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.

Evaluation of antioxidant network proteins as novel prognostic biomarkers for head and neck cancer patients.

OBJECTIVES: Recurrence rates for head and neck squamous cell carcinoma (HNSCC) approach 50% at 5 years. Current staging fails to identify patients with a worse prognosis who might benefit from intensified treatment, which warrants improved prognostic biomarkers. The purpose of this retrospective case study is to identify potential prognostic biomarkers in patients with HNSCC including APE1 (DNA repair/redox gene regulator), NRF2 and PPARGC1A (redox gene regulators), SOD3 and DCN (antioxidant proteins). MATERIALS AND METHODS: Differential protein expression between benign, carcinoma in situ (CIS), and invasive HNSCC tissue specimens from 77 patients was assessed using immunohistochemistry. Protein expression was analyzed with multivariate, pair-wise, and Kaplan-Meier survival analyses to identify potential prognostic biomarkers. Utilizing The Cancer Genome Atlas's transcriptome database, pair-wise and survival analysis was performed to identify potential prognostic biomarkers. RESULTS: APE1, NRF2, PPARGC1A, SOD3, and DCN expression in HNSCC in relation to, lymph node invasion, and patient survival were examined. Elevated APE1 protein expression in CIS corresponded with reduced survival (p = 0.0243). Increased APE1 gene expression in stage T4a HNSCC was associated with reduced patient survival (p < 0.015). Increased PPARGC1A in invasive tumor correlated with reduced survival (p = 0.0281). Patients with lymph node invasion at diagnosis had significantly increased APE1 protein in the primary sites (p < 0.05). Patients with poorly differentiated invasive tumors had reduced PPARGC1A in CIS proximal to the invasive tumor and had elevated DCN and SOD3 in proximal benign tissue (p < 0.05). CONCLUSIONS: The expression of APE1, DCN, and SOD3 is a potential prognostic signature that identifies patients with worsened survival.

Prognostic indicators and survival in salvage surgery for laryngeal cancer.

BACKGROUND: 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. METHODS: We conducted a retrospective review of patients who underwent salvage laryngectomy between 2006 and 2014. RESULTS: Seventy-eight patients were included in this study; PNI was diagnosed in 48 patients (61.54%) and LVI in 25 patients (32.05%). Median overall survival was 32 months; PNI was associated with decreased survival; and the unadjusted hazard ratio (HR) was 2.69 (P = .006). Cases of LVI trended toward a decreased survival; with an unadjusted HR of 1.74 (P = .076). On multivariate analysis, PNI, LVI, or both conferred decreased survival compared to having neither (P = .01). Extracapsular spread and nodal metastases significantly impacted survival, and positive margins trended toward significance. CONCLUSION: The presence of PNI, LVI, nodal disease, and extracapsular spread significantly affected survival in this cohort of patients with laryngeal cancer.

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.

Size of sentinel node tumor deposits and extent of axillary lymph node involvement: which breast cancer patients may benefit from less aggressive axillary dissections?

BACKGROUND: In most breast cancer series, nearly 30% to 40% of all patients are sentinel node positive; however, in a large proportion of these, the disease is limited to three or fewer positive nodes. On the basis of these observations, the object of this study is to identify a subset of patients who might benefit from a less aggressive axillary dissection, without compromising staging or local disease control. We reviewed known clinicopathologic variables associated with a higher risk for axillary metastasis in 467 patients who underwent sentinel node mapping at our institution. We then compared the incidence of these variables in patients with N1a versus N2-3 stage disease. RESULTS: Although the presence of lymphvascular invasion in the primary tumor and extracapsular extension of tumor in the sentinel node were statistically significantly different between N1a and N2-3 patients (P < .025 and P < .01, respectively), the variable that most reliably separated N1a from N2-3 patients was the size of the tumor deposits in the sentinel node (P < .001). All patients with sentinel node tumor deposits

Ultrasound-guided fine-needle aspiration of clinically negative lymph nodes versus sentinel node mapping in patients at high risk for axillary metastasis.

BACKGROUND: Sonographically 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. METHODS: Radiographic, 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. RESULTS: According 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. CONCLUSIONS: This 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.

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.

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). kappa values for all four observers were 0.48 for CV (fair agreement) and 0.63 for TP (substantial). Pairwise kappa 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.