Yolanda M. Brill

Ultrasound-Guided Fine-Needle Aspiration of Clinically Negative Lymph Nodes Versus Sentinel Node Mapping in Patients at High Risk for Axillary Metastasis

BackgroundSonographically directed fine-needle aspiration is a less invasive and less costly alternative to sentinel node (SN) mapping in breast cancer patients at high risk for metastatic disease but with clinically negative axillae.MethodsRadiographic, cytological, and histological diagnostic data on breast primary tumors from 114 consecutive SN candidates were prospectively assessed for clinicopathologic variables associated with an increased incidence of axillary metastases. Patients in whom these variables were identified underwent sonographic examination of their axillae followed by fine-needle aspiration when abnormal nodes were detected. SN mapping was performed in patients with normal axillary sonogram results or negative cytological results. Patients with positive cytological results proceeded to complete axillary dissection. Final axillary histological outcomes from patients not meeting the high-risk criteria were recorded. Additionally, a cost analysis was performed in which the costs of ultrasonography and ultrasound-guided fine-needle aspiration of the axilla were compared with those of SN mapping.ResultsAccording to our selection criteria, a third of the patients with clinically negative axillae (37 of 114; 32%) were considered at high risk for axillary metastases. Fifty-nine percent of these patients (22 of 37) had metastatic disease on final histological analysis. Forty percent (15 of 37) of high-risk patients were spared SN mapping, with a reduction in health care costs of 20% in this patient population. Eighty-seven percent of patients not meeting high-risk criteria were SN negative.ConclusionsThis study suggests that in patients at increased risk for axillary metastases, the use of sonographic evaluation of the axilla in combination with fine-needle aspiration is not only clinically justified, but also cost-effective.

Distinct lymph nodal sonographic characteristics in breast cancer patients at high risk for axillary metastases correlate with the final axillary stage

The purpose of this study was to assess the clinical relevance, limitations and most common findings of axillary ultrasound and subsequent image-guided aspiration cytology in clinically node-negative breast cancer patients who are at high risk for axillary metastasis. Following institutional review board approval and Health Insurance Portability and Accountability Act (HIPAA) compliance, sonographic axillary surveys from 112 patients considered at high risk for axillary metastases were reviewed retrospectively for the following abnormal features: asymmetric cortical thickening/lobulations; loss or compression of the hyperechoic medullary region; absence of fatty hilum; abnormal lymph node shape; hypoechoic cortex; admixture of normal and abnormal appearing nodes; and increased peripheral blood flow. Patients with either normal or abnormal ultrasound exams, but negative cytology, underwent sentinel node mapping. Patients with abnormal ultrasound and positive cytology proceeded to complete axillary dissection. The number of positive nodes, the size of tumour deposits and the histological pattern of metastatic disease on the positive nodes were then correlated and compared with their corresponding sonographic abnormalities. Abnormalities related to the lymph node cortex were indicative of N1a disease. Features such as loss or compression of the hyperechoic medullary region, absence of fatty hilum, abnormal lymph node shape and increased peripheral blood flow were predictors of N2-3 disease. In conclusion, nodal sonographic characteristics of patients at high risk for metastases are useful predictors of tumour burden in the axilla. When combined with the results from aspiration cytology, these findings could modify the surgical approach to the axilla, eliminating the need for sentinel node mapping in a significant proportion of patients.

Sentinel node micrometastasis in breast carcinoma may not be an indication for complete axillary dissection.

The decision whether to proceed with complete axillary node dissection based on sentinel node status is clear for patients with negative or macrometastatic disease. However, the course of action based on sentinel node micrometastasis remains controversial. We reviewed 358 cases from 6/1999 to 7/2003. All sentinel nodes were evaluated at three levels by frozen section, touch preparation, and scrape preparation. Micrometastasis was defined as tumor deposits between 0.2 and 2 mm. Size, grade, and lymphvascular invasion of the primary tumor, as well as number, status, size of metastatic disease, and presence of extranodal capsular extension of sentinel and nonsentinel nodes were recorded. Of the 358 cases, 89 had positive sentinel nodes, 29 of which represented micrometastases. Only one (3%) of the 29 cases contained a nonsentinel node with macrometastasis. In 60 of the 89 cases sentinel nodes contained macrometastases. Of these, 38 cases (63%) had metastatic tumor in nonsentinel nodes. Intraoperative consult was performed in 53 of the 89 cases with positive sentinel nodes. Only 1 of the 19 (5%) intraoperative consult cases with micrometastatic sentinel nodes had positive nonsentinel nodes, while 21 of 34 (62%) of macrometastatic sentinel nodes at intraoperative consult had tumor in nonsentinel nodes. No single variable studied discriminated between micro- vs macrometastatic disease. At intraoperative consult, macrometastatic disease was present in all three diagnostic preparations, while diagnostic material in micrometastatic sentinel nodes was usually present in only one modality. This analysis suggests that the risk of finding tumor in nonsentinel nodes differs significantly between cases with micro (3%)- vs macro (63%)-metastatic disease in sentinel nodes. This holds true for cases assessed by intraoperative consult. Considering the known morbidity of complete axillary dissection, assessments of risk vs benefit of undertaking this procedure should be performed on a case-by-case basis in patients with sentinel node micrometastases.

The Critical Role of Axillary Ultrasound and Aspiration Biopsy in the Management of Breast Cancer Patients with Clinically Negative Axilla

BackgroundSonographic evaluation of the axilla can predict node status in a significant proportion of clinically node-negative patients. This review focuses on the value of ultrasound followed by ultrasound-guided cytology in assessing the need for sentinel node mapping and conservative versus complete axillary dissections.DesignBreast primaries from 168 sentinel node candidates were prospectively assessed for clinicopathologic variables associated with increased incidence of axillary metastases. Patients were classified accordingly, and those at a higher risk underwent ultrasound of their axillae, followed by aspiration biopsy if needed. Sentinel node mapping was performed in all low-risk patients, and in high-risk patients with normal axillary ultrasounds or negative cytology. Final axillary status was compared in terms of nodal stage, number of positive nodes, and size of metastasis.Results112 patients were at high risk for nodal disease (67%), with a statistically significant lower probability for remaining node-negative and a statistical significantly higher risk for having more than one positive node. All patients with more than three positive nodes were detected by ultrasound-guided cytology. High-risk patients with final positive axillae missed by ultrasound or ultrasound guided cytology had tumor deposits measuring ≤5 mm.ConclusionExtent of axillary dissections can be decided based on the risk for axillary metastases: sentinel node mapping for low-risk patients; less-aggressive axillary dissections for high-risk patients with negative ultrasound and/or negative cytology; and a standard dissection for high-risk patients with positive cytology.

Nuclear protein in testis midline carcinomas: a lethal and underrecognized entity.

A 54-year-old woman presented with a nasal mass. Biopsy demonstrated undifferentiated tumor cells with extensive apoptosis and necrosis. Chromosome analysis identified a 46,XX,t(15;19)(q13;p13.1) pattern. Nuclear protein in testis (NUT) immunohistochemistry and fluorescence in situ hybridization confirmed NUT rearrangement. A Ewing sarcoma-based chemotherapy regimen and concurrent irradiation obtained a dramatic response; however, the patient died of her disease less than 7 months after initial diagnosis. NUT midline carcinomas are rare, aggressive tumors defined by rearrangement of the NUT gene on 15q14. A solitary translocation involving 15q14 is usually the sole chromosomal abnormality in these carcinomas. Immunohistochemical expression of NUT in the nuclei of non-germ cell tumors is theoretically diagnostic. More widespread use of a newly available NUT immunohistochemical stain will facilitate the diagnosis of NUT rearranged carcinomas. From the growing numbers of identified cases, effective targeted therapies can be developed.

Reproducibility of subclassification of squamous intraepithelial lesions: conventional versus ThinPrep paps.

Objective. Liquid-based cytologic methods are increasingly used, and classification of squamous intraepithelial lesions (SIL) affects patient management. This study compared interobserver reproducibility in SIL subclassification on conventional (CV) and ThinPrep (TP) cytologic specimens. Materials and Methods. Four reviewers independently subclassified SIL on 69 CV and 60 TP Paps. Specimens were retrieved by computer search of biopsy-confirmed SIL cases. A consensus interpretation of low-grade SIL (LSIL) or high-grade SIL (HSIL) was assigned when three or four observers agreed. Results. All four observers agreed in 40 of 69 CV with consensus reached in 56 of 69 CV Paps (81%; 20 LSIL, 36 HSIL). For TP Paps, 38 of 60 had 100% agreement, with consensus reached in 56 of 60 TP Paps (93%; 28 LSIL, 26 HSIL, 2 SIL, difficult to grade). &kgr; values for all four observers were 0.48 for CV (fair agreement) and 0.63 for TP (substantial). Pairwise &kgr; values ranged from 0.44 to 0.60 for CV and 0.54 to 0.76 for TP. Most of the nonconsensus cases included SIL, difficult to grade interpretations; in several, the original cytologic or biopsy SIL classification, or both, was also indeterminate, or cytologic and biopsy results did not correlate exactly. High-grade biopsies followed 15% of LSIL CV and 36% of LSIL TP. Conclusions. Interobserver reproducibility in SIL subclassification may be better on TP Paps; however, both CV and TP have indeterminate lesions with low interobserver agreement. The TP specimens did not show improved correlation with histologic analysis, and specimens with consensus do not always have correlating biopsy findings.

p16INK4a Status and Response to Induction Low-Dose Fractionated Radiation in Advanced Head and Neck Cancer.

Objective: To evaluate the impact of p16INK4a (p16) expression on clinical efficacy of induction low-dose fractionated radiation therapy (LDFRT) with concurrent chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Study Design: Historical cohort study. Setting: Tertiary medical center. Methods: A total of 66 Patients with locally advanced SCCHN were enrolled in 2 clinical trials using paclitaxel, carboplatin, and concurrent LDFRT induction therapy. Patients were evaluated for response to induction by a multidisciplinary team and then were given definitive treatment. Adequate tissue samples from the pretreatment biopsies of 42 individuals were identified and analyzed for p16 expression. Expression was correlated with clinical outcomes. Results: Of 42 tumors, 15 (35.7%) were positive for p16. Patients with p16-positive tumors had improved response to induction, but this was not statistically significant (P = .06). Five-year overall survival was 80% in p16-positive patients and 58% in p16-negative patients (P = .025). Conclusions: p16 Expression affects treatment response in patients treated with induction LDFRT with concurrent chemotherapy. This is similar to results reported for standard induction chemotherapy.

Soluble VEGFR-2 Expression in Head and Neck Malignant Tumors

Objective: 1) Define the spatial pattern of expression of soluble vascular endothelial growth factor receptor 2 (sVEGFR-2), a recently discovered receptor that has an important role in tumor lymphangiogenesis, in head and neck malignant tumors. 2) Examine the relationship between sVEGFR-2 expression and lymphatic vessel density in head and neck malignant tumors. Method: One hundred ten paraffin-embedded tissue samples from patients with malignant tumors were stained using immunohistochemistry for sVEGFR-2 and podoplanin, a marker for lymphatic vessels. Tissues studied included: squamous cell carcinoma of the larynx (61), oral cavity (16), oropharynx (20), hypopharynx (5), nasopharynx (1). Papillary (4), medullary (2), and follicular (1) thyroid cancers were also examined. Results: sVEGFR-2 expression was identified in all squamous cell carcinomas of the head and neck. Expression was specific to the endothelial cells in blood vessels of both malignant tissue as well as adjacent normal tissues. sVEGFR-2 was not expressed in lymphatic vessels. This secreted protein was also expressed in tissue stroma. Decreased expression of sVEGFR-2 was correlated with increased lymphatic vessel density in tumors, as measured by podoplanin expression. sVEGFR-2 was minimally expressed in normal thyroid tissue but was abundant in the basement membrane of papillary thyroid cancer cells. Conclusion: We have provided the first evidence of sVEGFR-2 expression in head and neck malignant tumors. Its expression correlates with lymphatic vessel density in head and neck malignant tumors and ongoing studies will reveal the precise function of sVEGFR-2 in nodal metastasis and disease progression.

Prognostic indicators and survival in salvage surgery for laryngeal cancer

Perineural invasion (PNI) and lymphovascular invasion (LVI) are known to be poor prognostic indicators in primary surgery. The purpose of this study was to determine their impact on survival in the setting of salvage laryngectomy.

Abstract 4142: Regulation of tumor suppressor decorin by APE1 in head and neck squamous cell carcinoma

Oral cancers have a high rate of recurrence, and a tendency to develop treatment resistance. From 2009 to 2013, Kentucky had a disproportionately higher incidence of invasive oral cancers and resultant higher mortality compared to the national average (SEER & NPCR, Kentucky Cancer Registry). Apurinic/Apyrimidinic endonuclease (APE1) is a key protein in DNA repair, and an important transcriptional regulator. Gene array analysis in pMEFs expressing wild-type APE1 and extremely low levels of APE1 showed an eight-fold reduction of tumor suppressor decorin (DCN), with wild-type APE1. Decorin is a known tumor suppressor and extracellular matrix protein, which can suppress tumor proliferation, migration and angiogenesis. Tumors with decreased decorin are associated with increased mortality. These studies aim to elucidate APE1’s role in decorin regulation in oral cancer and identify biomarkers, which may aid in diagnosis, treatment, or predicting prognosis. Immunohistochemistry studies of head and neck squamous cell carcinoma from Kentuckians were analyzed aided by Aperio’s high resolution scanning capabilities, and software. Analysis showed a significant decrease in decorin in both tumor and carcinoma in situ compared to benign tissue. Whereas, APE1 was significantly increased in tumors. Additionally there was a significant negative correlation between APE1 and decorin total protein in carcinoma in situ. This data supports that increased APE1 may deplete decorin. Superoxide Dismutase 3, which is important in detoxifying extracellular ROS, was also significantly decreased in tumor and in carcinoma in situ. This along with previous research showing increased ROS in the tumor microenvironment and APE1 activation by ROS may explain the origination of decorin suppression. We hypothesize that the overexpression of APE1 in early stages of oral cancer leads to diminished decorin translation, which may drive cancer progression and increase mortality. Better understanding how APE1 influences tumor suppressors may eventually aid in development of therapeutics that would increase patient survival. Citation Format: Christina A. Wicker, Timothy L. Scott, Rangaswamy Suganya, Susan M. Arnold, Yolanda M. Brill, Craig M. Horbinski, Dana Napier, Joseph Valentino, Mahesh R. Kudrimoti, Guoqiang Yu, Tadahide Izumi. Regulation of tumor suppressor decorin by APE1 in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4142. doi:10.1158/1538-7445.AM2017-4142