Cost-effectiveness of active surveillance versus hemithyroidectomy for micropapillary thyroid cancer.

BACKGROUND: The management of low-risk micropapillary thyroid cancer <1 cm in size has come into question, because recent data have shown that nonoperative active surveillance of micropapillary thyroid cancer is a viable alternative to hemithyroidectomy. We conducted a cost-effectiveness analysis to help decide between observation versus operation. METHODS: We constructed Markov models for active surveillance and hemithyroidectomy. The reference case was a 40-year-old patient with recently diagnosed, low-risk micropapillary thyroid cancer. Costs and health utilities were determined using extensive literature review. The willingness-to-pay threshold was set at $100,000/quality-adjusted life year gained. Deterministic and probabilistic sensitivity analyses were performed to account for uncertainty in the model's variables. RESULTS: Active surveillance is dominant (less expensive and more quality-adjusted life years) for a health utility <0.01 below that for disease-free, posthemithyroidectomy state, or for a remaining life expectancy of <2 years. For a utility difference ≥0.02, the incremental cost-effectiveness ratio (the ratio of the difference in costs between active surveillance and hemithyroidectomy divided by the difference in quality-adjusted life years) for hemithyroidectomy is <$100,000/QALY gained and thus cost-effective. For a utility difference of 0.11-the reference case scenario-the incremental cost-effectiveness ratio for hemithyroidectomy is $4,437/quality-adjusted life year gained. CONCLUSION: The cost-effectiveness of hemithyroidectomy is highly dependent on patient disutility associated with active surveillance. In patients who would associate nonoperative management with at least a modest decrement in quality of life, hemithyroidectomy is cost-effective.

Frequency of High-Risk Characteristics Requiring Total Thyroidectomy for 1-4 cm Well-Differentiated Thyroid Cancer.

BACKGROUND: The extent of thyroidectomy for low-risk well-differentiated thyroid cancer (WDTC) remains controversial. Historically, total thyroidectomy (TT) has been recommended for WDTC ≥1 cm in size. However, recent National Comprehensive Cancer Network and American Thyroid Association guidelines recognize unilateral thyroid lobectomy as a viable alternative for 1-4 cm cancers due to their otherwise favorable prognosis, with TT remaining the preferred option for tumors with unfavorable pathological characteristics. This study sought to determine how often a completion TT would be recommended based on these guidelines if lobectomy was initially performed in patients with 1-4 cm WDTC without preoperatively known risk factors. METHODS: Patients who underwent thyroidectomy for 1-4 cm WDTC (January 2000 to January 2010) were retrospectively reviewed. Patients with preoperatively known high-risk characteristics, including gross extrathyroidal extension (ETE) on preoperative imaging, clinically apparent lymph node metastases, distant metastases, history of radiation, and positive family history, were excluded. The pathology specimens from the cancer-containing lobe were evaluated for features that would lead to a recommendation for TT based on current guidelines, including aggressive histology, vascular invasion, microscopic ETE, positive margins, and any positive lymph nodes within the specimen. RESULTS: Of 1000 consecutive patients operated for WDTC, 287 would have been eligible for lobectomy as the initial operation. The mean age in this cohort was 45 years, and 80% were women. Aggressive tall-cell variant histology was found in one patient (0.5%), angio-invasion in 34 (12%), ETE in 48 (17%), positive margins in 51 (18%), and positive lymph nodes in 49 (18%) patients. Completion TT would have been recommended in 122/287 (43%) patients. Even in those with 1-2 cm cancers, completion TT would have been recommended in 52/143 (36%) patients. CONCLUSIONS: Nearly half of the patients with 1-4 cm WDTC who are eligible for lobectomy under current guidelines would require completion TT based on pathological characteristics of the initial lobe. Surgeons, endocrinologists, and patients need to balance the relative benefits, risks, and costs of initial TT versus the possible need for reoperative completion TT.

The underestimated risk of cancer in patients with multinodular goiters after a benign fine needle aspiration.

IMPORTANCE: Ultrasound-guided fine needle aspiration (FNA) is an excellent tool for evaluating patients with solitary thyroid nodules, with a false-negative malignancy rate of <3%. The utility of FNA in patients with a cervical multinodular goiter (MNG) is unknown, because biopsy and surveillance of thyroids with numerous nodules may be impractical. OBJECTIVE: To evaluate the incidence and risk factors for unsuspected thyroid cancer on final pathology in patients with a non-functional, cervical MNG who had a benign preoperative FNA and underwent thyroidectomy. DESIGN, SETTING AND PARTICIPANTS: Retrospective review of patients with non-functional, cervical MNG at a high-volume tertiary referral center between 2005 and 2012. MAIN OUTCOME MEASURE(S): Incidence of thyroid cancer on surgical pathology. RESULTS: Of the 134 patients included in the study, 31 (23.1%) were found to have thyroid cancer on final pathology. Twenty-one (15.7%) patients had a microscopic papillary cancer (<1 cm) and 10 (7.5%) patients had other forms of thyroid cancer [five follicular, four papillary (>1 cm), and one patient with a papillary and follicular cancer]. On univariate analysis, male gender had a near-significant association with non-micropapillary thyroid cancer (p = 0.06). On multivariate analysis, male gender (OR = 10.2, 95% CI 1.35-76.8) and FNA cytology not reviewed at our institution (OR = 6.0, 95% CI 1.2-30) were independently associated with non-micropapillary thyroid cancer. CONCLUSIONS AND RELEVANCE: The incidence of thyroid cancer in patients with MNG and benign FNA is significant. Men and patients in whom the FNA cytology is not reviewed by an experienced cytopathologist may be at an increased risk for an undetected thyroid cancer.

Unanticipated thyroid cancer in patients with substernal goiters: are we underestimating the risk?

BACKGROUND: The rate of unexpected thyroid cancers found at the time of thyroidectomy is thought to be similar in patients with cervical and substernal multinodular goiters (MNGs). METHODS: The objective of this study was to compare the prevalence of undiagnosed cancer found in patients undergoing a thyroidectomy for a cervical or substernal MNG. We conducted a review of patients with a preoperative diagnosis of an MNG (both cervical and substernal) at a tertiary referral center between 2005 and 2012. RESULTS: We identified 538 patients who underwent thyroidectomy for an MNG (144 with substernal MNGs and 394 with cervical MNGs). Patients with substernal MNGs were older (59.6 vs. 52.3; p < 0.001), more likely to be men (34 vs. 11.1 %; p < 0.001), and less likely to have a history of radiation exposure to the neck (2.1 vs. 12.4 %; p < 0.001). Thyroid cancer (>1 cm) was found in 13.7 % of substernal MNG specimens and in 6.3 % of cervical MNG specimens (p = 0.003). On multivariate analysis, substernal location [odds ratio (OR) = 2.360; confidence interval (CI), 1.201-4.638] was the only variable independently associated with an unexpected thyroid cancer on surgical pathology. CONCLUSION: The rate of postoperatively discovered thyroid cancer is significant in patients with substernal MNGs and is increased when compared to patients with cervical MNGs. Surgeons should counsel their patients regarding the possibility of this unexpected result.

Utility of serum thyroglobulin measurements after prophylactic thyroidectomy in patients with hereditary medullary thyroid cancer.

INTRODUCTION: Prophylactic thyroidectomy can be curative for patients with hereditary medullary thyroid cancer (MTC) caused by RET proto-oncogene mutations. Calcitonin is a sensitive tumor marker used to follow patients. We suggest that thyroglobulin (Tg) levels should also be monitored postoperatively in these patients. METHODS: We reviewed patients with RET mutations who underwent prophylactic thyroidectomy between 1981 and 2011 at an academic endocrine surgery center. Patients were excluded if they had no postoperative Tg levels recorded. RESULTS: Of the 22 patients who underwent prophylactic thyroidectomy, 14 were included in the final analysis. The average age at thyroidectomy was 9.8 years (range, 4-29). Tg levels were detectable 1.5 months to 31 years postoperatively in 11 patients (79%), all of whom were <15 years old at thyroidectomy. Median thyroid-stimulating hormone (TSH) was 2.5 mIU/L and 13.4 mIU/L in patients with undetectable and detectable Tg, respectively. Of those with detectable Tg, 5 had cervical ultrasonographic examination: Two showed no residual tissue in the thyroid bed, and 3 showed remnant thyroid tissue. CONCLUSION: Tg levels can identify patients with remnant thyroid tissue after prophylactic thyroidectomy. Ultrasonography can determine whether thyroid tissue remains posterolaterally that is at risk of MTC recurrence. Maintaining normal TSH may prevent growth of remaining thyroid follicular cells.

Adrenalectomy outcomes are superior with the participation of residents and fellows.

BACKGROUND: Adrenalectomy is a complex procedure performed in many settings, with and without residents and fellows. Patients often ask, "Will trainees be participating in my operation?" and seek reassurance that their care will not be adversely affected. The purpose of this study was to determine the association between trainee participation and adrenalectomy perioperative outcomes. STUDY DESIGN: We performed a cohort study of patients who underwent adrenalectomy from the 2005 to 2011 American College of Surgeons NSQIP database. Trainee participation was classified as none, resident, or fellow, based on postgraduate year of the assisting surgeon. Associations between trainee participation and outcomes were determined via multivariate linear and logistic regression. RESULTS: Of 3,694 adrenalectomies, 732 (19.8%) were performed by an attending surgeon with no trainee, 2,315 (62.7%) involved a resident, and 647 (17.5%) involved a fellow. The participation of fellows was associated with fewer serious complications (7.9% with no trainee, 6.0% with residents, and 2.8% with fellows; p < 0.001). In a multivariate model, the odds of serious 30-day morbidity were lower when attending surgeons operated with residents (odds ratio = 0.63; 95% CI, 0.45-0.89). Fellow participation was associated with significantly lower odds of overall (odds ratio = 0.51; 95% CI, 0.32-0.82) and serious (odds ratio = 0.31; 95% CI, 0.17-0.57) morbidity. There was no significant association between trainee participation and 30-day mortality. CONCLUSIONS: In this analysis of multi-institutional data, the participation of residents and fellows was associated with decreased odds of perioperative adrenalectomy complications. Attending surgeons performing adrenalectomies with trainee assistance should reassure patients of the equivalent or superior care they are receiving.

Ultrasound-guided methylene blue dye injection for parathyroid localization in the reoperative neck.

BACKGROUND: The goal of this study was to review a single institution's experience using intraoperative ultrasound-guided (ioUSG) methylene blue dye injection for the localization and removal of enlarged parathyroid glands in patients with primary hyperparathyroidism and a history of previous neck surgery. METHODS: We performed a retrospective review of nine consecutive patients who underwent reoperative parathyroidectomy using ioUSG methylene blue dye injection. RESULTS: All patients had successful resolution of their hyperparathyroidism, with at least a 50 % decrease in intraoperative parathyroid hormone level after resection. One patient had transient recurrent laryngeal nerve paresis. There were no permanent recurrent laryngeal nerve injuries or cases of permanent hypoparathyroidism. CONCLUSIONS: Blue dye injection is a safe and effective method of localizing diseased parathyroid glands in the reoperative neck.

Controversies in familial thyroid cancer 2014.

Thyroid cancer is the sixth most common cancer in women, and the majority of patients with thyroid cancer has sporadic disease. However, about 25% of patients with medullary thyroid cancer and 5% with papillary thyroid cancer have familial tumors. Currently, there are numerous controversies regarding the mode of inheritance, tumor behavior, extent of surgical resection for optimal results, coexisting thyroid pathology, risk of other cancers, and extent of postoperative treatment of patients with familial thyroid cancer. This review aimed to give insight to surgeons on this interesting topic.

New evidence about thyroid cancer prevalence: prevalence of thyroid cancer in younger and middle-aged Japanese population.

We have made a cross-sectional investigation of men in the Japanese military for the presence of thyroid abnormalities and thyroid cancer to document the prevalence of thyroid disease in these persons. Six thousand, four hundred and twenty-two Japanese military men and women were screened for thyroid disease by history, physical examination and ultrasound examination. Among them, 6,182 were men 50 years of age, 47 were women 50 years of age, and 149 were men 40 years of age and 44 were women 40 years of age. Among the 50 years old men, thyroid nodules were found in 924 men (14.9%): Nineteen individuals (0.31%) had thyroid cancers ranging from 1 mm to 30 mm in diameter (12.5 mm in mean), pathological TNM staging revealed 7 cases of stage I, 2 cases of stage II and 9 cases of stage III. There was a significant increase in thyroid nodules in 50 years old men compared to that in 40 year old men, but there was no significant difference between men and women (p>0.05). Our data document that the detection rate of thyroid cancer in 50 years old men was 0.31%, and the rate of thyroid nodules increased with age in men, but the frequency of thyroid nodules were similar in men and women of the same age.

Practice patterns and job satisfaction in fellowship-trained endocrine surgeons.

BACKGROUND: Debates about the difficult job market for young endocrine surgeons are ongoing. This study aimed to analyze the practice patterns and work-related satisfaction levels of recently trained endocrine surgeons. METHODS: An anonymous survey was utilized. Participants were divided into 3 groups: "Young" (<3 years in practice), "middle" (3-5 years), and "older" (>5 years). RESULTS: Fifty-six of 78 surgeons (72%) responded to the survey. Time in practice ranged from 1 to 9 years (mean, 3.9 ± 0.28). Forty-five (80%) described their practice as academic. Participants performed 244.1 ± 17.8 operations within the last year; 75.4 ± 3.3% were endocrine cases. More surgeons in the "young" group have academic practices (92%) and joined established endocrine surgery groups (54%) versus older surgeons (67% and 42%; P = .05). Of surgeons in the "young" group, 4% started their own practice versus 33% in the "older" group (P = .04). Level of satisfaction with financial compensation (3.2 on a 4-point scale versus 2.9) and lifestyle (3.6 vs 3.1) was also higher in the younger group (P = .009). CONCLUSION: Despite widespread speculation about scarcity of academic jobs after fellowship, recently trained endocrine surgeons are more likely to practice in academic settings and join established endocrine surgery practices when compared with older surgeons. Overall satisfaction level is higher among recently trained surgeons.

Fluorodeoxyglucose-positron emission tomography scan-positive recurrent papillary thyroid cancer and the prognosis and implications for surgical management.

BACKGROUND: To compare outcomes for patients with recurrent or persistent papillary thyroid cancer (PTC) who had metastatic tumors that were fluorodeoxyglucose-positron emission tomography (FDG-PET) positive or negative, and to determine whether the FDG-PET scan findings changed the outcome of medical and surgical management. METHODS: From a prospective thyroid cancer database, we retrospectively identified patients with recurrent or persistent PTC and reviewed data on demographics, initial stage, location and extent of persistent or recurrent disease, clinical management, disease-free survival and outcome. We further identified subsets of patients who had an FDG-PET scan or an FDG-PET/CT scan and whole-body radioactive iodine scans and categorized them by whether they had one or more FDG-PET-avid (PET-positive) lesions or PET-negative lesions. The medical and surgical treatments and outcome of these patients were compared. RESULTS: Between 1984 and 2008, 41 of 141 patients who had recurrent or persistent PTC underwent FDG-PET (n = 11) or FDG-PET/CT scans (n = 30); 22 patients (54%) had one or more PET-positive lesion(s), 17 (41%) had PET-negative lesions, and two had indeterminate lesions. Most PET-positive lesions were located in the neck (55%). Patients who had a PET-positive lesion had a significantly higher TNM stage (P = 0.01), higher age (P = 0.03), and higher thyroglobulin (P = 0.024). Only patients who had PET-positive lesions died (5/22 vs. 0/17 for PET-negative lesions; P = 0.04). In two of the seven patients who underwent surgical resection of their PET-positive lesions, loco-regional control was obtained without evidence of residual disease. CONCLUSION: Patients with recurrent or persistent PTC and FDG-PET-positive lesions have a worse prognosis. In some patients loco-regional control can be obtained without evidence of residual disease by reoperation if the lesion is localized in the neck or mediastinum.

Successful localization of recurrent thyroid cancer in reoperative neck surgery using ultrasound-guided methylene blue dye injection.

BACKGROUND: Reoperation in the neck can be challenging and is associated with increased complication rates and operative times. Here we analyze our methylene blue dye injection method to localize reoperative neck pathology in patients with thyroid cancer and lymph node metastases. STUDY DESIGN: We retrospectively reviewed the records of all patients at a single university tertiary care center who had reoperative neck surgery for recurrent thyroid cancer between 2004 and 2009, and who also underwent intraoperative methylene blue dye injection. Outcomes measured were efficacy and safety of the injection technique as well as complication rates. RESULTS: Fifty-three operations were performed in 44 patients (average age, 51.2 years [range 16 to 83 years]). Ninety-one percent (48 of 53) of the operations resulted in successful resection of recurrent disease. Of these, 96% (46 of 48) were guided successfully by blue dye injection. Thyroglobulin became undetectable in 42% (11 of 26) of patients. Neck pathology included the following thyroid cancers: papillary (48 of 53), follicular (2 of 53), medullary (2 of 53), and tall cell variant (1 of 53). Among these patients, there were a total of 26 central and 38 lateral neck dissections. The average number of previous neck dissections was 2 (range 1 to 5). The mean intraoperative ultrasound/injection time was 21.3 min (n = 13). Median operative time was 90 minutes (range 40 to 300 minutes). Complications included 2 permanent vocal cord paralyses, 1 instance of permanent hypocalcemia, and 3 instances of temporary hypocalcemia. There were no complications related to the dye injection. CONCLUSIONS: Intraoperative, ultrasound-guided, methylene blue dye injection is a safe and effective technique. It facilitates tumor localization and removal especially in patients requiring reoperative neck surgery.

Impact of race on intraoperative parathyroid hormone kinetics: an analysis of 910 patients undergoing parathyroidectomy for primary hyperparathyroidism.

HYPOTHESIS African American patients exhibit different intraoperative parathyroid hormone (IOPTH) profiles than non-African American patients. DESIGN Retrospective review. SETTING University medical center. PATIENTS Nine hundred ten patients who underwent parathyroidectomy for primary hyperparathyroidism between July 2005 and August 2010. INTERVENTIONS All patients underwent preoperative imaging with ultrasonography and sestamibi; operative exploration; and IOPTH measurement at 2 points preexcision and 5 and 10 minutes postexcision. MAIN OUTCOME MEASURES Preexcision and postexcision IOPTH measurements. RESULTS Of the 910 patients, 734 self-reported their race as white (81%); 91, Latino/other (10%); 56, Asian (6%); and 28, African American (3%). African American patients had significantly higher initial preexcision IOPTH levels compared with white patients (348 vs 202 pg/mL; P = .048) and significantly higher 5-minute postexcision IOPTH levels (151 vs 80 pg/mL; P = .01). The 10-minute postexcision IOPTH levels were similar between the 2 groups (52 vs 50 pg/mL). A similar percentage of white and African American patients had a 50% drop in IOPTH level at 10 minutes postexcision. No differences in IOPTH kinetics were observed in the other racial groups examined. CONCLUSIONS African American patients with primary hyperparathyroidism exhibit significantly higher preincision and 5-minute postexcision IOPTH values when compared with white patients. The 10-minute postexcision IOPTH values did not differ between races. The altered IOPTH kinetics identified in African American patients may reflect the severity of biochemical disease but may also be related to genetically predetermined differences in parathyroid hormone metabolism.

Neuroendocrine tumors.

Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.

A population-based prospective cohort study of complications after thyroidectomy in the elderly.

CONTEXT: Data on the risk of postthyroidectomy complications in elderly patients are sparse, unclear, and conflicting. OBJECTIVE: We sought to use a population-based cohort to determine whether thyroid operations in the elderly are as safe as those done in younger patients. DESIGN: This was a prospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2008, with 30-d postoperative follow-up. SETTING: The American College of Surgeons National Surgical Quality Improvement Program data set contains operative cases from a nationwide sampling of academic and community-based as well as high-volume and low-volume hospitals. PATIENTS: All thyroidectomy and parathyroidectomy patients reported to the database during the study period were included in the analysis resulting in an experimental cohort of 7915 thyroidectomy cases and a control cohort of 3575 parathyroidectomy cases. MAIN OUTCOME MEASURES: We aggregated 83 complications into the following outcome measures: urinary tract infection, wound infection, systemic infection, cardiac complications, pulmonary complications, 30-d mortality, and total hospital length of stay. RESULTS: Increased age is a risk factor for significant pulmonary, cardiac, and infectious complications after thyroidectomy. Elderly patients are twice as likely (odds ratio 2.1, 95% confidence interval 1.4-3.3), and the superelderly are 5 times as likely (odds ratio 4.9, 95% confidence interval 2.5-9.6) to have a complication compared with their young counterparts. Preexisting comorbidities are effect modifiers and increase the risk of complications even further. CONCLUSIONS: Elderly thyroidectomy patients are at increased risk for major systemic complications. A systematic approach to the care of elderly thyroidectomy patients is necessary to minimize their risk of serious postoperative complications.

MicroRNA expression profiling is a potential diagnostic tool for thyroid cancer.

BACKGROUND: Approximately 30% of fine-needle aspiration (FNA) biopsies of thyroid nodules are indeterminate or nondiagnostic. Recent studies suggest microRNA (miRNA, miR) is differentially expressed in malignant tumors and may have a role in carcinogenesis, including thyroid cancer. The authors therefore tested the hypothesis that miRNA expression analysis would identify putative markers that could distinguish benign from malignant thyroid neoplasms that are often indeterminate on FNA biopsy. METHODS: A miRNA array was used to identify differentially expressed genes (5-fold higher or lower) in pooled normal, malignant, and benign thyroid tissue samples. Real-time quantitative polymerase chain reaction was used to confirm miRNA array expression data in 104 tissue samples (7 normal thyroid, 14 hyperplastic nodule, 12 follicular variant of papillary thyroid cancer, 8 papillary thyroid cancer, 15 follicular adenoma, 12 follicular carcinoma, 12 Hurthle cell adenoma, 20 Hurthle cell carcinoma, and 4 anaplastic carcinoma cases), and 125 indeterminate clinical FNA samples. The diagnostic accuracy of differentially expressed genes was determined by analyzing receiver operating characteristics. RESULTS: Ten miRNAs showed >5-fold expression difference between benign and malignant thyroid neoplasms on miRNA array analysis. Four of the 10 miRNAs were validated to be significantly differentially expressed between benign and malignant thyroid neoplasms by quantitative polymerase chain reaction (P < .002): miR-100, miR-125b, miR-138, and miR-768-3p were overexpressed in malignant samples of follicular origin (P < .001), and in Hurthle cell carcinoma samples alone (P < .01). Only miR-125b was significantly overexpressed in follicular carcinoma samples (P < .05). The accuracy for distinguishing benign from malignant thyroid neoplasms was 79% overall, 98% for Hurthle cell neoplasms, and 71% for follicular neoplasms. The miR-138 was overexpressed in the FNA samples (P = .04) that were malignant on final pathology with an accuracy of 75%. CONCLUSIONS: MicroRNA expression differs for normal, benign, and malignant thyroid tissue. Expression analysis of differentially expressed miRNA could help distinguish benign from malignant thyroid neoplasms that are indeterminate on thyroid FNA biopsy.

Controversies in the management of papillary thyroid cancer revisited.

The debate on the appropriate treatment of patients with papillary thyroid cancer (PTC) has persisted for several decades. The main controversies focus on the extent of surgery, the timing of central neck dissection, and the indications for radioactive iodine ablation. These controversies continue, for the most part, due to the good prognosis of PTC patients and the questionable effect these treatment modalities have on patient survival. This paper addresses these three controversies and the role of molecular tumor markers in the appropriate treatment selection.

Unique patterns of metastases in common and rare types of malignancy.

This review on the unique patterns of metastases by common and rare types of cancer addresses regional lymphatic metastases but also demonstrates general principles by consideration of vital organ metastases. These general features of successfully treated metastases are relationships to basic biological behavior as illustrated by disease-free interval, organ-specific behavior, oligo-metastatic presentation, genetic control of the metastatic pattern, careful selection of patients for surgical resection, and the necessity of complete resection of the few patients eligible for long-term survival after resection of vital organ metastasis. Lymph node metastases, while illustrating these general features, are not related to overall survival because lymph node metastases themselves do not destroy a vital organ function, and therefore have no causal relationship to overall survival. When a cancer cell spreads to a regional lymph node, does it also simultaneously spread to the systemic site or sites? Alternatively, does the cancer spread to the regional lymph node first and then it subsequently spreads to the distant site(s) after an incubation period of growth in the lymph node? Of course, if the cancer is in its incubation stage in the lymph node, then removal of the lymph node in the majority of cases with cancer cells may be curative. The data from the sentinel lymph node era, particularly in melanoma and breast cancer, is consistent with the spectrum theory of cancer progression to the sentinel lymph node in the majority of cases prior to distant metastasis. Perhaps, different subsets of cancer may be better defined with relevant biomarkers so that mechanisms of metastasis can be more accurately defined on a molecular and genomic level.