistic of 0.71.ConclusionFor patients with a CNB diagnosis of DCIS, our validated nomogram using DCIS grade on biopsy, and imaging factors of mass lesion, multicentric disease, and largest linear dimension, may be used for preoperative assessment of risk of upstaging to invasive disease, allowing patient counseling regarding axillary staging at the time of definitive surgery.

Factors Associated With Positive Margins in Women Undergoing Breast Conservation Surgery

Objective: To identify factors predicting positive margins at lumpectomy prompting intraoperative reexcision in patients with breast cancer treated at a large referral center. Patients and Methods: We reviewed all breast cancer lumpectomy cases managed at our institution from January 1, 2012, through December 31, 2013. Associations between rates of positive margin and patient and tumor factors were assessed using χ2 tests and univariate and adjusted multivariate logistic regression, stratified by ductal carcinoma in situ (DCIS) or invasive cancer. Results: We identified 382 patients who underwent lumpectomy for definitive surgical resection of breast cancer, 102 for DCIS and 280 for invasive cancer. Overall, 234 patients (61.3%) required intraoperative reexcision for positive margins. The reexcision rate was higher in patients with DCIS than in those with invasive disease (78.4% [80 of 102] vs 56.4% [158 of 280]; univariate odds ratio, 2.80; 95% CI, 1.66‐4.76; P<.001). Positive margin rates did not vary by patient age, surgeon, estrogen receptor, progesterone receptor, or ERBB2 status of the tumor. Among the 280 cases of invasive breast cancer, the only factor independently associated with lower odds of margin positivity was seed localization vs no localization (P=.03). Conclusion: Ductal carcinoma in situ was associated with a higher rate of positive margins at lumpectomy than invasive breast cancer on univariate analysis. Within invasive disease, seed localization was associated with lower rates of margin positivity.

An Athymic Rat Model for Mandibular Osteoradionecrosis Allowing for Direct Translation of Regenerative Treatments

Objective We aim to create a model of mandibular osteoradionecrosis in athymic rats. Athymic rats provide an immunosuppressed environment whereby human stem cells and biomaterials can be used to investigate regenerative solutions for osteoradionecrosis, bridging the gap between in vivo testing and clinical application. Study Design Prospective animal study. Setting Academic otolaryngology department laboratory. Subjects and Methods After Institutional Animal Care and Use Committee approval, 10 athymic nude rats were divided into 2 groups. The experimental group (n = 6) underwent irradiation (20 Gy), while the control group (n = 4) underwent sham irradiation catheter placement only. All 10 rats underwent extraction of the second mandibular molar 7 days later. The rats were sacrificed 28 days after dental extraction, and their mandibles were harvested. The mandibles were examined with histologic analysis and bone volume analysis based on 3-dimensional micro–computed tomography. Results All 10 rats survived the experiment period. Radiographic and histologic analysis revealed decreased bone formation in the experimental group compared with the control group. Jaw region volume ratio was 0.83 for the experimental group versus 0.97 in the control group (P = .003). The region-of-interest volume ratio was 0.75 in the experimental group and 0.97 in the control group (P = .005). Histologically, there were increased osteoclasts (P = .02) and decreased osteoblasts (P = .001) as well as increased fibrosis in the experimental group versus the control group. Conclusion Mandibular osteoradionecrosis can be effectively and reproducibly produced in an athymic rat model. This will allow further research to study regenerative medicine in an athymic rat model.

Human Adipose-Derived Mesenchymal Stem Cells for Osseous Rehabilitation of Induced Osteoradionecrosis: A Rodent Model

Objective Human adipose-derived mesenchymal stem cells (ADSCs) were used to rehabilitate bone damaged by osteoradionecrosis (ORN) in an established animal model. Study Design Prospective animal study. Setting Academic department laboratory. Subjects and Methods After institutional review board and Institutional Animal Care and Use Committee approval, 24 athymic nude rats were divided into 5 groups: 4 groups irradiated (20 Gy) by brachytherapy catheter placed at the left hemimandible and 1 mock irradiation control (n = 4). For all groups, ORN was initiated by extraction of the central molar 1 week later. After 28 days, animals (n = 5/group) received injection at the extraction site with saline (SAL), ADSCs, platelet-rich plasma and collagen (PRP/COL), or ADSCs + PRP/COL. Rats were sacrificed 28 days later and their mandibles harvested for histopathology analysis (osteoblasts, osteoclasts, and fibrosis) and bone volume measurement using 3-dimensional micro–computed tomography. Results All but 1 rat survived the experiment period (23/24). Radiographic and histological analysis revealed 60% bone loss in the SAL group compared with the nonirradiated control. Injection of ADSCs increased jaw region bone volume by up to 36% (P < .01). All experimental groups (ADSC, PRP/COL, and ADSC + PRP/COL) showed dramatically decreased osteoclast counts (P < .001) while injection of PRP/COL with or without ADSCs increased osteoblasts. Increased fibrosis was observed after ADSC injection (P < .05). Conclusion The application of human ADSCs to an induced mandibular osteoradionecrosis model in athymic rats results in increased deposition or preservation of bone, demonstrated both histologically and radiographically. This offers an encouraging possible treatment option for translational research in this difficult disease.

Is axillary surgery beneficial for patients with adenoid cystic carcinoma of the breast

Adenoid cystic carcinoma (ACC) is a rare, typically triple‐negative, breast cancer reported to have a favorable prognosis and low rate of nodal metastasis. No consensus guidelines exist for axillary staging and treatment.