Melanotic oncocytic metaplasia of the nasopharynx is a rare condition which is characterized by the presence of usually a small, brown to black colored pigmented lesion around the Eustachian tube opening. Although it is a benign lesion, it may be clinically misdiagnosed as malignant melanoma. Microscopically, melanotic oncocytic metaplasia is a combination of oncocytic metaplasia of the epithelium of the gland and melanin pigmentation in its cytoplasm. In our present study, we report three cases of melanotic oncocytic metaplasia of the nasopharynx. All the three cases occurred in men and were presented as multiple black pigmented lesions around the torus tubarius. Microscopically, mucous glands with diffuse oncocytic metaplasia and numerous black pigments were observed. No cellular atypia was observed. Immunohistochemically, the scattering of S-100 protein-positive, and human melanoma black 45-negative dendritic melanocytes was evident. This is the first report of cases of melanotic oncocytic metaplasia of the nasopharynx in Korea.
Metaplasia; Oxyphil cells; Melanins; Nasopharynx
Cystic hypersecretory lesions of the breast are rare. These breast lesions include cystic hypersecretory hyperplasia (CHH), atypical CHH, and cystic hypersecretory carcinoma (CHC). The characteristic features are dilated ducts and cysts filled with thyroid colloid-like eosinophilic secretion. Only seven cases of invasive CHC have been reported in the literature. Here, we report an additional case of invasive CHC. The histologic features of the tumor showed both micropapillary intraductal carcinoma and focal high-grade invasive carcinoma in a background of CHH. This case suggests that cystic hypersecretory breast lesions encompass a spectrum of pathologic lesions including CHH, atypical CHH, CHC, and invasive CHC.
Breast; Neoplasms; Carcinoma; Cystic Hypersecretory Carcinoma; Cystic Hypersecretory Hyperplasia
Metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key pathways of tumor growth, invasion and metastasis, but little is known about their expression according to different molecular subtypes of breast cancer. The aims of this study were to assess the prevalence and clinical significance of MMP and TIMP expression in invasive breast cancer and to determine its association with immunohistochemical-based molecular classification.
Tissue microarray sections were immunostained for estrogen receptor-α (ER-α), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and with specific antibodies against MMP-1, 2, 7, 9, 11, 13, and 14 and TIMP-1, 2, and 3. Based on the immunostaining data from five of the markers used (ER-α, PR, HER2, EGFR and CK5/6), three major subtypes (123 luminal A, 31 basal-like, and 17 HER2-overexpressing) were selected.
Statistically significant differences in the expression of MMPs and TIMPs among the three subtypes were found in tumoral MMP7 (P = 0.005), tumoral MMP-9 (P = 0.000), tumoral MMP-13 (P = 0.016) and stromal MMP-13 (P = 0.016). The incidence of tumoral MMP-9 expression in the HER2-overexpressing subtype was significantly higher than in the luminal A subtype (P = 0.021). Tumoral MMP-9 and stromal MMP-13 expression were significantly higher in the HER2-overexpressing subtype than in the basal-like subtype (P = 0.000 and P = 0.016, respectively). Tumoral MMP-7 expression was significantly higher in the basal-like subtype compared to luminal A (P = 0.007) and HER2-overexpressing subtype (P = 0.004). Tumoral MMP-13 showed a higher expression in the basal-like subtype than in the HER2-overexpressing subtype (P = 0.010). In multivariate analysis, stage and stromal MMP-1 expression were significantly related to overall survival. Stage was of independent prognostic significance for disease-free survival.
We found some variations in MMP and TIMP expression among the immunohistochemical-based molecular subtypes of breast carcinomas, suggesting differences in their tumor pathophysiology. Additional studies are needed to determine the mechanisms underlying the differences of MMP and TIMP expression in the molecular subtypes for the development of specific therapeutic targets for breast cancer subtypes.
Breast cancer; Molecular subtype; Immunohistochemistry; Matrix metalloproteinase; Tissue inhibitor of metalloproteinase
Several studies have reported a high frequency of papillary thyroid cancer (PTC) in patients with acromegaly. The aim of this study was to determine the prevalence and predictors of thyroid cancer in patients with acromegaly and to investigate the frequency of the BRAFV600E mutation in PTC patients with and without acromegaly.
Materials and Methods
We conducted a retrospective study of 60 patients with acromegaly. Thyroid ultrasonography (US) and US-guided fine needle aspiration were performed on nodules with sonographic features of malignancy. We selected 16 patients with non-acromegalic PTC as a control group. The BRAFV600E mutation was analyzed in paraffin-embedded surgical specimens of PTC by real-time polymerase chain reaction, and tumor specimens from patients with PTC were stained immunohistochemically with an antibody against insulin-like growth factor-1 receptor β (IGF-1Rβ).
Thyroid cancer was found in 15 (25.0%) patients. No differences in age, sex, initial growth hormone (GH) and IGF-1 percentage of the upper limit of normal values or treatment modalities were observed between patients with and without PTC. Acromegaly was active in 12 of 15 patients at the time of PTC diagnosis; uncontrolled acromegaly had a significantly higher frequency in the PTC group (60%) than in the non-PTC group (28.9%) (p = 0.030). The BRAFV600E mutation was present in only 9.1% (1/11) of PTC patients with acromegaly, although 62.5% (10/16) of control patients with PTC had the mutation (p = 0.007). IGF-1Rβ immunostaining showed moderate-to-strong staining in all malignant PTC cells in patients with and without acromegaly. Significantly less staining for IGF-1Rβ was observed in normal adjacent thyroid tissues of PTC patients with acromegaly compared with those without (p = 0.014).
The prevalence of PTC in acromegalic patients was high (25%). An uncontrolled hyperactive GH-IGF-1 axis may play a dominant role in the development of PTC rather than the BRAFV600E mutation in patients with acromegaly.
Insulin-like growth factor 1 receptor (IGF-1R) is commonly expressed in primary breast cancers. Understanding the role of IGF-1R signaling in the different subtypes of breast cancer is important because each subtype has a different outcome and requires different treatment modalities. However, the precise biological significance of IGF-1R expression in cancer cells is still unclear. In this study, we examined the expression of IGF-1R in the different molecular subtypes of breast cancer. The effects of IGF-1R expression on the survival rates and outcomes of breast cancer were also examined.
IGF-1R expression was evaluated immunohistochemically in tissue microarray blocks constructed from 1,198 invasive breast cancer samples collected from six medical institutions. IGF-1R expression was interpreted according to the human epidermal growth factor receptor 2 (HER2)/neu immunohistochemistry scoring system. Scores of 2+ and 3+ were considered positive.
Positive IGF-1R expression was observed in 65.4% of invasive breast cancer samples. IGF-1R expression was detected in all cancer subtypes (luminal A, 84.4%; luminal B, 75.9%; HER2, 21.2%; triple-negative, 46.6%) and was found to be associated with a positive hormone receptor status and the absence of HER2 amplification (p<0.001). Positive IGF-1R expression was significantly associated with high survival rates (p=0.014). However, a multivariate analysis revealed that the expression levels of IGF-1R did not achieve statistical significance. In the triple-negative cancer subtype, IGF-1R expression was found to be associated with a lower disease-free survival rate (p=0.031).
Positive IGF-1R expression is associated with a favorable prognosis in breast cancer. IGF-1R is frequently expressed in the luminal A/B subtypes of breast cancer, and its expression is related to the hormone receptor status.
Breast neoplasms; Insulin-like growth factor 1 receptor; Immunohistochemistry
This study was performed to analyze the surgical pathology results of the "atypia of undetermined significance" (AUS) category from thyroid fine needle aspiration (FNA) and to describe the characteristics to distinguish a malignant from a benign nodule.
A retrospective analysis was done on 116 patients who underwent thyroid surgery from December 2008 to December 2012, following a diagnosis of AUS from preoperative thyroid FNA. We investigated the age, gender, size and site of the nodules, ultrasonographic criteria, cytological features, the number of atypia results after repeated FNAs, surgical method, and final pathologic results.
Sixty-five out of 116 patients underwent total thyroidectomy and the rest had partial thyroidectomy. The final pathologic results were 41 malignancies (35.3%) and 75 benign diseases (64.7%). AUS was divided into group 1: 'cannot rule out malignancy' or group 2: 'cannot rule out follicular neoplasm'. After surgery, group 1 revealed papillary thyroid cancer in most cases and group 2 revealed follicular adenoma in most cases. Age over 40 years, ultrasonographic findings suggestive of malignancy, more than 2 results of atypia from repeated FNAs and nodules less than 2 centimeters were risk factors for malignancy on univariate analysis. Multivariate analysis showed that ultrasonographic findings suggestive of malignancy was a significant risk factor for malignancy.
For proper evaluation of the risk for malignancy in thyroid AUS patients, the ultrasonographic criteria should be considered along with other clinicopathological findings such as age, nodule size, number of atypia, cytologic features.
Atypia of undetermined significance; Fine needle aspiration; Thyroid neoplasms
Our previous studies have revealed that the human FOXF1 gene, encoding a transcription factor member of the forkhead box (FOX) family, functions as a tumor suppressor and its expression is frequently silenced in breast cancer via DNA hypermethylation. Moreover, we recently reported that FOXF1 expression is preferentially silenced in colorectal cancer cell lines with inactive p53 and knockdown of FOXF1 caused genomic instability in FOXF1-expressing colorectal cancer cells with a defect in the p53-p21WAF1 checkpoint, suggesting that FOXF1 plays a key role in colorectal tumorigenesis. Given that the in vivo role of FOXF1 in colorectal cancer remains unknown, the study here was aimed at delineating the clinical relevance of FOXF1 in colorectal adenocarcinomas. To characterize FOXF1 protein expression in colorectal cancer, designed tissue microarrays, comprising 50 cases of primary colorectal adenocarcinoma paired with matched adjacent normal tissue, were utilized in the immunohistochemistry (IHC) study. The IHC results showed that for adjacent normal colorectal tissue, the FOXF1 protein was only detected in stroma, not in epithelium, with either cytoplasmic staining (70% of total cases) or a mix of cytoplasmic and nuclear staining (6%). In contrast, for colorectal adenocarcinomas, FOXF1 staining was predominately identified in the cytoplasm of tumor epithelial cells (40% of total cases) and tumor-associated stromal cells of some cases (10%) also exhibited FOXF1 positivity in their cytoplasm. Cytoplasmic FOXF1 protein expression in tumor epithelial cells positively correlated with the histologic grade, depth of invasion, stage and lymphatic metastasis of colorectal adenocarcinomas (p < 0.05). Moreover, in silico meta-analysis of Oncomine’s cancer microarray database indicates that FOXF1 mRNA is overexpressed in a significant subset of colorectal adenocarcinoma tumors compared with normal colorectal tissue and other types of cancers. Our findings for the first time have revealed that the FOXF1 protein is overexpressed as well as mislocalized in cancerous epithelial cells and underexpressed/lost in tumor-associated stromal fibroblasts of colorectal adenocarcinomas, and suggest that FOXF1 is a potential prognostic marker due to its association with the malignancy and metastasis of colorectal cancer.
colorectal cancer; FOXF1; tumor suppressor gene; tissue microarrays; immunohistochemistry; cytoplasmic mislocalization
Ultrasonographic (US) criteria on malignant thyroid bed mass have been suggested, including taller than wide shape, loss of echogenic hilum, abnormal vascularity, and microcalcification. The relationship between fine-needle aspiration (FNA) cytology findings and US findings on thyroid bed mass is unknown. We have retrospectively assessed the malignant thyroid bed mass after total thyroidectomy due to papillary thyroid carcinoma (PTC).
We retrospectively evaluated 2,048 patients who underwent total thyroidectomy due to PTC. FNA was performed in 97 patients on the thyroid bed under US surveillance. The 97 suspicious thyroid bed masses were divided into two groups: metastatic thyroid bed group (n = 34) and nonmetastatic group (n = 63). The groups were evaluated according to various clinical, serologic, and US findings.
Within a median 47.0 months of follow-up, the proportion of malignant thyroid bed mass was high in large tumor size (1.37 cm vs. 1.03 cm), isthmic position (10.3% vs. 3.9%), and previous N1a (55.9% vs. 34.9%). US findings revealed that the presence of microcalcification or macrocalcification (47.1% vs. 19.0%) and thyroid bed mass height (5.4 mm vs. 3.9 mm) were the only discriminable criteria for central compartment recurrence. But, degree of echogenicity, loss of hilum, and irregularity of margin failed to discriminate malignant thyroid bed mass.
US findings on malignant thyroid bed mass were different from previously reported general criteria on lateral metastatic nodes. Additional FNA cytology should be performed on patients, even low-risk patients, who present the above findings.
Ultrasonography; Fine-needle biopsy; Thyroidectomy; Papillary thyroid cancer
Our previous studies have shown that HOXB7 mRNA is overexpressed in ~50% of invasive breast carcinomas and promotes tumor progression in breast cancer cells grown as xenografts in mice. In silico analysis of published microarray data showed that high levels of HOXB7 predict a poor outcome in HER-2–positive (P = 0.046), but not in HER-2–negative breast cancers (P = 0.94). To study the function of HOXB7 in vivo in the context of HER-2 overexpression, we generated mouse mammary tumor virus (MMTV)-Hoxb7 transgenic mice, and then crossed them with MMTV-HER-2/neu transgenic mice. In the mice carrying both Hoxb7 and HER-2/neu transgenes, Hoxb7 plays a dual role in mammary tumorigenesis. In double transgenic mice, overexpression of Hoxb7 delayed tumor onset and lowered tumor multiplicity. However, consistent with the clinical data, once the tumors appeared, their growth was faster and metastasis to the lungs occurred at a higher frequency. Our data show, for the first time, that deregulated expression of Hoxb7 in mammary tumor cells can significantly modulate HER-2/neu-oncogene induced tumorigenesis in vivo.
To analyze the magnetic resonance (MR) imaging findings of invasive micropapillary carcinoma of the breast.
Materials and Methods
MR images were retrospectively evaluated in 14 patients (age range: 37-67, mean age: 49 years) with pathologically confirmed invasive micropapillary carcinoma of the breast. The enhancement type (mass/non-mass), shape, margin, contrast enhancement, and time-intensity curve pattern on the dynamic study were correlated with the histopathologic features. Associated findings, such as edema, nipple change, skin change and enlarged axillary lymph nodes were also studied.
The most common features of the masses were irregular shape (12 of 14 patients, 85.8%) and irregular or spiculated margin (11 of 14 patients, 78.7%). The contrast enhancement was heterogeneous in 11 patients (78.7%), rim enhancement in 2 cases (14.2%), and homogeneous in one patient (7.1%). The predominant kinetic pattern was rapid increase (14 of 14, 100%) in the initial phase and washout (11 of 14, 78.7%) in the delayed phase. Associated non-mass like enhancement was shown in 4 patients, representing ductal carcinoma in situ. MR imaging helped detect additional sites of cancer other than the index lesion in 3 patients (21.4%). Enlarged axillary lymphadenopathy was identified in 7 of the 14 patients (50%).
Invasive micropapillary carcinoma appears as a mass with an irregular shape, irregular or spiculated margin and heterogeneous enhancement on MR imaging. Though these findings are not specific and are also observed with other breast malignancies, invasive micropapillary carcinoma frequently showed multiple lesions, accompanying non-mass enhancement and axillary lymph node enlargement.
Breast neoplasms; Diagnosis; Micropapillary carcinoma; Breast neoplasms; MR
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of cutaneous lymphoma. There have been a few case reports describing the radiologic imaging findings of SPTCL. We report a case of SPTCL, rarely presented with a breast mass. Here, we review her clinical history and radiologic (mammography and ultrasound) findings.
Subcutaneous panniculitis-like T-cell lymphoma; Breast; Mammography; Ultrasound
We previously identified FOXF1 as a potential tumor suppressor gene with an essential role in preventing DNA rereplication to maintain genomic stability, which is frequently inactivated in breast cancer through the epigenetic mechanism. Here we further addressed the role of the p53-p21WAF1 checkpoint pathway in DNA rereplication induced by silencing of FOXF1. Knockdown of FOXF1 by small interference RNA (siRNA) rendered colorectal p53-null and p21WAF1-null HCT116 cancer cells more susceptible to rereplication and apoptosis than the wild-type parental cells. In parental HCT116 cells with a functional p53 checkpoint, the p53-p21WAF1 checkpoint pathway was activated upon FOXF1 knockdown, which was concurrent with suppression of the CDK2-Rb cascade and induction of G1 arrest. In contrast, these events were not observed in FOXF1-depleted HCT116-p53−/− and HCT116-p21−/− cells, indicating the p53-dependent checkpoint function is vital for inhibiting CDK2 to induce G1 arrest and protect cells from rereplication. The pharmacologic inhibitor (caffeine) of Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) protein kinases abolished activation of the p53-p21WAF1 pathway upon FOXF1 knockdown, suggesting that suppression of FOXF1 function triggered the ATM/ATR-mediated DNA damage response. Cosilencing of p53 by siRNA synergistically enhanced the effect of FOXF1 depletion on stimulation of DNA rereplication and apoptosis in wild-type HCT116. Finally, we show that FOXF1 expression is predominantly silenced in breast and colorectal cancer cell lines with inactive p53. Our study demonstrated that the p53-p21WAF1 checkpoint pathway is an intrinsically protective mechanism to prevent DNA rereplication induced by silencing of FOXF1.
FOXF1; tumor suppressor gene; DNA rereplication; p53; p21WAF1
Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 18% to 20% of breast cancers, and it is recognized as a prognostic and predictive marker. We investigated the HER2 status in Korean breast cancer by immunohistochemistry (IHC) and silver-enhanced in situ hybridization (SISH), as the first step toward building a nationwide quality assurance program for HER2 testing.
A total of 1,198 breast carcinoma samples were collected from six institutions and IHC and SISH were performed using tissue microarrays in central laboratories. The results were compared to those of local laboratories.
Available data were obtained from 959 samples. Central IHC results were negative, equivocal, and positive for 756 (78.8%; range among institutions, 76.8-81.8%), 37 (3.9%; 1.9-6.2%), and 166 (17.3%; 13.6-20%), respectively. SISH results were negative, equivocal, and positive for 756 (78.8%; 77.4-79.9%), 2 (0.2%; 0-0.7%), and 201 (21%; 20.1-22.2%), respectively. HER2 gene amplification was observed in 4.4%, 19%, and 73.9% of the negative, equivocal and positive groups stratified by local IHC results, respectively. When central SISH was considered to be the gold standard method for measuring HER2 status, the false-negative and false-positive rates of local IHC were 14.4% (29/201) and 7.1% (54/756). The concordance rate between central IHC and SISH was 98.4%.
Central IHC and SISH markedly decreased the interlaboratory variability of HER2 status and the results of the two were highly concordant. The quality control program for HER2 testing must be focused on decreasing both the false negativity and positivity of IHC in local laboratories.
Breast neoplasms; HER2 gene; Immunohistochemistry; Silver-enhanced in situ hybridization
We investigated the prognosis according to age in papillary thyroid carcinoma (PTC) patients.
We retrospectively evaluated 2,890 patients who underwent thyroidectomy due to PTC between May 2004 and Aug 2008. We divided patients into 3 groups: young (≤35 years old), middle (between 35 and 54 years old), and old (≥55 years old).
Median age was 47.0 years old (range, 15 to 82 years). Within a follow-up period median of 50 months, there were 148 (5.1%) locoregional recurrences, 6 (0.2%) PTC-related deaths, and 18 (0.6%) PTC-unrelated deaths. Outcomes were more favorable in the young group, with no PTC-related death despite the frequent locoregional recurrence. In the old group compared to the middle, there was a higher proportion of male, and more aggressive types as T3 or N1b, higher mean tumor number, more multiplicity, and bilaterality. The old group of ≥55 years did not show a significant difference in PTC-related deaths than other age groups in Cox analysis (OR, 0.9; P = 0.677), but a significant cutoff age in PTC-related deaths at 62.5 years was determined in ROC analysis (area under curve = 0.912).
We showed that the ≤35 years group shows favorable prognosis despite the frequent locoregional recurrence and ≥62.5 years group shows a poor prognosis regardless of other factors such as male sex or tumor aggressiveness. Further multiinstitutional studies are needed to elucidate the prognosis according to patient's age.
Age; Prognosis; Papillary thyroid carcinoma
There are no guidelines for the optimal timing of the decision of when to perform completion thyroidectomy, and controversy exists regarding how the timing of completion thyroidectomy impacts survival patterns. We investigated the legitimacy of an observational strategy in central node metastasis after thyroid lobectomy for papillary thyroid cancer (PTC).
We retrospectively evaluated 522 consecutive patients who underwent thyroid lobectomy. Of the 69 patients with central metastasis, 61 patients (88.4%) were included in an observational study under cautious evaluation with informed consent by the patients, and compared with an observation arm of 180 postlobectomy N0 (node negative proven) patients.
Of the 522 patients, six (1.1%) thyroid, five (0.9%) central, and two (0.4%) lateral recurrences were observed. Lateral recurrences occurred in the immediate completion N0 and Nx groups but not in the N1a observation arms. There were two (3.3%) central recurrences without thyroid or lateral recurrence on the observation arm of N1a observation patients. But two (1.1%) thyroid and three (1.7%) central recurrences were on the observation arm of N0 patients. In Kaplan-Meier survival curves for central or lateral recurrences between observation arms for the N1a and N0 groups, no significant difference was found between the N1a and N0 observation arms (P = 0.365).
The timing of when to perform completion thyroidectomy in central metastases-proven patients after lobectomy for PTC should be based on the patient's risk category.
Observation; Lymphatic metastasis; Thyroid neoplasms; Thyroidectomy
Although branchial cleft cysts are common, papillary carcinomas arising from them are rare. Here we report a 41-year-old woman with papillary carcinoma originating from a right lateral branchial cleft cyst without any evidence of a papillary carcinoma in the thyroid gland. The patient underwent right lateral neck dissection followed by total thyroidectomy. We then confirmed papillary carcinoma arising from the branchial cleft cyst through microscopic and immunohistochemical staining with thyroglobulin (TG), thyroid-associated transcription factor-1 (TTF-1) and p63. It is the 10th case worldwide describing papillary carcinoma in a branchial cleft cyst with a review of the literature on the features of the disease and discussion of the role of immunohistochemical staining with TG, TTF -1 and p63. In conclusion, it should be emphasized that the surgeon must be cautioned of the possibility of primary papillary carcinoma in the branchial cleft cyst.
Branchioma; Thyroid neoplasms; Papillary carcinoma
A primary cancer causing thyroid metastasis is extremely rare. In western countries, the most common primary tumors causing thyroid metastases include kidney, lung, breast, and gastrointestinal cancers. In contrast, breast is the most common primary site, followed by kidney, colon, and lung cancers in Korea. To the best of our knowledge, surgically confirmed thyroid metastasis from cholangiocarcinoma has not been reported. Herein, we report the first case of thyroid metastasis secondary to cholangiocarcinoma on which surgery was performed.
Presentation of case
A 55-year-old man was diagnosed with hepatic malignancy in December 2008. He subsequently received 2 cycles of transarterial chemoembolization and 4 cycles of radio-frequency ablation between 2008 and 2010. At follow-up in January 2011, brain metastasis was identified in the right parietal area secondary to cholangiocarcinoma. In April 2011, the patient was found to have palpable masses on the left thyroid and lateral neck. The patient subsequently underwent total thyroidectomy followed by left radical neck dissection. Intraoperatively, an ill-defined mass measuring 6.0 cm was found infiltrating the subcutaneous tissue into the prevertebral fascia. Microscopic and immunohistochemical findings confirmed that the thyroid masses and lymph nodes were metastatic cholangiocarcinoma.
Positive immunohistochemical staining for cytokeratin 7, cytokeratin 19, and AFP and negative results for TG, TTF-1, and cytokeratin 20 can be definitely helpful in arriving at a correct diagnosis.
To the best of our knowledge, this is the first case report on surgically resected thyroid and lateral neck metastases secondary to cholangiocarcinoma.
Neoplasm metastasis; Thyroid metastasis; Cholangiocarcinoma
Metastasis to the thyroid gland from distant cancer is rare, and, in some cases, is a diagnostic challenge. Here, we report a case of metastatic renal cell carcinoma of the thyroid gland. A 77-year-old man presented with a neck mass detected about 1 month previously. He had undergone a right nephrectomy owing to renal cell carcinoma 14 years previously. Fine needle aspiration cytology showed a few atypical follicular cells with nuclear atypia. Under a tentative diagnosis of papillary thyroid carcinoma, a total thyroidectomy was performed. The histologic and immunohistochemical studies of the surgical specimens indicated that the thyroid masses were metastatic renal cell carcinoma to the thyroid.
Metastasis; Renal cell carcinoma; Thyroid cancer
The expression of several members of the FOX gene family is known to be altered in a variety of cancers. We show that in breast cancer, FOXF1 gene is a target of epigenetic inactivation and that its gene product exhibits tumor suppressive properties. Loss or downregulation of FOXF1 expression is associated with FOXF1 promoter hypermethylation in breast cancer cell lines and in invasive ductal carcinomas (IDCs). Methylation of FOXF1 in IDC (37.6% of 117 cases) correlated with high tumor grade. Pharmacologic unmasking of epigenetic silencing in breast cancer cells restored FOXF1 expression. Re-expression of FOXF1 in breast cancer cells with epigenetically silenced FOXF1 gene led to G1 arrest concurrent with or without apoptosis to suppress both in vitro cell growth and in vivo tumor formation. FOXF1-induced G1 arrest resulted from a blockage at G1-S transition of cell cycle through inhibition of the CDK2-RB-E2F cascade. Si-RNA-mediated depletion of FOXF1 in breast cancer cells led to increased DNA rereplication, suggesting that FOXF1 is required for maintaining the stringency of DNA replication and genomic stability. Further, expression profiling of cell-cycle regulatory genes showed that abrogation of FOXF1 function resulted in increased expression of E2F-induced genes involved in promoting progression of S and G2 phases. Therefore, our studies have identified FOXF1 as a potential tumor suppressor gene that is epigenetically silenced in breast cancer, which plays an essential role in regulating cell cycle progression to maintain genomic stability.
FOXF1; breast cancer; epigenetic silencing
Recent microarray profiling studies on breast cancer have identified distinct subtypes that are associated with different clinical outcomes. Promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of breast cancer. We proposed that immunohistopathologic subtypes of breast cancer are likely to contain distinct promoter methylation patterns. A panel of ten gene promoters was assessed by quantitative multiplex methylation-specific PCR in 114 invasive ductal carcinomas from Korea representing the three major subtypes [57 luminal, 24 human epidermal growth factor 2 (HER2), and 33 basal-like] based on immunohistochemical findings of estrogen receptor, progesterone receptor, HER2, cytokeratin 5/6 and epidermal growth factor receptor. The median methylation levels of HIN1, RASSF1A and TWIST, and the average methylation ratio were significantly lower in basal-like subtype compared to luminal or HER2 subtypes. In contrast, BRCA1 methylation level was significantly higher in basal-like subtype than in luminal subtype. The methylation status of a panel of four genes (APC1, CDH, BRCA1 and RAR-β) in luminal and HER2 subtypes were dissimilar, where HER2 tumors showed a significantly higher level of methylation compared to luminal tumors. These results suggest that gene methylation in breast cancer can potentially serve as epigenetic biomarkers and may contribute further to current breast cancer classification.
breast cancer; basal-like; luminal; HER2; methylation; quantitation
A sclerosing stromal tumor of the ovary is an extremely rare benign tumor; it usually is found during the second and third decades of life. Patients present with pelvic pain or a palpable abdominal mass. Hormonal effects such as masculinization are uncommon. Here, an 11-year old premenarchal girl presented with deepening of the voice. In addition, clitoromegaly and hirsutism with a male suprapubic hair pattern were observed. The laboratory findings showed that the testosterone level was elevated to 3.67 ng/mL, andostenedione to above 10 ng/mL, dehydroepiandrosterone-sulfate to 346 µg/dL and 17-hydroxy progesterone (17-OHP) to 11.28 ng/mL. The chromosome evaluation revealed a 46,XX female karyotype. An adrenocorticotropic hormone stimulation test was performed. The 17-OHP to cortisol ratio in 30 minutes was 0.045, which suggested a heterozygote for the 21-hydroxylase deficiency. However, the CYP21A2 gene encoding steroid 21-hydroxylase showed normal. The pelvic ultrasound showed a heterogeneous mass consisting of predominantly solid tissue in the pelvic cavity. The pelvic magnetic resonance imaging revealed an 8.9×6.2×6.6 cm mass of the left ovary. A left oophrectomy was performed and microscopic examination confirmed a sclerosing stromal tumor. Immunohistochemical studies showed that the tumor was positive for smooth muscle actin and vimentin, but negative for S-100 protein and cytokeratin. Following surgery, the hormone levels returned to the normal range and the hirsutism resolved.
Ovary; Ovarian neoplasms; Sex cord-gonadal stromal tumors; Virilism
The genes encoding Slits and their Robo receptors are silenced in many types of cancer, including breast, suggesting a role for this signaling pathway in suppressing tumorigenesis. The molecular mechanism underlying these tumor-suppressive effects has not been delineated. Here, we show that loss of Slits, or their Robo1 receptor, in murine mammary gland or human breast carcinoma cells results in coordinate up-regulation of the Sdf1 and Cxcr4 signaling axis, specifically within mammary epithelium. This is accompanied by hyperplastic changes in cells and desmoplastic alterations in the surrounding stroma. A similar inverse correlation between Slit and Cxcr4 expression is identified in human breast tumor tissues. Furthermore, we show in a xenograft model that Slit overexpression down-regulates CXCR4 and dominantly suppresses tumor growth. These studies classify Slits as negative regulators of Sdf1 and Cxcr4 and identify a molecular signature in hyperplastic breast lesions that signifies inappropriate up-regulation of key prometastatic genes.
We investigated the patterns of pretreatment expression of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) by immunohistochemical staining and determined their correlation with treatment response and survival in 44 patients with esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT). The definitive CCRT consisted of a median dose of 54 Gy (range: 40.0-68.4 Gy) and two cycles of concurrent administration of mostly 5-fluorouracil + cisplatinum. High expression of EGFR, VEGF, and COX-2 was found in 79.5%, 31.8%, and 38.6%, respectively. The Cox regression analysis for overall survival (OS) showed that both the treatment response and COX-2 expression were significant. The 3-yr OS rates of patients that achieved a complete response and those that did not were 46.7% and 5.3%, respectively (P = 0.006). The logistic regression analysis for treatment response with various parameters showed that only a high expression of VEGF was significantly associated with a complete response. Unlike other well-known studies, higher expression of VEGF was significantly correlated with a complete response to CCRT in this study. However, higher expression of COX-2 was significantly associated with shorter survival. These results suggest that VEGF might be a predictive factor for treatment response and COX-2 a prognostic factor for OS in patients with ESCC after definitive CCRT.
Esophageal Neoplasms; Chemoradiotherapy; Epidermal Growth Factor Receptor; Vascular Endothelial Growth Factor; Cyclooxygenase 2
This is a case report on papillary thyroglossal duct cyst (TGDC) carcinoma along with synchronous occult papillary thyroid microcarcinoma. A 46-year-old woman visited our hospital because she had an anterior midline neck mass below her hyoid bone. Preoperative ultrasound-guided fine-needle aspiration cytology revealed signs of papillary TGDC carcinoma. We performed a Sistrunk operation and a total thyroidectomy. Histopathological examination of the specimen revealed papillary carcinoma arising in the TGDC and papillary microcarcinoma of the thyroid gland without extrathyroidal extension. Surgeons should be aware of TGDC carcinoma during surgical planning and postoperative treatment and should differentiate this carcinoma from an anterior midline neck mass.
Thyroglossal duct cyst carcinoma; synchronous; occult; thyroid microcarcinoma