Metaplastic breast cancer has a poor response to neoadjuvant systemic therapy.

OBJECTIVE: Metaplastic breast cancer (MetaBC) is a rare breast cancer subtype poorly responsive to systemic therapy in the metastatic setting with high recurrence rates in the adjuvant setting. However, limited data exist regarding response to neoadjuvant chemotherapy (NAC). We performed a single institutional study to assess the clinical and pathological complete response rates (pCR) of MetaBC to NAC. METHODS: Mayo Clinic Rochester patients with MetaBC treated with NAC were identified using the institutional medical index. Patient demographics, tumor characteristics, chemotherapy treatment, clinical and pathological response, and long-term outcomes were reviewed. Pathologic response was assessed by direct pathology review (n = 14) or review of outside surgical and pathology reports (n = 4). RESULTS: Women with MetaBC (n = 18) received NAC from January 1991 to June 2014. The mean age was 50 years (range 33-79) with a mean tumor size of 5.1 cm (range 2.3-11 cm) and 6/18 had pathologically confirmed lymph nodes prior to surgery. The majority (13/18; 72%) were estrogen receptor (ER), progesterone receptor (PR) and HER-2 negative (TNBC), and 1/18 (5.5%) was HER-2 positive. Five had BRCA testing and 2/5 were BRCA-2 positive. The chemotherapy regimens included anthracycline/cyclophosphamide (AC) (n = 1), AC/taxane (n = 3), AC/taxane/platinum (n = 8), taxane/platinum-based regimens (n = 4), taxane/cyclophosphamide (n = 1) and taxane/trastuzumab (n = 1). Five of 18 (28%) progressed on initial treatment including two who developed metastatic disease during NAC. The overall pCR rate was 2/18 (11%). CONCLUSION: MetaBC is poorly responsive to NAC, with a pCR rate (11%), that is lower than expected in a predominantly TNBC cohort. MetaBC patients should be considered for clinical trials testing new NAC regimens and in the absence of clinical trial enrollment, MetaBC patients with resectable disease should proceed directly to definitive operative management.

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

BACKGROUND: Approximately 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. METHODS: We 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. RESULTS: The 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. CONCLUSION: For 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.

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

BACKGROUND AND OBJECTIVES: 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. METHODS: We identified all patients with ACC evaluated at our institution from January 1994 to August 2016. Patient, tumor, and treatment variables were abstracted and analyzed. RESULTS: We identified 20 pure ACCs (0.13% of all invasive breast cancers) with size range 0.2-4.8 cm, in 19 women, median age 59 years. Preoperative axillary ultrasound was normal in 10/13 women and suspicious in 3/13 who had a subsequent negative lymph node fine needle aspiration (FNA). Fifteen patients (75%) had sentinel lymph node surgery and were pathologically node-negative, while the remaining five had no axillary surgery. With 3.6 years median follow-up (range 0.2-38.6 years), three patients experienced an in-breast recurrence at 2, 16, and 17 years, respectively, while none recurred in regional nodes. CONCLUSIONS: We observed no cases of nodal metastasis in 20 consecutive cases of ACC of the breast. Preoperative axillary ultrasound with FNA of suspicious nodes accurately predicted pathologic nodal stage. These data suggest axillary surgery might be omitted safely in patients with pure ACC and a clinically negative axilla.

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

BACKGROUND AND OBJECTIVES: 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. METHODS: Eight hundred and thirty-four operations for DCIS were performed at our institution between January 2004 and October 2014. We evaluated patient and biopsy tumor characteristics to determine pre-operative factors associated with no residual disease at surgical resection using uni- and multivariable analyses. RESULTS: Sixty-nine patients (8%) had no residual disease on final pathology. On multivariable analysis, low- or intermediate-grade lesions, <1 cm in size on mammography, and lesions where ≥90% of calcifications were removed correlated with finding no residual disease on final pathology, c-statistic 0.84. Of the 14 patients with all three low-risk factors, 36% had no residual disease on final pathology. CONCLUSIONS: Although our multivariable analysis performed well, its clinical utility would be limited as we were unable to identify a subset of patients with DCIS in whom the probability of finding no residual disease is low enough to consider routine use of non-surgical management.

Increased ERBB2 Gene Copy Numbers Reveal a Subset of Salivary Duct Carcinomas with High Densities of Tumor Infiltrating Lymphocytes and PD-L1 Expression.

Salivary duct carcinoma (SDC) commonly expresses androgen receptor (AR) and HER2, giving rise to treatment implications. SDC may also express programmed-death-ligand-1 (PD-L1), a predictive marker of response to checkpoint inhibitors. PD-L1 can be associated with genomic instability and high density of tumor infiltrating lymphocytes (TILs). Evaluation of HER2 immunohistochemistry (IHC) in SDC is not standardized, and relationships between ERBB2 copy numbers, PD-L1 expression and TILs in SDC are unknown. We evaluated 32 SDCs for HER2, AR and PD-L1 expression (IHC), ERBB2 status (FISH) and TILs (slide review). HER2 was scored with three different systems (breast, gastric, proposed salivary gland). PD-L1 was evaluated with the combined positive score. Most patients were older men, presenting at advanced clinical stage with nodal or distant metastases. During follow-up (mean 5 years, range 6 months to 21 years), 25 of the 32 patients (78%) died of SDC. We propose a HER2 IHC scoring system which accurately predicts underlying ERBB2 amplification or increased copy numbers in SDC. Most tumors had increased ERBB2 copy numbers (19/32 amplification, 6/32 aneusomy), a finding associated with higher TIL densities (p = 0.045) and PD-L1 expression (p = 0.025). Patients with TILs ≥ 40% had better prognoses (Log-Rank p = 0.013), with TILs being favorable prognosticators in univariate analysis (Hazard ratio: 0.18, p = 0.024). A subset of SDCs with increased ERBB2 copy numbers have higher TILs and PD-L1 expression. TILs ≥ 40% are associated with better prognosis.

Management of the axilla in metaplastic breast carcinoma.

BACKGROUND: Metaplastic breast cancer (MBC), characterized by admixed epithelial, squamous or mesenchymal elements, constitutes <1% of breast cancers and has a poor prognosis but a paradoxically low reported rate of axillary lymph node (LN) involvement. Due to its rarity, data on appropriate axillary management is lacking, prompting this investigation of LN status and outcomes. METHODS: We identified 41 MBC patients treated at our institution 2001-2011 who were followed for a median of 66 months. Statistical analyses evaluated axillary ultrasound (AUS), fine needle aspiration (FNA), and sentinel LN biopsy (SLNB) in association with LN status. RESULTS: Median tumor size was 2.7 cm and 76% were triple-negative. Twenty-three patients (56%) had preoperative AUS: 9 (39%) showed ≥1 suspicious LN, 6 proceeded to LN FNA and 3 were confirmed positive. Six patients had neoadjuvant chemotherapy, including 2 FNA LN+. Ten patients were LN+ at operation. Among 19 patients undergoing AUS and axillary surgery, AUS ± FNA sensitivity was 100% and specificity was 94%. LN positivity correlated with increasing tumor size, grade and angiolymphatic invasion. 16 patients recurred, 63% with distant disease (10/16) and one with isolated axillary disease after a negative SLNB not preceded by AUS. Overall SLNB accuracy was 96% (23/24), but absent preoperative AUS, 1/7 (14%) of SLNBs were falsely negative. CONCLUSIONS: Our study is the first to specifically address the performance and utility of AUS/FNA and SLNB for MBC patients. AUS/FNA at diagnosis followed by SLN surgery provided accurate nodal staging and critical prognostic information to inform treatment recommendations. We recommend this approach for axillary management of MBC patients.

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.

Ability of Intraoperative Pathologic Analysis of Ductal Carcinoma In Situ to Guide Selective Use of Sentinel Lymph Node Surgery.

For patients with ductal carcinoma In Situ (DCIS), sentinel lymph node (SLN) surgery is generally reserved for patients at high risk of being upstaged to invasive disease. The use of frozen section (FS) pathologic analysis of the primary tumor may allow for selective surgical nodal staging within one procedure. We sought to define the reliability of FS for detection of upstaging. Eight hundred and twenty-seven patients were identified with DCIS on core needle biopsy that underwent 834 operations at our institution between January 2004 and October 2014. We calculated the rate of upstage from DCIS to invasive cancer on both intraoperative FS and final pathology to determine the performance of FS. Upstage rate on final pathology was 118/834 (14.1%) 95 per cent confidence interval 11.8 to 16.7 per cent. FS identified 88/118 (74.6%) of the upstages. Specificity was 99.3 per cent (711/716). Overall accuracy was 95.8 per cent (799/834) and the positive predictive value was 96.0 per cent (711/741 patients). Mean size of invasive cancers identified on FS was 5.6 mm, versus 3.5 mm for those identified only on permanent section, P = 0.11. Intraoperative FS analysis of DCIS is useful for identification of upstage to invasive disease. This may facilitate a selective approach to SLN surgery that both decreases unnecessary SLN surgery and the need for a second operation.

Non-BRCA familial breast cancer: review of reported pathology and molecular findings.

The majority of women evaluated for a clinical concern of possible hereditary breast cancer syndromes have no identified pathogenic variants in genes predisposing them to breast cancer. Non-BRCA1- or BRCA2-related familial breast cancer, also called 'BRCAX', thus comprises a sizeable proportion of familial breast cancer but it is poorly understood. In this study, we reviewed 14 studies on histopathology and molecular studies of BRCAX to determine if there were differences between 'sporadic' breast cancers and compared to cancers arising in women harbouring variants in known cancer predisposition genes. Across available literature, there was inconsistency on inclusion and exclusion criteria, reported parameters, and use of controls. Cohorts were small, and while several studies reported findings that appeared to distinguish the BRCAX cases from sporadic and/or gene-positive controls, no findings were reported in more than one study. To determine whether the BRCAX families might still contain important genetic subsets awaiting discovery will require prospective ascertainment of a large number of women with familial breast cancer who are screened for all currently established predisposition genes, whose tumours are assessed for multiple parameters in a uniform manner, and in which controls (BRCA1/2+ and non-familial 'sporadic' cases) are collected from the same population.

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.

Relapse Rates With Surgery Alone in Human Papillomavirus-Related Intermediate- and High-Risk Group Oropharynx Squamous Cell Cancer: A Multi-Institutional Review.

PURPOSE: To evaluate whether historic risk categories and indications for adjuvant therapy in the pre-human papillomavirus (HPV) and pre-transoral surgery (TOS) era were associated with clinically significant relapse rates in HPV+ oropharyngeal squamous cell cancer patients undergoing TOS. METHODS AND MATERIALS: A multi-institutional retrospective review of intermediate- and high-risk HPV+ oropharyngeal squamous cell cancer patients not receiving adjuvant therapy after TOS was performed. Perineural invasion, lymphovascular invasion, T3-T4, or ≥N2 disease were considered to be intermediate-risk factors, and extracapsular extension or positive margins were considered to be high-risk features, according to established risk categories. RESULTS: Median follow-up was 42.9 months. Among all 53 patients, the 3-year cumulative incidence of relapse was 26.0%. The 3-year cumulative incidence was 11.8% in the 37 intermediate-risk patients and 52.4% in the 16 high-risk patients. On univariate analysis only high-risk status was significantly associated with an increased risk of relapse (hazard ratio 3.9; P=.018). The salvage rate for relapse was 77%, with 10 of 13 patients undergoing salvage therapy. CONCLUSIONS: Risk category was associated with clinically significant relapse rates after TOS alone in HPV+ oropharyngeal cancer, comparable to historical data and traditional indications for adjuvant therapy for all oropharyngeal cancer.

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.

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

BACKGROUND: 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. METHODS: We conducted a retrospective case series of medical records. Standard Kaplan-Meier survival analyses and accompanying log-rank tests were used. RESULTS: Twenty-eight patients were identified. All patients had surgery in attempt to remove the primary lesion. Nine patients received adjuvant radiation therapy, 2 received chemotherapy, and 14 received chemoradiation therapy postoperatively. Metastases on initial presentation and tumor size >4 cm decreased survival. No significant effect on overall survival or local tumor recurrence with histologic subtype, lymph node involvement at diagnosis, tumors >5 cm, or when comparing adjuvant therapy types. CONCLUSION: Although surgery remains the mainstay of treatment, our results do not suggest that adding chemotherapy to postoperative radiotherapy confers a survival or control benefit.

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.

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.

Maturation and long-term hypoxia alters Ca2+-induced Ca2+ release in sheep cerebrovascular sympathetic neurons.

The contribution of sympathetic nerves arising from the superior cervical ganglia (SCG) toward the growth and function of cerebral blood vessels is pertinent throughout maturation as well as in response to cardiovascular stress imposed by high-altitude long-term hypoxia (LTH). The function of SCG sympathetic neurons is dependent on intracellular Ca2+ concentration ([Ca2+]i) signaling, which is strongly influenced by a process known as Ca(2+)-induced Ca2+ release (CICR) from the smooth endoplasmic reticulum (SER). In this study, we used the sheep SCG neuronal model to test the hypotheses that maturation decreases CICR and high-altitude LTH depresses CICR in fetal SCG neurons but not in those of the adult. We found that the contribution of CICR to electric field stimulation (EFS)-evoked [Ca2+]i transients was greatest in SCG cells from normoxic fetuses and was abolished by LTH. The decline in CICR was associated with a reduction in sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) function in fetal SCG cells during LTH, reducing SER Ca2+ levels below the threshold needed for the coupling of Ca2+ influx and CICR. With respect to the maturation from the fetus to adult, the decrease in CICR may reflect both a reduction in the levels of ryanodine receptor isoforms 2 and 3 and SERCA function. In response to LTH and in contrast to the fetus, CICR function in adult SCG cells is maintained and may reflect alterations in other mechanisms that modulate the CICR process. As CICR is instrumental in the function of sympathetic neurons within the cerebrovasculature, the loss of this signaling mechanism in the fetus may have consequences for the adaptation to LTH in terms of fetal susceptibility to vascular insults.