Impact of breast density on the presenting features of malignancy.

PURPOSE: To determine the relationship between breast density, presenting features and molecular subtype of cancer, and surgical treatment received. METHODS: Retrospective review of a prospectively maintained database. Eligible patients had stage 1-3 cancer, were treated between 1/2005 and 6/2007, and had estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) measurements and films available for review. Density was classified at presentation as 1-4 using the Breast Imaging Reporting and Data System (BI-RADS) classification. RESULTS: 1,323 patients were included. Significant differences across the four density groups were present in age, race, multicentricity/focality, and presence of an extensive intraductal component (EIC). When density was combined into two groups, after adjustment for age, only an EIC and mammographically occult cancer were significantly more common in the dense groups. Extremely dense breasts (BI-RADS density 4) more commonly had luminal A tumors (p = 0.05), lobular cancers (p = 0.03), multicentricity (p = 0.02), and occult tumors (p < 0.0001). Greater density was associated with increased mastectomy use, with 61% of the extremely dense group having mastectomy versus 43% of those of lesser density (p = 0.01). CONCLUSIONS: Cancers in extremely dense breasts occur in younger women, are more often mammographically occult, and appear to be phenotypically different from those arising in other density groups. The more common use of mastectomy may be related to these features, although density itself is not a selection criterion for mastectomy.

The chemokine receptors CXCR4 and CCR7 are associated with tumor size and pathologic indicators of tumor aggressiveness in papillary thyroid carcinoma.

BACKGROUND: Functional chemokine receptors are expressed in many malignant tumors, including papillary thyroid carcinoma (PTC). These receptors promote tumor growth and metastasis in response to endogenous chemokines. The purpose of this study was to examine the expression of two chemokine receptors-CXCR4 and CCR7-in a series of PTCs. We hypothesized that CXCR4 and CCR7 would correlate with indicators of tumor aggressiveness, including tumor size, extrathyroidal extension (ETE), angiolymphatic invasion (ALI), and lymph node metastasis. METHODS: CXCR4 and CCR7, as well as their specific chemokine ligands (CXCL12 and CCL21, respectively), were assessed in 88 PTCs from 65 patients using a semiquantitative measure of immunohistochemical (IHC) staining intensity for each molecule. Staining intensity was compared with clinicopathologic features including patient age, gender, tumor size, multifocality, ETE, ALI, and lymph node metastasis. Differences in CXCR4 and CCR7 mRNA levels were sought in a subset of tumors using gene microarrays and quantitative RT-PCR. [ STATISTICS: t test, Mann-Whitney U test; P < .05]. RESULTS: High-intensity IHC staining for CXCR4 was associated with larger tumor size (P = .02), while PTCs exhibiting ETE, ALI, or lymph node metastasis showed higher-intensity IHC staining for CCR7 than those without (P = .01, .03, and .01, respectively). CCR7 mRNA levels were also higher in tumors with ALI (P = .04). CONCLUSION: Expression of CXCR4 and CCR7 by PTCs is associated with indicators of tumor aggressiveness, including tumor size, ETE, ALI, and lymph node metastasis. Further studies are necessary to define the mechanisms underlying this association and to determine its potential prognostic and therapeutic implications.

Sentinel node positivity rates with and without frozen section for breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is used to detect breast cancer axillary metastases. Some surgeons send the sentinel lymph node (SLN) for intraoperative frozen section (FS) to minimize delayed axillary dissections. There has been concern that FS may discard nodal tissue and thus underdiagnose small metastases. This study examines whether evaluation of SLN by FS increases the false-negative rate of SLNB. METHODS: A retrospective analysis of SLNB from 659 patients was conducted to determine the frequency of node positivity among SLNB subjected to both FS and permanent section (PS) versus PS alone. Statistical analysis was performed by the chi(2) square test, and a logistic regression model was applied to estimate the effect of final node positivity between the two groups. RESULTS: FS was performed in 327 patients and PS was performed in all 659 patients. Among patients undergoing both FS and PS (n = 327), the final node positivity rate was 33.0% compared with 19.6% among patients undergoing PS alone (n = 332). After adjustment for patient age, tumor diameter, grade, and hormone receptor status in a multivariate logistic regression model, there remained an increased likelihood of final node positivity for patients undergoing both procedures relative to PS alone (adjusted odds ratio, 2.1; 95% confidence interval, 1.3-3.6; P = .005). CONCLUSIONS: There was a higher rate of SLN positivity in specimens evaluated by both FS and PS. Therefore, evaluating SLN by FS does not underdiagnose small metastases nor produce a higher false-negative rate. Intraoperative FS offers the advantage of less delayed axillary dissections.

In vitro expression studies of a novel mutation delta299 in a patient affected with apparent mineralocorticoid excess.

Apparent mineralocorticoid excess syndrome (AME) is an autosomal recessive disorder that results in low renin hypertension and other characteristic clinical features. Typical patients present with severe hypertension, hypokalemia, and undetectable aldosterone. Most patients also have low birth weight, failure to thrive, and nephrocalcinosis. The 11betahydroxysteroid dehydrogenase type 2 (11betaHSD2) defect is documented by demonstrating a failure to convert cortisol to cortisone. Here, we report a patient with typical phenotypic features of AME who does not carry any of the previously described mutations in the HSD11B2 gene. This female patient from a consanguineous Pakistani family presented at age 9 yr. She had a low birth weight compared with her siblings and presented with hypertension (225/120 mm Hg), low plasma renin activity, hypokalemic metabolic alkalosis, suppressed aldosterone, and bilateral nephrocalcinosis. Echocardiogram did not reveal left ventricular hypertrophy, and baseline ophthalmological evaluation did not demonstrate hypertensive retinopathy. However, at age 12 yr, she developed mild to moderate hypertensive retinopathy. Biochemical analysis showed an elevated urinary cortisol to cortisone metabolites ratio (tetrahydrocortisol and 5alpha-tetrahydrocortisol/tetrahydrocortisone) of 28 (normal, 0.66-2.44). She had a cortisol secretion rate of 0.43 mg/d (normal, 5-25 mg/d). Sequence analysis of the HSD11B2 gene revealed a novel homozygous delta299 mutation in exon 5. In vitro expression in Chinese hamster ovary cells revealed that this mutation resulted in no activity.

Molecular profiling distinguishes papillary carcinoma from benign thyroid nodules.

Recently we identified a molecular basis for differentiating benign and malignant follicular thyroid tumors. The purpose of these studies was to determine whether molecular analysis can be used to differentiate papillary thyroid carcinomas from benign thyroid nodules. Gene expression patterns of 14 papillary thyroid carcinomas and 21 benign tumors were analyzed by oligonucleotide array analysis. The carcinomas included seven classical papillary thyroid carcinomas (PTC) and seven follicular variant of PTC (FVPTC), and the benign tumors included 14 follicular adenomas and seven hyperplastic nodules. A hierarchical clustering analysis was performed to examine the groups for potential differences. The combined PTC and FVPTC groups had a distinct gene expression profile compared with the benign lesions. The sensitivity for a diagnosis of carcinoma was 93%, with a 100% specificity (one FVPTC clustered with the benign nodules). Cancer gene profiles contained both known (Met and galectin-3) and previously unidentified genes. Gene profiling is a reliable means of distinguishing PTC, FVPTC, and benign tumors of the thyroid. These gene profiles may provide insight into the pathogenesis of papillary thyroid carcinoma and may ultimately enhance the preoperative diagnosis of thyroid nodules on a molecular basis.

Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two?

BACKGROUND: The clinical significance of papillary thyroid microcarcinoma (PTMC) tumors < or =1 cm is widely debated. The objective of this study was to compare conventional papillary thyroid carcinoma (PTC) (tumors >1 cm) to PTMC and assess for differences in tumor characteristics and patient outcome. METHODS: A retrospective chart review of patients with PTC or PTMC who were followed for a minimum of 3 years postoperatively and managed at a single academic institute was performed. RESULTS: Of 202 patients in the study, 66 (32.7%) had PTMC and 136 (67.3%) had conventional PTC. Patient and tumor characteristics including tumor multifocality, extrathyroidal extension, angiolymphatic invasion, and lymph node metastasis were similar between both groups. Twenty-one percent of the PTMC tumors were discovered incidentally. Patients with conventional PTC were significantly more likely to undergo treatment with radioactive iodine therapy compared to PTMC patients (86.4% vs. 66.7%, respectively, p < 0.003). Disease recurrence was observed in 40 patients and was not statistically different between the two groups; 11 (16.7%) in PTMC and 29 (21.3%) in conventional PTC, p = 0.57. Within the PTMC group, tumors of patients that recurred were significantly larger than those who remained disease free (8.1 mm vs. 6.4 mm, p < 0.05). None of the patients with incidental PTMC had disease recurrence. Angiolymphatic invasion was the only significant prognostic indicator of recurrence on multivariate analysis (p < 0.02). CONCLUSIONS: Nonincidental PTMC can have aggressive tumor features and disease recurrence similar to conventional PTC. These tumors should be managed like any other papillary thyroid malignancy.

Identification of borderline thyroid tumors by gene expression array analysis.

BACKGROUND: A subset of follicular lesions of the thyroid is encapsulated similar to follicular adenomas but with partial nuclear features suggestive of papillary thyroid carcinoma (PTC), raising the possibility of biologically borderline tumors. METHODS: Gene expression profiling and advanced significance analyses were performed on 50 histologically unequivocal benign and malignant tumors, and a list of 61 differentially expressed genes was generated. By using this 61-gene list, unsupervised hierarchical and K-means cluster analyses were performed on 40 additional tumors, including 15 histologically borderline tumors, 11 benign tumors, and 14 PTCs. RESULTS: Analysis revealed 3 distinct tumor groups-benign, malignant, and intermediate. Tumors in the intermediate group (n = 15) were mostly histologic borderline tumors and had an expression profile overlapping with the benign and malignant groups. Twenty-seven genes were expressed differentially between the benign and intermediate groups, including the cyclic AMP response element-binding protein/p300-interactivator with glutamic acid/aspartic acid-rich carboxy-terminal domain 1 or CITED1 gene and the fibroblast growth factor receptor 2 or FGFR2 gene. Fourteen genes were expressed differentially between the intermediate group and malignant tumors, notably overexpression of the met proto-oncogene and of the high-mobility group adenine/thymine-hook 2 or HMGA2 gene in malignancies. Mutations of the v-raf murine sarcoma viral oncogene homolog B1 or BRAF gene were identified in 4 of 14 malignant tumors but not in benign or intermediate tumors. Patients who had either histologically or molecularly borderline tumors did not have metastasis or recurrences. CONCLUSIONS: Gene expression profiling supported the finding that encapsulated thyroid follicular lesions with partial nuclear features of PTC are biologically borderline tumors that are distinct molecularly from benign and malignant tumors.

Do benign thyroid nodules have malignant potential? An evidence-based review.

BACKGROUND: Benign thyroid tumors account for most nodular thyroid disease. Determination of whether a thyroid nodule is benign or malignant is a major clinical dilemma and underlies the decision to proceed to surgery in many patients. Although the accuracy of thyroid nodule fine-needle aspiration (FNA) has reduced the need for surgery over the years, questions regarding how to follow FNA-designated benign nodules remain unresolved. This is true at least in part because of uncertainty over whether some benign nodules harbor malignant potential. METHODS: An evidence-based review of recent clinical, pathologic, and molecular data is presented. A summary of data and observations from our own experience is also provided. RESULTS: Review of our recent 10-year experience indicates that 2% of thyroid malignancies arise within a preexisting benign thyroid nodule. In addition, both cytologic and molecular tumor markers, including Gal-3, CITED1, HBME-1, Ras, RET/PTC, and PAX8/PPAR gamma, have been identified in some histopathologically classified benign nodules. Gene expression profiling suggests that follicular adenomas and Hürthle cell adenomas have similarities to both benign and malignant tumors, suggesting that some of these tumors are premalignant. In addition, 10% of surgically excised follicular tumors are encapsulated follicular lesions with nuclear atypia, which have been termed "well-differentiated tumors of uncertain malignant potential." The data available suggest that these tumors could be precursors to carcinoma. CONCLUSION: Some benign thyroid nodules have malignant potential. Further molecular testing of these tumors can shed light on the pathogenesis of early malignant transformation.

Extrathyroidal extension is not all equal: Implications of macroscopic versus microscopic extent in papillary thyroid carcinoma.

BACKGROUND: Extrathyroidal extension (ETE) is a risk factor for recurrence of papillary thyroid carcinoma (PTC). Although initial data supporting this was based on gross ETE noted at surgery, current treatment regimens group patients with microscopic ETE-identified only on histopathology-similarly to those with macroscopic (gross) ETE. This study was designed to assess the influence of microscopic ETE on disease recurrence. METHODS: Retrospective analysis of 212 patients undergoing thyroidectomy for PTC between 1995 and 2004 with minimum 3-year follow-up was conducted. RESULTS: Of 212 patients, 71 had ETE; 32% were macroscopic and 68% microscopic. Patient demographics, tumor variables, and adjuvant therapy were similar between both ETE groups. Recurrence rates were 52% for macroscopic ETE, 21% for microscopic ETE, and 13% without ETE. On multivariate analysis, patients with macroscopic ETE had a 6.4-fold increased relative risk of recurrence compared with patients with microscopic ETE (P < .02; 95% confidence interval, 1.6-25.9) and a significantly decreased disease-free survival (DFS). Furthermore, patients with microscopic ETE had neither a significantly increased risk of recurrence nor different DFS compared with patients without ETE. CONCLUSION: Macroscopic ETE has a higher incidence of disease recurrence than microscopic ETE, implying they should be considered separately when devising adjuvant treatment regimens. The significance of microscopic ETE is undetermined.

Effectiveness of a noninvasive digital infrared thermal imaging system in the detection of breast cancer.

BACKGROUND: Digital infrared thermal imaging (DITI) has resurfaced in this era of modernized computer technology. Its role in the detection of breast cancer is evaluated. METHODS: In this prospective clinical trial, 92 patients for whom a breast biopsy was recommended based on prior mammogram or ultrasound underwent DITI. Three scores were generated: an overall risk score in the screening mode, a clinical score based on patient information, and a third assessment by artificial neural network. RESULTS: Sixty of 94 biopsies were malignant and 34 were benign. DITI identified 58 of 60 malignancies, with 97% sensitivity, 44% specificity, and 82% negative predictive value depending on the mode used. Compared to an overall risk score of 0, a score of 3 or greater was significantly more likely to be associated with malignancy (30% vs 90%, P < .03). CONCLUSION: DITI is a valuable adjunct to mammography and ultrasound, especially in women with dense breast parenchyma.

Clinicopathologic features of papillary lesions on core needle biopsy of the breast predictive of malignancy.

BACKGROUND: The necessity for surgical excision of papillary lesions identified on percutaneous breast biopsy remains controversial. We reviewed data from patients with papillary lesions found on core needle biopsies to identify features associated with carcinoma. METHODS: A retrospective chart review was performed on patients with papillary lesions diagnosed from image-guided breast biopsies over a 10-year period. Patients had surgical excision or were followed-up radiographically for a 2-year minimum. RESULTS: Papillary lesions were identified in 154 core needle biopsies. Ninety-five lesions were diagnosed as either benign or atypical. Eighty-nine of these patients had surgical excisions of their lesions. Malignancy was discovered in 22 (25%) of these lesions. Only atypical lesions on biopsy were malignant (P < .005). Forty-six percent of patients age 65 or older were found to have cancer at surgical excision (P < .01). CONCLUSIONS: Papillary lesions found on core needle biopsy frequently harbor malignancy (25%). Atypia and age 65 or older are significant risk factors for malignancy.

Seminars: local and regional anesthesia for thyroid surgery.

BACKGROUND: Thyroid surgery is performed by a large number of surgeons with varying experience in thyroidectomy. The standard technique involves the use of general anesthesia, which provides patient comfort and virtually unlimited time to conduct the operation. Historically, thyroid surgery was conducted under local anesthesia by surgeons with significant expertise in the treatment of thyroid diseases. Over the past decade, there has been a renewed interest in the art of performing thyroidectomy under local/regional anesthesia in some specialized high volume endocrine surgery centers. METHODS: Here we review the indications and contraindications and technical considerations for performing thyroidectomy under local or regional anesthesia. RESULTS AND CONCLUSION: Local and regional anesthesia is safe and well tolerated for the majority of thyroid surgery.