Skin punch biopsy sectioning: before or after tissue processing?

BACKGROUND: We intended to study whether there is a meaningful difference in microscopic examination between dividing a biopsy section into two equal parts before tissue processing (first method) or after (second method). METHODS: A total of 400 cases were included in the study. Punch biopsies (PB) were cut into two pieces using the first method in 200 cases and just before paraffin embedding in another 200 cases using the second method. We microscopically evaluated the epidermal mesh view, the presence of a cross-cut hair follicle and bow shape because of epidermal angling, the presence of two pieces on the slide and if there was a difference of >2 mm between the parts, and the number of new sections and new slides. RESULTS: Cross-cut hair follicle (p = 0.018), epidermal mesh view (p = 0.036), difference of >2 mm between the parts (p = 0.008), the number of new sections (p < 0.001) and new slides (p < 0.001) were considerably higher when the first method was used compared with the second method. The presence of two pieces was less (p < 0.001) when using the first method. CONCLUSIONS: We noted a meaningful difference in the quality of microscopic evaluation between the first and second methods. Better sections were obtained with the second method. In addition, the decrease in the number of new slides will reduce workload, archival work and cost.

The correlation of sodium iodide symporter and BRAF(V600E) mutation in classical variant papillary thyroid carcinoma.

BRAF(V600E) mutation was analyzed by real-time polymerase chain reaction in 96 consecutive cases with classical variant papillary thyroid cancer, and immunohistochemical staining of Na+/I- symporter (NIS) protein was evaluated. Localization (intracellular or membranous), density, and the intensity of cytoplasmic staining were characterized semiquantitatively. Extrathyroidal invasion, surgical margin positivity, and lymph node metastasis were compared with BRAF(V600E) mutation and NIS expression. Eighty-eight patients who had at least 24-month follow-up were also included in survival analysis. BRAF(V600E) mutation was determined in 78.1% (75/96) and functional NIS activity in 74% (71/96) of the cases. There were statistically significant differences in mean ages between BRAF(V600E) mutation-positive (48.6) and BRAF(V600E) mutation-negative cases (37.3; Levene test, P=.419; Student t test, P=.001). The surgical margin positivity (46.7%) and extrathyroidal extension percentage (54.7%) in the BRAF(V600E) mutation-positive group were higher than the negative (28.6% and 33.3%, respectively) group, without statistical significance (P=.138 and P=.084, respectively). Functional NIS activity was higher in BRAF(V600E) mutation-positive cases (78.1%) than mutation-negative ones (57.1%; P=.047). The possibility of moderate and intense cytoplasmic staining in BRAF(V600E) mutation-positive cases (72%) was 6.3 times higher than the possibility of weak staining (28%) in the mutation-positive cases (95% confidence interval, 2.2-18.8; P=.001). Functional NIS expression is higher in patients with classical variant papillary thyroid cancer with BRAF(V600E) mutation. However, the clinical features were not found to be associated with NIS expression. There may be different mechanisms determining the outcome of therapy.

Clinicopathological analysis of 38 male patients diagnosed with breast cancer.

BACKGROUND: Male breast cancer (MBC) accounts for one percent of all breast cancers. Due to the lack of awareness and routine screening programs, most patients present with systemic disease at the time of diagnosis with low overall survival. OBJECTIVES: This study aims to investigate the prognostic factors of male breast cancer and its correlation with established prognostic parameters and patient outcomes. METHODS: Thirty-eight male breast cancer patients are identified from the MKA Breast Cancer Clinic database, and their corresponding clinical and pathological characteristics are obtained. Cut-off values of 1% and 10% are applied to further classify ER and PR results. RESULTS: Older men are more likely to develop MBC than younger men and are more likely to have spread to axillary lymph nodes. Invasive ductal carcinoma is a more common histologic type in MBC. All the tested patients have ER and PR positivity. Distant metastasis developed in 17/38 (44.7%) patients. Bone metastasis is seen commonly in metastatic MBC. CONCLUSIONS: According to our cohort, MBC is seen in older males, presents in later stages, and shows hormone receptor positivity and a tendency to bone involvement. MBC is a heterogenous but distinct biological entity requiring a specific clinical and pathological approach.

Stem cell-related markers in primary breast cancers and associated metastatic lesions.

It has been reported previously that: (1) normal-breast epithelial cells that are CD24-/44+ express higher levels of stem/progenitor cell-associated genes; (2) cancer cells that have undergone epithelial to mesenchymal transition display CD24-/44+ cell-surface expression, a marker for breast cancer stem cells; (3) loss of E-cadherin is a preliminary step in epithelial to mesenchymal transition; and (4) vimentin is a marker of mesenchymal phenotype. We hypothesized that stem cell subpopulations would be more frequent in metastatic than in primary tumors. Therefore we assessed by immunohistochemical analysis, tissue microarrays containing tissue from primary and associated metastatic breast cancers for expression of CD24, CD44, E-cadherin and vimentin to evaluate candidate cancer-initiating cell populations in breast cancer subtypes and metastatic lesions. The occurrence of CD24-/44+ and CD24+/44- cells did not differ in primary vs matched lymph node or distant and locoregional metastatic lesions; E-cadherin expression was decreased in primary vs lymph node metastases (P=0.018) but not decreased in distant and locoregional metastases relative to primary tumor, whereas vimentin, was more frequently expressed in lymph node and distant and locoregional metastases (P=0.013, P=0.004) than in matched primary cancers. Thus, the frequency of CD24-/44+ cells does not differ in metastases relative to the primary breast cancer but differs by tumor stage and subtype.

Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features.

Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.

The effects of thyroid dysfunction on DNA damage and apoptosis in liver and heart tissues of rats.

OBJECTIVES: Thyroid hormones affect many enzymes, organs, and systems. They also play a role in complex biological events including development and growth. The main objective of this study was to analyze the effects of thyroid dysfunction on DNA damage and apoptosis in liver and heart tissues as well as the treatment of these disorders. METHODS: Thirty-eight Wistar-albino male rats were randomly divided into five groups: 1. Control group (n=6): The rats were sacrificed without any application and liver and heart samples were collected. 2. Hypothyroidism group (n=8): Prophyltiouracil (PTU)-10 mg/kg/day was applied to induce hypothyroidism by intraperitoneal route for two weeks. 3. Hypothyroidism + Thyroxine group (n=8): After one week of PTU application (10 mg/kg/day), a high dose of l-thyroxine (1.5 mg/kg/day) was applied by intraperitoneal route for one week. 4. Hyperthyroidism group (n=8): l-thyroxine (0.3 mg/kg/day) was applied intraperitoneally to induce hyperthyroidism for two weeks. 5. Hyperthyroidism + PTU group (n=8): After one week of high dose l-thyroxine application, PTU (10 mg/kg/day) was applied for one week. RESULTS: Liver and heart tissues were collected to evaluate 8-hydroxy-2 deoxyguanosine (8-OHdG), caspase-8 and caspase-9 levels. Hypothyroidism caused DNA damage in the liver, while hyperthyroidism caused DNA damage in the heart tissue. Hyperthyroidism also led to a significant increase in levels of caspase-8 and caspase-9 in liver tissue. CONCLUSIONS: The results of the study show that DNA damage and caspase levels in the heart and liver are affected differently in experimental hypothyroidism and hyperthyroidism.

FHIT gene sequence variants and reduced Fhit protein expression in glioblastoma multiforme.

Molecular studies have an important role in the elucidation of the mechanisms involved in Glioblastoma multiforme (GBM) development. The occurrence of FHIT gene alterations, which has an important role in different cancers, has not yet been studied well in GBM. We aimed to investigate the occurrence of alterations of FHIT gene sequence and protein expression in the GBMs. Sequence alterations in exons 5-9 of the FHIT gene were screened in 63 GBMs using the single-strand conformational polymorphism method, followed by DNA sequencing. Additionally, the level of Fhit protein expression in tissues of 48 tumors was assessed by immunohistochemistry (IHC). In our investigation, FHIT gene alterations in the coding region were detected in 11 of the 63 GBM cases (17.5%). Two different sequence variants were determined: one novel missense variant (G-->C transition at codon 49) and one previously described silent alteration (C-->T transition at codon 88). Using web-based programs, such as SIFT and ESEfinder, it was determined that both alterations might have caused significant modification on protein function. In addition, we identified a previously reported an intronic polymorphism (T-->A transition at IVS8-17) in 47.5% of cases as a similar rate (45%) in the control group. Moreover, it was observed that Fhit protein expression was reduced in 87.5% of tumors. In conclusion, the reduction or loss of Fhit protein expression by genetic alterations or epigenetic mechanisms in GBM might be associated with brain tumorigenesis.

Papillary apocrine metaplasia and columnar cell lesion with atypia: is there a shared common pathway?

Papillary apocrine metaplasia (PAM) and columnar cell lesion with atypia (CCL) are considered as candidates of early premalignant breast lesions. In this study, we investigated their relationship at the morphological level, as we noticed their histologic coexistence and proximity in daily routine. We selected 93 neoplastic and nonneoplastic cases with both PAM and CCL among 477 breast specimens and reevaluated sections by measuring the distance between these lesions. Ninety-three (19.4%) of 477 breast specimens contained both PAM and CCL; in 73.1% of the cases, the 2 lesions were in continuity with or adjacent to each other. Lesions less distant than 1 mm are grouped as "adjoining lesions"; and the rest, as "distant lesions." A significant difference (P = .006) was found between adjoining ("zero" + "<1 mm") and distant ("≥ 1 mm") lesions; that is, PAM and CCL were much closer in the neoplastic group, especially tumors with low grade, high estrogen and progesterone receptor expression, and less lymph node metastasis. During the detailed examination of adjoining lesions, some "hybrid cells" showing properties of both lesions were encountered. Papillary apocrine metaplasia and CCL tend to appear in close contact, especially in neoplastic breasts with favorable features. This result implies that PAM and CCL may be included in the same pathogenetic pathway despite their distinct immunophenotypical properties.

Investigation of MMAC/PTEN gene mutations and protein expression in low grade gliomas.

The MMAC/PTEN tumor suppressor gene has an essential biological role in the formation of glioblastomas. It is known that there are variations in genetic alterations in tumors that develop in patients with different ethnic backgrounds; thus, we aimed to evaluate the incidence of MMAC/PTEN mutations and protein expression among various low grade gliomas of Turkish patients. We investigated 28 low grade gliomas for mutations of the MMAC/PTEN gene using single strand conformational polymorphism method followed by DNA sequencing. Additionally, the level of MMAC/PTEN protein expression in the tissues of 26 tumors was assessed by immunohistochemistry. In our investigation, MMAC/PTEN mutations were detected in 2 of 28 tumors (7.14%). One novel sequence variant G --> A transition at codon 159 was identified. This missense variation was a result of an alteration from AGG (Arginine) to AAG (Lysine). Moreover, it was observed that MMAC/PTEN protein expression was reduced to 73.08% of tumors. In conclusion, reduced MMAC/PTEN expression by genetic and/or epigenetic mechanisms in low grade gliomas might be associated with glioma tumorigenesis.

Wwox and Ap2gamma expression levels predict tamoxifen response.

PURPOSE: Assessment of expression levels of Wwox, Wwox-interacting proteins Ap2alpha, Ap2gamma, and ErbB4, the Ap2gamma transcriptional target protein Her2, and the possible Ap2alpha transcriptional target PrkaRIalpha, in breast cancers, to determine their roles in tamoxifen resistance. The hypothesis was that sequestration of Wwox interactors in the cytoplasm might control tamoxifen response. EXPERIMENTAL DESIGN: Tissue sections from 51 tamoxifen-sensitive and 38 tamoxifen-resistant, estrogen receptor alpha-positive breast cancers were stained for the above proteins, as well as progesterone receptor (PR). The relation of tamoxifen resistance and other clinical features, with level of expression of these proteins, and pairwise correlations among various immunohistochemical markers were determined. RESULTS: Menopausal status, tumor, node, and stage, loss of PR, lost or reduced expression of Wwox, and high level of expression of PrkaRIalpha, Ap2gamma, and Her2 were significantly correlated with tamoxifen resistance. In multivariate analysis, Wwox, PrkaRIalpha, Ap2gamma, and ErbB4 were found to be independent markers of tamoxifen resistance. Reduced Wwox expression was better than PR in prediction of resistance, especially in high-risk patients, and nuclear Ap2gamma expression was better than Her2, especially in low-risk patients. CONCLUSION: The results illustrate the complex relationships among the marker proteins assessed in this in vivo study and suggest new markers for prediction of response to tamoxifen treatment as well as possible new targets for treatment of breast cancer. Wwox and Ap2gamma emerge as new biomarkers that may be superior to PR and Her2 in predicting tamoxifen response.

Brachial plexus neuroma mimicking local recurrence of malignant mesenchymal tumor after forequarter amputation.

A stump neuroma is an attempt for the repair of a nerve following amputation. This article presents a case of a 60-year-old woman who was suspected of having a local recurrence on the chest wall following amputation of the left arm for a malignant mesenchymal tumor. The tumor did not show any invasion to adjacent structures thereby any necessity for chest wall resection and reconstruction. The patient underwent local excision of the tumor with reamputation of the branches of the lower brachial plexus, subclavian artery, and proximal one third of the clavicle. The tumor was eventually diagnosed as a brachial plexus neuroma. Although rare, cases that require left pneumonectomy with a transthoracic forequarter amputation including brachial plexus resection have been reported. Transection of the brachial plexus also may be needed during resection of a superior sulcus tumor. These cases often undergo an aggressive chest wall resection that includes the subclavian artery and vein in addition to the brachial plexus, particularly in tumors involving the lower truncus. Therefore, when recurrent chest wall tumor is suspected in such cases, stump neuroma resulting from transection of the brachial plexus should be included in the differential diagnosis.

Atypical teratoid/rhabdoid tumors: imaging findings of two cases and review of the literature.

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant embryonal central nervous system (CNS) tumor, manifesting in children, and composed of rhabdoid cells, with or without fields resembling a classical primitive neuroectodermal tumor (PNET), epithelial tissue and neoplastic mesenchyme. Around 200 cases of CNS AT/RT have been documented in the literature. Although the clinical and pathological findings have been defined in large series previously, and AT/RT has become increasingly recognized, awareness of typical AT/RT is important in making the correct diagnosis of this uncommon but probably underdiagnosed entity. Neuroradiologists rarely mention AT/RT in their differential diagnosis and this paper presents two additional cases in which clinical and pathological findings are combined with neuroradiological presentation.

Investigation of mutations and expression of the FHIT gene in Turkish patients with brain metastases derived from non-small cell lung cancer.

AIMS AND BACKGROUND: Brain metastases occur in 20-40% of patients with cancer, and their frequency has increased over time. Lung, breast and skin (melanoma) are the most common sources of brain metastases. Recent studies show that several genes such as CD44 and PTEN have roles in the suppression of metastatic growth. Although it has been determined that there is a relationship between the FHIT gene and several primary tumors, its role in the initiation and progression of brain tumors has not yet been entirely explained. Furthermore, it is not known whether the FHIT gene has a role in the formation of brain metastases. PATIENTS AND METHODS: The present study investigated mutations of the FHIT gene in Turkish patients with brain metastases derived from non-small cell lung cancer (NSCLC). Single-strand conformational polymorphism and sequencing analysis of the coding exons (5-9) of the FHIT gene were performed on 26 tissues. Furthermore, the level of Fhit protein expression of 36 tumor tissues was identified by immunohistochemistry. RESULTS: Using single-strand conformational polymorphism and sequencing analyses, no point mutations of the FHIT gene were detected in brain metastases derived from NSCLC. However, it was observed that Fhit protein expression was reduced in 88.9% of subjects. CONCLUSIONS: We suggest that the FHIT gene may be turned off in brain metastases via other genetic/epigenetic mechanisms rather than mutations.

Comparison of Clinicopathologic Parameters and Survivals Between Epstein-Barr Virus-positive and Her2-positive Gastric Cancers.

Gastric carcinomas are highly mortal neoplasms for which new therapeutic options are being searched. The molecular subtyping of gastric adenocarcinomas was proposed recently, and the relationship between etiopathogenetic types is still under investigation. Here we compared histopathologic, prognostic, and survival differences between Epstein-Barr virus (EBV)-positive and Her2-positive gastric adenocarcinomas. In a retrospective design, we searched the EBV status with Epstein Barr Virus encoded small RNA (EBER) in situ hybridization, and the Her2 status both by immunohistochemistry and by chromogenic in situ hybridization of 106 gastrectomized gastric carcinomas. Histologic and clinical prognostic parameters and survival information were determined, and retrieved from archival tissues and clinical notes. The Her2 positivity rate was 12.3% and the EBV positivity rate was 7.6%. Among EBER-positive cases, Her2 positivity was not detected. Her2 positivity was detected more in intestinal differentiated tumors, whereas EBER positivity was detected in undifferentiated tumors (P=0.003). There was no correlation of Her2 or EBER positivity with the tumor stage. Median survivals of EBER-positive, Her2-positive, and both negative cases were 11.5, 18, and 20.5 months, respectively. The tumor stage and distant metastasis were found to be significant for survival in the multivariate analysis. In our 106 gastrectomized gastric carcinoma cases, EBV-positive and Her2-positive groups were found to be unrelated as proposed in the upcoming classification of gastric carcinomas.

Clinical and pathological characteristics of gastrointestinal stromal tumor (GIST) metastatic to bone.

Our aim in this study was to describe the clinical, morphological, and molecular profile of gastrointestinal stromal tumor (GIST) metastatic to bone. We analyzed the morphological, phenotypic, and molecular characteristics of seven cases, and in addition reviewed 17 cases from literature. Sequence analysis of KIT and PDGFRA genes was possible for six cases. For the GIST cases with bone metastasis, the most common primaries were small intestine (29%), stomach (25%), and rectum (21%). Sites of bone metastases were vertebrae (11), pelvis (8), femur (8), ribs (6), humerus (5), skull (3), scapula (1), and mandible (1). The size ranged from 1.5 to 13 cm (median, 3.8 cm). Bone metastases without involvement of any other organ were seen in 17% of the cases and were solitary in 14 (58%). Adjacent soft tissue involvement was present in nearly half of the patients. Bone metastasis was either manifest at the time of diagnosis (28%) or occurred after a mean period of 4.7 years (3 months-20 years). Morphologically, neoplastic cells were spindle in 67%, epithelioid in 13%, and mixed epithelioid and spindle in 20%. CD117, DOG1, and CD34 were positive in 88, 86, and 85% of the cases, respectively. KIT Exon 11 mutations were the most frequent gene alteration (78%), followed by KIT Exon 13 mutations. Of 17 of the cases with available follow-up information, 7 (41%) patients developed bone metastasis under imatinib therapy. Five patients (29%) died of disease within a mean of 17 months. Bone metastases from GIST are usually found in patients with advanced disease and typically present as lytic masses with occasional soft tissue involvement. We could not identify any KIT or PDGFRA alterations predisposing to bone metastasis.

Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer.

This study aimed to (a) determine if DNA methylation is a mechanism of WWOX (WW domain containing oxidoreductase) and FHIT (fragile histidine triad) inactivation in lung, breast and bladder cancers; (b) examine distinct methylation patterns in neoplastic and adjacent tissues and (c) seek correlation of methylation patterns with disease status. Protein expression was detected by immunohistochemistry, and methylation status by methylation-specific PCR (MSP) and sequencing, in lung squamous cell carcinomas and adjacent tissues, invasive breast carcinomas, adjacent tissues and normal mammary tissues and bladder transitional cell carcinomas. Wwox and Fhit expression was reduced in cancers in association with hypermethylation. Differential patterns of WWOX and FHIT methylation were observed in neoplastic vs adjacent non-neoplastic tissues, suggesting that targeted MSP amplification could be useful in following treatment or prevention protocols. WWOX promoter MSP differentiates DNA of lung cancer from DNA of adjacent lung tissue. WWOX and FHIT promoter methylation is detected in tissue adjacent to breast cancer and WWOX exon 1 MSP distinguishes breast cancer DNA from DNA of adjacent and normal tissue. Differential methylation in cancerous vs adjacent tissues suggests that WWOX and FHIT hypermethylation analyses could enrich a panel of DNA methylation markers.

Roles of FHIT and WWOX fragile genes in cancer.

It was hypothesized as early as 1986, that the recently discovered common fragile sites could facilitate recombination events, such as deletions and translocations, that result in clonally expanded cancer cell populations with specific chromosome alterations in specific cancer types. A natural extension of this hypothesis is that the clonal expansion must be driven by alteration of genes at recombination breakpoints whose altered functions actually drive clonal expansion. Nevertheless, when the FHIT gene was discovered at FRA3B, the most active common chromosome fragile region, and proposed as an example of a tumor suppressor gene altered by chromosome translocations and deletions, a wave of reports suggested that the FHIT gene was altered in cancer simply because it was in a fragile region and not because it had contributed to the clonal expansion, thus turning the original hypothesis upside down. Now, after nearly ten years and more than 500 FHIT reports, it is apparent that FHIT is an important tumor suppressor gene and that there are genes at other fragile regions that contribute significantly to development of cancer. A second fragile gene with a demonstrated role in cancer development is the WWOX gene on chromosome 16q; alterations to the WWOX gene contribute to development of hormone responsive and other cancers. Results of our recent studies of these two fragile tumor suppressor genes were summarized at the first Fragilome meeting in Heidelberg, Feb. 2005.

Metastasis of prostate adenocarcinoma to the frontal and ethmoid sinus.

Intracranial metastasis of prostate cancer is rarely seen, and there are few studies in this regard in the literature. Most of these studies in the literature comprise the metastasis of prostate cancer to the sphenoid sinus, and metastasis to the frontal and ethmoid sinus is a much rare entity. Association of visual symptoms, epistaxis, headache, and hematuria may indicate a urologic malignancy in terms of the origin of the primary tumor. This study was aimed to present the prostate cancer case of a 73-year-old patient whose paranasal sinus tomograms revealed the presence of frontal and ethmoid sinus metastasis.

Retrospective analysis of oncogenic human papilloma virus and Epstein-Barr virus prevalence in Turkish nasopharyngeal cancer patients.

Nasopharyngeal carcinoma (NPC) is associated with the Epstein-Barr virus (EBV). Human papilloma virus (HPV) has also been detected in NPC cases. In this retrospective study, we analyze the frequency of EBV and HPV infection in 82 Turkish patients with NPC. A total of 82 were evaluated for EBV and HPV. In situ hybridization (ISH) was performed for EBV. HPV-ISH and P16 immunohistochemistry used to determine the HPV status. Seventy-two of the 82 (87%) NPC patients were EBV-positive. The highest rate of EBV-positivity was found in undifferentiated NPC patients, which accounted for 65 of 68 (95.6%) undifferentiated cases. One of the 82 NPC patients whose tumor was non-keratinizing differentiated, contained HPV. Our data shows that EBV is closely associated with NPC in Turkey. We found lower rates of HPV-positivity in NPC patients than in North American populations. In addition, both EBV and HPV-negativity were more associated with decreased survival than EBV-positive cases.

Thyroid FNAC containing hürthle cells and hürthle-like cells: A study of 128 cases.

AIM: It is a diagnostic challenge to differentiate benign and malignant cytology in the presence of Hürthle cells. In our previous study, it was determined that in fine needle aspirations (FNA), the malignancy outcome of the Hürthle cells containing group tend to be papillary thyroid carcinoma (PTC) in a higher percentage. The most common misinterpretation is caused by PTC cells with large cytoplasm-like Hürthle cells. The aim of this study is to predict histologic outcome of the nodules, which have Hürthle cells in FNA according to cytological, clinical features, and BRAFV600E mutation status. MATERIALS AND METHODS: Detailed cytological features of 128 cases were compared with histopathological diagnosis. The analysis of BRAFV600E mutation of the PTC cases were performed by real-time polymerase chain reaction. RESULTS: The neoplastic outcome was increased statistically significantly with younger age (P = 0.020), increase in cellular dyshesion (P = 0.016), presence of nuclear budding (P = 0.046), and granular chromatin (P = 0.003). Nuclear budding (P = 0.014), granular chromatin (P = 0.012), and hypoechoic nodules in ultrasonography (P = 0.011) were significant independent factors for the increase in the malignancy risk. Increased lymphocytes (P= 0.015) and colloid were related to non-neoplastic outcome. According to the surgical outcome, more than half of the malign cases were PTC (74%). BRAFV600E mutation was detected in 27.8% of the PTC cases. CONCLUSION: PTC cases containing Hürthle cell-like cells may lead to diagnostic errors. Nuclear budding and granular chromatin of Hürthle cells are significant, remarkable findings to predict the outcome of neoplasm and malignancy.