Microcarcinoma papilar de tiroides: vigilancia activa. Revisión de la bibliografía / Papillary thyroid microcarcinoma: active surveillance. Literature review

El cáncer de tiroides ha aumentado en incidencia, sin embargo, la mortalidad se mantiene estable. Muchas de estas lesiones son a expensas de un microcarcinoma papilar de tiroides definido por la OMS como aquel carcinoma papilar de tiroides que en su diámetro máximo no sobrepasa los 10 mm. El avance de la imagenología sobre todo la ecografía de alta resolución y el hallazgo en pieza de anatomía patológica por lesiones benignas son las principales causas del aumento en el diagnóstico de esta entidad. La vigilancia activa surge entonces como alternativa de manejo para pacientes portadores de microcarcinoma papilar con bajo riesgo de progresión, obteniendo resultados oncológicos comparables. Independiente de su tratamiento el pronóstico de estos pacientes es excelente con sobrevida cercana al 100% en 10 años. A pesar de lo dicho la morbilidad de las distintas opciones terapéuticas es muy distinta. Será fundamental buscar elementos clínicos y paraclínicos que permitan tomar una decisión práctica, con el fin de determinar qué pacientes con microcarcinomas papilares que podrán entrar en un protocolo de vigilancia activa. Esta revisión pretende examinar la bibliografía publicada al respecto como alternativa de manejo, y su eventual aplicación en Uruguay.

Thyroid cancer has increased in incidence; however, mortality remains stable. Many of these lesions are at the expense of papillary thyroid microcarcinoma defined by the WHO as papillary thyroid carcinoma that in its maximum diameter does not exceed 10 mm. The advance of imaging, especially high-resolution ultrasound and the finding of benign lesions in pathological anatomy specimens are the main causes of the increase in the diagnosis of this entity. Active surveillance arises then as a management alternative for patients with papillary microcarcinoma with low risk of progression, obtaining comparable oncologic results. Regardless of their treatment, the prognosis of these patients is excellent with a survival rate close to 100% in 10 years. In spite of what has been said, the morbidity of the different therapeutic options is very different. It will be essential to look for clinical and paraclinical elements that will allow making a practical decision, in order to determine which patients with papillary microcarcinomas will be able to enter an active surveillance protocol. This review aims to examine the literature published on this subject as a management alternative, and its eventual application in Uruguay.

Ultrasound-guided radiofrequency ablation for papillary thyroid microcarcinoma: a retrospective analysis of 198 patients.

Purpose: To evaluate the safety and efficacy of ultrasound-guided RFA for the treatment of papillary thyroid microcarcinoma (PTMC).Materials and methods: The data of 204 nodules from 198 PTMC patients who were treated using RFA were retrospectively reviewed in this study. Demographic variables, complication details and CEUS results in different time points were collected. The volumes and volume reduction rate (VRR) of the ablated area under CEUS at different follow-up time points were calculated and compared.Results: All the patients were successfully treated without major complication. Mild complications included cervical discomfort in three cases, postoperative cervical pain in one case, and transient hoarse voice in five cases. The volume of the ablated area in the 1st, 3rd, 6th, 12th, 18th and 24th month postoperatively were 241.7 ± 298.3mm3, 89.8 ± 147.2 mm3, 37.6 ± 87.2 mm3, 13.6 ± 59.8 mm3, 2.4 ± 14.4 mm3, and 0.2 ± 2.0 mm3 respectively, with a statistically significant decrease (F = 138.1, p = .000), and the VRR in those time points were 73.9 ± 13.7%, 90.5 ± 8.2%, 96.1 ± 5.9%, 98.8 ± 3.2%, 99.6 ± 1.9% and 99.8 ± 1.0% respectively, with a statistically significant decrease (F = 695.3, p = .000).Conclusions: US-guided RFA is safe and effective for PTMC, with a good oncological outcome and VRR. Further randomized controlled prospective trials are still needed to compare the value of RFA and surgery.

Smoking Cessation and the Risk of Bladder Cancer among Postmenopausal Women.

Smoking is the strongest established risk factor for bladder cancer. Former smokers have a lower risk of bladder cancer compared with current smokers, but findings on the dose-response relationship between years after quitting and the risk of bladder cancer are inconsistent. A total of 143,279 postmenopausal women from the Women's Health Initiative Study were included. Cox proportional hazards regression models were applied for estimating age- and multivariable-adjusted HRs and their 95% confidence intervals (CI). There were 870 bladder cancer cases identified over an average of 14.8 years of follow-up. After adjusting for pack-years of smoking, bladder cancer risk among former smokers declined by 25% within the first 10 years of cessation and continued to decrease as cessation time increased but remained higher than never smokers after 30 years of quitting (HR, 1.92; 95% CI, 1.43-2.58). Smokers who quit smoking had a lower risk of bladder cancer compared with current smokers (HR, 0.61; 95% CI, 0.40-0.94). We conclude that among postmenopausal women, there is a significant reduction in the risk of bladder cancer after quitting smoking. In addition to primary prevention, smoking cessation is critical to prevent the incidence of bladder cancer in older women.

Germline Variants in DNA Repair Genes, Diagnostic Radiation, and Risk of Thyroid Cancer.

Background: Radiation exposure is a well-documented risk factor for thyroid cancer; diagnostic imaging represents an increasing source of exposure. Germline variations in DNA repair genes could increase risk of developing thyroid cancer following diagnostic radiation exposure. No studies have directly tested for interaction between germline mutations and radiation exposure.Methods: Using data and DNA samples from a Connecticut population-based case-control study performed in 2010 to 2011, we genotyped 440 cases of incident thyroid cancer and 465 population-based controls for 296 SNPs in 52 DNA repair genes. We used multivariate unconditional logistic regression models to estimate associations between each SNP and thyroid cancer risk, as well as to directly estimate the genotype-environment interaction between each SNP and ionizing radiation.Results: Three SNPs were associated with increased risk of thyroid cancer and with thyroid microcarcinoma: HUS rs2708896, HUS rs10951937, and MGMT rs12769288. No SNPs were associated with increased risk of larger tumor (>10 mm) in the additive model. The gene-environment interaction analysis yielded 24 SNPs with Pinteraction < 0.05 for all thyroid cancer, 12 SNPs with Pinteraction < 0.05 for thyroid microcarcinoma, and 5 SNPs with Pinteraction < 0.05 for larger tumors.Conclusions: Germline variants in DNA repair genes are associated with thyroid cancer risk and are differentially associated with thyroid microcarcinoma and large tumor size. Our study provides the first evidence that germline genetic variations modify the association between diagnostic radiation and thyroid cancer risk.Impact: Thyroid microcarcinoma may represent a distinct subset of thyroid cancer. The effect of diagnostic radiation on thyroid cancer risk varies by germline polymorphism. Cancer Epidemiol Biomarkers Prev; 27(3); 285-94. ©2017 AACR.

Efficacy and Safety of Ultrasound-Guided Radiofrequency Ablation for Treating Low-Risk Papillary Thyroid Microcarcinoma: A Prospective Study.

BACKGROUND: Papillary thyroid microcarcinoma (PTMC) has a high incidence and a good prognosis. Surgical operation for all PTMC might be an overtreatment. The objective of this study was to evaluate the efficacy and safety of ultrasound (US)-guided radiofrequency ablation (RFA) for treating low-risk PTMC. METHODS: Ninety-eight PTMC in 92 patients were included in this study. US and contrast-enhanced ultrasound (CEUS) examinations were performed before ablation. RFA was performed using the moving-shot technique. The ablation area exceeded the tumor edge to prevent marginal residue and recurrence. Patients were followed at 1, 3, 6, and 12 months and every six months thereafter. US and CEUS examinations were used to evaluate the ablation area. At three months after ablation, US-guided core-needle biopsy (CNB) was performed in the center, at the edge of the ablation area, and in the surrounding thyroid parenchyma to exclude recurrence. RESULTS: The mean tumor volume was 118.8 ± 106.9 mm3. The mean volume reduction ratio (VRR) was 0.47 ± 0.27, 0.19 ± 0.16, 0.08 ± 0.11, 0.04 ± 0.10, and 0 at 1, 3, 6, 12, and 18 months after RFA, respectively. Significant differences in the VRR were found between every two follow-up times before six months (p < 0.01), and no significant differences in the VRR were found between six months and after 12 months (p = 0.42). Of all the nodules, 10 (41.7%) resolved in six months, and 23 (95.8%) resolved in 12 months. No residual or recurrent tumor tissue was detected in RFA area or in residual thyroid tissue during follow-up. No suspicious metastatic lymph nodes were detected. The histological pathology results of US-guided CNB confirmed the absence of residual or recurrent tumor. No major complications were encountered. CONCLUSIONS: RFA can effectively eliminate low-risk PTMC with a very small complication rate. RFA may be an alternative strategy for the treatment of PTMC.

Iodine deficiency and thyroid nodular pathology--epidemiological and cancer characteristics in different populations: Portugal and South Africa.

BACKGROUND: The prevalence and pathology pattern of iodine deficiency (ID) related disorders are influenced by the dietary iodine intake: low iodine leads to thyroid nodular enlargement, to an increase in the incidence of thyroid cancer, an increase in anaplastic carcinomas and to an alteration in the papillary to follicular neoplasia ratio. This study aims at highlighting the effects of ID by comparatively evaluating the pattern of thyroid nodular pathology in different populations that, although geographically distant and heterogeneous, both had iodine deficiency at the time of data gathering and are at high altitude: Beira Interior (BI) in Portugal and Johannesburg (JHB) in South Africa. (S.A.) Mandatory salt iodization introduced in S. A. in 1995 has recently been shown to have resulted in the correction of ID. METHODS: Evaluation of thyroid histology reports over a 6 year period in BI and a 5 year period in the JHB area. RESULTS: Region of BI: 278 patients with histology reports-60 were malignancies (21.2 %): 31 papillary carcinomas, 22 follicular cancers (18 follicular carcinomas and 4 Hürthle cell tumours), 3 medullary carcinomas and 4 anaplastic carcinomas. Region of JHB: 136 histology reports- 33 were malignancies (24.3 %): 13 papillary carcinomas, 15 follicular cancers (10 follicular carcinomas and 5 Hürthle cell tumours), 1 medullary carcinoma, 3 anaplastic carcinomas and 1 metastatic carcinoma into the thyroid. There was an overlap in the frequencies of all histology types, of particular relevance in the relatively high anaplastic carcinoma incidences and in the papillary to follicular carcinoma ratios which was close to 1 in both areas- BI area ratio: 1.4 and JHB area ratio: 0.87, with overlapping 95 % CI's, also confirmed by the results of the chi-square calculations. CONCLUSIONS: During the study periods evaluated both study areas displayed pathology patterns usually found in ID. Public information regarding the negative consequences of ID combined with the availability of affordable iodized salt are likely to achieve the goal of the elimination of ID. Sea based nutrition, (naturally iodine containing), may also contribute to the elimination of ID, particularly at times when salt restriction tends to be generally advised.

The clinical prognosis of patients with cN0 papillary thyroid microcarcinoma by central neck dissection.

BACKGROUND: Central lymph node metastasis of papillary thyroid microcarcinoma (PTMC) is common; however, prophylactic central lymph node dissection (CLND) is still controversial because of the possible increased morbidity. The purpose of this study is to determine the clinical outcome of patients with cN0 PTMC by central neck dissection. METHODS: A retrospective cohort study was conducted on patients with PTMC without preoperative evidence of lymph node disease (cN0), and the outcomes were compared between patients undergoing total thyroidectomy (TT) alone (group A) and patients undergoing TT with CLND (group B). RESULTS: In this study, 242 patients with cN0 PTMC were included. Group A had 108 patients and group B had 134 patients. During a follow-up of over 60 months, the long-term postoperative complications were equivalent between the two groups. In group B, the presence of involved central neck lymph nodes upstaged 16% of patients to stage III disease, which necessitated additional postoperative radioactive iodine treatment. More patients had recurrences in group A. The rate of reoperation in the central compartment was higher in group A than in group B (8.3% vs 2.2%, P < 0.01). CONCLUSIONS: Prophylactic CLND does not increase long-term postoperative complications and reduces the risk of recurrence in the central compartment.

Predictive factors and pattern of locoregional recurrence after prophylactic central neck dissection in papillary thyroid carcinoma.

BACKGROUND: Prophylactic central neck dissection (pCND) at the time of the total thyroidectomy (TT) remains controversial in clinically nodal-negative (cN0) papillary thyroid carcinoma. Our study was designed to examine the predictive factors and pattern of locoregional recurrence (LRR) after pCND in the context of the postoperative stimulated Tg (sTg) level. METHODS: A total of 341 patients who underwent TT and unilateral pCND were analyzed. Patients with an identifiable lesion on ultrasonography or whole-body scan within 6 months of surgery were excluded. LRR was defined as an identifiable lesion on USG, which was later confirmed by cytology/histology. Preablation sTg level was taken 2 months after surgery, whereas postablation sTg level was taken 8 months after surgery. Cox regression was used in the univariate and multivariate analyses to identify significant independent factors for LRR. RESULTS: After a follow-up of 66.6 ± 38.6 months, 14 (4.1 %) suffered from LRR. The duration to first LRR was 36.4 ± 21.7 months. The estimated 5- and 10-year LRR rates were 5.1 and 6.1 %, respectively. Of these 14 LRR, 3 (21.4 %) involved the central compartment alone, 9 (64.3 %) involved the lateral compartment alone, and 2 (14.3 %) involved both central and lateral compartments. After adjusting for other clinicopathological factors, postablation sTg level ≥ 1 µg/L (hazard ratio 265.109, 95 % confidence interval 1.132-62075.644, p = 0.045) was the only independent predictor of LRR. CONCLUSIONS: Annualized risk of LRR after pCND was approximately 1 % in the first 5 years and 0.2 % in the subsequent 5 years. Most (78.6 %) LRRs involved the lateral compartment. Postablation sTg ≥ 1 µg/L significantly predicted risk of LRR.

Prognostic nomograms to predict oncological outcome of thyroid cancers.

CONTEXT: Thyroid cancers represent a conglomerate of diverse histological types with equally variable prognosis. There is no reliable prognostic model to predict the risks of relapse and death for different types of thyroid cancers. OBJECTIVE: The purpose of this study was to build prognostic nomograms to predict individualized risks of relapse and death of thyroid cancer within 10 years of diagnosis based on patients' prognostic factors. DESIGN: Competing risk subhazard models were used to develop prognostic nomograms based on the information on individual patients in a population-based thyroid cancer cohort followed up for a median period of 126 months. Analyses were conducted using R version 2.13.2. The R packages cmprsk10, Design, and QHScrnomo were used for modeling, developing, and validating the nomograms for prediction of patients' individualized risks of relapse and death of thyroid cancer. SETTING: This study was performed at CancerCare Manitoba, the sole comprehensive cancer center for a population of 1.2 million. PATIENTS: Participants were a population-based cohort of 2306 consecutive thyroid cancers observed in 2296 patients in the province of Manitoba, Canada, during 1970 to 2010. MAIN OUTCOME MEASURES: Outcomes were discrimination (concordance index) and calibration curves of nomograms. RESULTS: Our cohort of 570 men and 1726 women included 2155 (93.4%) differentiated thyroid cancers. On multivariable analysis, patient's age, sex, tumor histology, T, N, and M stages, and clinically or radiologically detectable posttreatment gross residual disease were independent determinants of risk of relapse and/or death. The individualized 10-year risks of relapse and death of thyroid cancer in the nomogram were predicted by the total of the weighted scores of these determinants. The concordance indices for prediction of thyroid cancer-related deaths and relapses were 0.92 and 0.76, respectively. The calibration curves were very close to the diagonals. CONCLUSIONS: We have successfully developed prognostic nomograms for thyroid cancer with excellent discrimination (concordance indices) and calibration.

[Nuclear-power-plant accidents: thyroid cancer incidence and radiation-related health effects from the Chernobyl accident]. / Accident de centrale nucléaire et risque de cancer de la thyroïde : les conséquences sanitaires de Tchernobyl.

Following the Chernobyl accident, enormous amounts of radioisotopes were released in the atmosphere and have contaminated surrounding populations in the absence of rapid protective countermeasures. The highest radiation doses were delivered to the thyroid gland, and the only direct consequence of radiation exposure observed among contaminated population is the increased incidence of thyroid cancers among subjects who were children in 1986 and who lived at that time in Belarus, Ukraine or Russia.

Changing clinical characteristics of thyroid carcinoma at a single center from Turkey: before and after the Chernobyl disaster.

AIM: The aim of the study was to determine the possible role of Chernobyl disaster on changing clinical features of thyroid carcinoma (TC) in a moderately iodine deficient region. METHODS: We retrospectively reviewed demographical features, presenting symptoms, tumor size, histopathological diagnosis and distant metastates in 160 patients with TC diagnosed between 1990-2007. We compared our findings with the database of 118 TC patients diagnosed between 1970-1990 in the same center. RESULTS: There were 123 female (76.9%) and 37 (23.1%) male patients with a mean age of 44.89±14.84. Sex distribution and age at diagnosis were similar between 1970-1990 and 1990-2007 (P=0.77 and P=0.42, respectively). Histopathological diagnoses were papillary in 114 (73.1%), follicular in 22 (14.1%), medullary in 9 (5.8%), hurthle cell in 7 (4.5%) and anaplastic TC in 4 (2.6%) patients. We observed a marked increase in papillary TC (P<0.001) and marked decreases in follicular (P<0.001) and anaplastic TC (P=0.01) compared to the period between 1970-1990. Thyroid microcarcinomas accounted for 27.1% and 37.1% of carcinomas in 1970-1990 and 1990-2007, respectively (P<0.05). CONCLUSION: We showed that incidence of papillary TC increased and incidences of follicular and anaplastic TC decreased in a period that might be affected by Chernobyl fallout in a moderately iodine deficient area. Presenting symptoms of TC have changed and microcarcinomas are diagnosed more frequently compared to past. Further large scale trials are needed to find out whether Chernobyl disaster has role on changing characteristic of TC in countries that are not very near but also not very far from Chernobyl such as Turkey.

[Thyroid cancer following exposure to ionising radiation]. / Cancer de la thyroïde après exposition aux rayonnements ionisants.

Exposure to ionising radiations during childhood increases the risk of thyroid cancer. Similar risk factors have been found after external radiation exposure or internal contamination with radioactive iodine isotopes. In case of contamination with radioiodines, administration of potassium iodide can prevent thyroid irradiation.

Knowledge discovery processing and data mining in karyometry.

OBJECTIVE: To present the rationale for applying different sequences of multivariate analysis algorithms to determine if and where, in the large and high-dimensional data space, events have led to change in karyometric features. STUDY DESIGN: Clinical materials and results from the analysis of 4 studies were used: the demonstration of chemopreventive efficacy of letrozole in a situation where only a small subset of cells is affected, the detection of a preneoplastic lesion in colorectal tissue, data processing to document clues that predict risk of recurrence of a bladder lesion and the use of metafeatures and second-order discriminant analysis in a study of efficacy of vitamin A in the chemoprevention of skin lesions. RESULTS: Evidence for chemopreventive efficacy was demonstrated in the first example only after processing identified the small subpopulation of affected nuclei in a study of breast epithelial cells. Detection of a preneoplastic development is linked to a progression curve connecting nuclei from normal tissue to nuclei from premalignant colorectal lesions. The prediction of risk of recurrence of papillary bladder lesions is possible by detecting changes in nuclei of a certain phenotype. Efficacy of vitamin A as a chemopreventive agent for skin cancer could be demonstrated with a dose-response curve after a second-order discriminant analysis was employed. CONCLUSION: In none of these instances would the information of biologic interest have been revealed by a straightforward, single algorithmic analysis.

[Papillary thyroid cancer: toward radical node resection?]. / Cancer papillaire de la thyroïde: vers un curage central systématique?

Thyroid cancers are the most common endocrine cancer. Cervical lymph node metastases are observed in 20 to 60% of patients with papillary thyroid cancer. In 2008, no prospective randomized study has defined whether prophylactic central neck dissection should be performed during initial surgery for papillary thyroid cancer. Prophylactic lymph node dissection remains controversial. Pros and cons for routine lymph node dissection of the central cervical compartment are discussed in this review of the literature which includes data from international and French consensus conferences.

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications.

B-Raf is an important mediator of cell proliferation and survival signals transduced via the Ras-Raf-MEK-ERK cascade. BRAF mutations have been detected in several tumors, including papillary thyroid carcinoma, but the precise role of B-Raf as a therapeutic target for thyroid carcinoma is still under investigation. We analyzed a panel of 93 specimens and 14 thyroid carcinoma cell lines for the presence of BRAF mutations and activation of the mitogen-activated protein/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. We also compared the effect of a B-Raf small inhibitory RNA construct and the B-Raf kinase inhibitor AAL881 on both B-Raf wild-type and mutant thyroid carcinoma cell lines. We found a high prevalence of the T1799A (V600E) mutation in papillary and anaplastic carcinoma specimens and cell lines. There was no difference in patient age, B-Raf expression, Ki67 immunostaining, or clinical stage at presentation between wild-type and BRAF(V600E) specimens. Immunodetection of phosphorylated and total forms of MEK and ERK revealed no difference in their phosphorylation between wild-type and BRAF(V600E) patient specimens or cell lines. Furthermore, a small inhibitory RNA construct targeting the expression of both wild-type B-Raf and B-Raf(V600E) induced a comparable reduction of viability in both wild-type and BRAF(V600E) mutant cancer cells. Interestingly, AAL881 inhibited MEK and ERK phosphorylation and induced apoptosis preferentially in BRAF(V600E)-harboring cells than wild-type ones, possibly because of better inhibitory activity against B-Raf(V600E). We conclude that B-Raf is important for the pathophysiology of thyroid carcinomas irrespective of mutational status. Small molecule inhibitors that selectively target B-Raf(V600E) may provide clinical benefit for patients with thyroid cancer.

Epidermal growth factor receptor (EGFR) is overexpressed in anaplastic thyroid cancer, and the EGFR inhibitor gefitinib inhibits the growth of anaplastic thyroid cancer.

PURPOSE: No effective treatment options currently are available to patients with anaplastic thyroid cancer (ATC), resulting in high mortality rates. Epidermal growth factor (EGF) has been shown to play a role in the pathogenesis of many types of cancer, and its receptor (EGFR) provides an attractive target for molecular therapy. EXPERIMENTAL DESIGN: The expression of EGFR was determined in ATC in vitro and in vivo and in human tissue arrays of ATC. We assessed the potential of the EGFR inhibitor gefitinib ("Iressa," ZD1839) to inhibit EGFR activation in vitro and in vivo, inhibit ATC cellular proliferation, induce apoptosis, and reduce the growth of ATC cells in vivo when administered alone and in combination with paclitaxel. RESULTS: EGFR was overexpressed in ATC cell lines in vitro and in vivo and in human ATC specimens. Activation of EGFR by EGF was blocked by the addition of gefitinib. In vitro studies showed that gefitinib greatly inhibited cellular proliferation and induced apoptosis in ATC cell lines and slowed tumor growth in a nude mouse model of thyroid carcinoma cells injected subcutaneously. CONCLUSIONS: ATC cells consistently overexpress EGFR, rendering this receptor a potential target for molecular therapy. Gefitinib effectively blocks activation of EGFR by EGF, inhibits ATC cellular proliferation, and induces apoptosis in vitro. Our in vivo results show that gefitinib has significant antitumor activity against ATC in a subcutaneous nude mouse tumor model and therefore is a potential candidate for human clinical trials.

Coexistent thyroid pathologies and high rate of papillary cancer in patients with primary hyperparathyroidism: controversies about minimal invasive parathyroid surgery.

Thyroid carcinoma and benign thyroid diseases associated with primary hyperparathyroidism (PHPT) may cause difficulties in the diagnosis, localization and therapy of PHPT. In this study, we analysed coexistent thyroid pathologies in 51 patients who underwent neck exploration with a diagnosis of PHPT between 1999--2002. Five hundred thirteen patients who underwent thyroidectomy for nodular thyroid disease without a parathyroid pathology in histopathological examination served as controls. In patients with PHPT there were 43 cases (84.3%) of coexistent thyroid pathology. Nine patients (17.6 %) had coexistent papillary thyroid cancer. Nine patients (17.6 %) had lymphocytic thyroiditis, two (3.9%) had benign thyroid adenoma and 24 (47%) had nodular hyperplasia. In one patient (2%), there was intrathyroidal metastasis from a parathyroid cancer. One patient had coexistent lymphocytic thyroiditis and multifocal papillary cancer. One of the two cases with thyroid adenomas was Hürthle cell type. In the control group only 28 patients (5.5%) had thyroid malignancy (27 papillary cancer and one follicular cancer). In conclusion, the coexistent thyroid pathologies are highly prevalent in patients with PHPT and pre- and intra-operative thyroid examination should be performed to avoid overlooking important thyroid pathologies.

Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an "intestinal" pathway of carcinogenesis in the pancreas.

Although general characteristics of intraductal papillary mucinous neoplasms (IPMNs) and their delineation from other pancreatic tumors have been well established, several issues regarding their biology and management remain unresolved. It has been noted briefly by us and other authors that there are different types of papillae in IPMNs; however, their frequency, biologic significance, and clinical relevance are unknown. In this study, the association of different papillary patterns with clinical, pathologic, and biologic parameters was studied in 74 IPMNs, and the expression profile of CDX2 (a specific marker and one of the key determinants of intestinal "programming," and a tumor suppressor) was determined immunohistochemically in addition to MUC1 (a marker of an "aggressive" phenotype in pancreatic neoplasia) and MUC2 ("intestinal type mucin," a marker of the "indolent" phenotype, and a tumor suppressor). The patterns of papillae identified and their association with these parameters were as follows: 1) The intestinal-type (Yonezawa's dark-cell type), similar to villous adenomas, was seen in 26 of 74 (35%) cases. The majority harbored carcinoma in situ (85%) or borderline atypia (15%). They tended to be large (mean, 5.5 cm). Most expressed CDX2 (95%) and MUC2 (92%) but not MUC1 (8%). This type was more commonly associated with colloid-type invasion (14 of 16 invasive carcinomas were of colloid type). 2) The pancreatobiliary type, characterized by arborizing papillae lined by cuboidal cells resembling papillary neoplasms of the biliary tract, was present in 22% of the cases. These were mostly graded as carcinoma in situ (94%); they rarely expressed CDX2 (6%) or MUC2 (19%) but often showed MUC1 labeling (44%). This pattern was more commonly associated with the tubular type of invasive carcinoma and had a slight tendency for a more aggressive clinical course. 3) The null type was characterized by abundant apical mucin and basally located nuclei, similar to the gastric foveolar epithelium. Thirty-one percent of IPMNs had this type of papillae, but this pattern was also present in the background of other IPMNs and in the cystic components of most cases as well. Most pure null-type IPMNs were devoid of complexity and consequently classified as adenoma (48%). They tended to be small (mean, 2.6 cm), were often negative for CDX2, MUC1, and MUC2, and were rarely associated with invasive carcinoma. 4) Some IPMNs (12%) exhibited features that were difficult to classify, and 2 cases had a mixture of pancreatobiliary and intestinal types of papillae. In conclusion, IPMNs include pathologically and biologically distinct epithelial patterns. CDX2 and MUC2 expression is relatively specific for the intestinal type papillae, confirming that these IPMNs indeed exhibit intestinal differentiation. Their close association with colloid carcinoma, which also shows consistent MUC2 and CDX2 expression, supports the existence of an intestinal pathway of carcinogenesis. This "metaplastic" pathway may reflect different genetic events in the development of these IPMNs, and the presence of intestinal differentiation may potentially be used in prognostication and stratification of patients into appropriate treatment categories.

Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-alpha activation via the mitogen-activated protein kinase pathway.

INTRODUCTION: Pregnancy protects against breast cancer development in humans and rats. Parous rats have persistently reduced circulating levels of growth hormone, which may affect the activity of the growth hormone/insulin-like growth factor (IGF)-I axis. We investigated the effects of IGF-I on parity-associated protection against mammary cancer. METHODS: Three groups of rats were evaluated in the present study: IGF-I-treated parous rats; parous rats that did not receive IGF-I treatment; and age-matched virgin animals, which also did not receive IGF-I treatment. Approximately 60 days after N-methyl-N-nitrosourea injection, IGF-I treatment was discontinued and all of the animal groups were implanted with a silastic capsule containing 17beta-estradiol and progesterone. The 17beta-estradiol plus progesterone treatment continued for 135 days, after which the animals were killed. RESULTS: IGF-I treatment of parous rats increased mammary tumor incidence to 83%, as compared with 16% in parous rats treated with 17beta-estradiol plus progesterone only. Tumor incidence and average number of tumors per animal did not differ between IGF-I-treated parous rats and age-matched virgin rats. At the time of N-methyl-N-nitrosourea exposure, DNA content was lowest but the alpha-lactalbumin concentration highest in the mammary glands of untreated parous rats in comparison with age-matched virgin and IGF-I-treated parous rats. The protein levels of estrogen receptor-alpha in the mammary gland was significantly higher in the age-matched virgin animals than in untreated parous and IGF-I-treated parous rats. Phosphorylation (activation) of the extracellular signal-regulated kinase-1/2 (ERK1/2) and expression of the progesterone receptor were both increased in IGF-I-treated parous rats, as compared with those in untreated parous and age-matched virgin rats. Expressions of cyclin D1 and transforming growth factor-beta3 in the mammary gland were lower in the age-matched virgin rats than in the untreated parous and IGF-I-treated parous rats. CONCLUSION: We argue that tumor initiation (transformation and fixation of mutations) may be similar in parous and age-matched virgin animals, suggesting that the main differences in tumor formation lie in differences in tumor progression caused by the altered hormonal environment associated with parity. Furthermore, we provide evidence supporting the notion that tumor growth promotion seen in IGF-I-treated parous rats is caused by activation of estrogen receptor-alpha via the Raf/Ras/mitogen-activated protein kinase cascade.