Ki-67, topoisomerase IIα and miR-221 have a limited prostate cancer risk stratification ability on a medium-term follow-up: results of a high-risk radical prostatectomy cohort.

Background: Currently, no biomarkers are able to differentiate lethal from relatively indolent prostate cancer (PCa) within high-risk diseases. Nonetheless, several molecules are under investigation. Amongst them, topoisomerase-II-alpha (TOPIIA), Ki67 and miR-221 showed promising results. Our aim was to investigate their prognostic role in the context of biochemical recurrence (BCR), clinical recurrence (CR) and PCa-related death (PcD). Methods: We included 64 consecutive cM0 high-risk PCa [prostate specific antigen (PSA) >20 ng/mL or Gleason Score (GS) >7 or cT >2] undergoing radical prostatectomy (RP). Changes in miR-221 expression and alternative splicing were determined using microarrays. Immunohistochemical determination of Ki67 and TOPIIa were performed using monoclonal antibody MIB-1 and 3F6 respectively. Cox proportional-hazards regression models were used to predict BCR and CR as multivariate analysis. BCR and CR were defined as three consecutive rises in PSA and PSA >0.2 ng/mL and histologically-proven local recurrence or imaging positive for distant metastasis respectively. Results: We included 64 men. Mean pre-operative PSA was 26.53 (range, 1.3-135); all GSs were ≥7 and pT was ≥ T3 in 78.13%. Positive margins and lymph-nodes were present in 42.19% and 32.81% respectively. At a mean follow-up of 5.7 years (range, 1.8-12.5), 42.18% experienced BCR (n=27), 29.68% CR (n=19) and 7.81% PcD (n=5). On univariate analysis positive nodes (<0.01), seminal vesicle invasion (0.02) and miR-221 downregulation (P=0.03), but not Ki67 and TOPIIA (both P>0.5) were associated with BCR whereas only PSA (P<0.01), seminal vesicle invasion (P<0.01) and positive nodes (both P<0.01) were linked to CR. No parameters predicted PcD (all P>0.05) or BCR and CR on multivariate analysis (all P>0.05 - miR-221 HR 0.776; 95% CI: 0.503-1.196 for BCR and HR 0.673; 95% CI: 0.412-1.099 for CR). Limitation of the study include its small sample size and limited follow-up. Conclusions: TOPIIA, Ki-67 and miR-221 may not predict BCR, CR or PcD in high-risk PCa patients who underwent RP at a medium-term follow-up. Longer follow-up and larger cohorts are needed to confirm our findings.

Impact of Macroscopic On-Site Evaluation (MOSE) on Accuracy of Endoscopic Ultrasound-Guided Fine-Needle Biopsy (EUS-FNB) of Pancreatic and Extrapancreatic Solid Lesions: A Prospective Study.

This is a prospective and comparative study including 76 consecutive patients performing EUS-FNB for pancreatic and extrapancreatic solid lesions, randomized by alternate allocation to macroscopic on-site evaluation (MOSE) (40 patients) or to a conventional technique (40 patients), with three passes each. MOSE samples were differentiated into score 0: no visible material, score 1: only necrotic or haematic material, score 2: white core tissue ≤ 2 mm, or score 3: white core tissue > 2 mm. The conventional technique consisted in pushing all the needle content into a test tube for evaluation by the pathologist. In both groups, a 22-25 Gauge Franseen-tip needle (Acquire, Boston Scientific Co., Natick, MA, USA) was used. The study evaluated the diagnostic accuracy and adequacy of MOSE compared to the conventional technique and whether MOSE could optimize the number of passes during EUS-FNB. Results: The analysis was performed on 76 patients (38 MOSE, 38 conventional). The overall diagnostic adequacy was 94.7% (72/76) and accuracy was 84.2% (64/76). The diagnostic accuracy was similar in the two groups: MOSE 86.8% (33/38 lesions), vs. conventional 81.6%, 31/38 lesions, p = 0.76). Regarding diagnostic adequacy, the MOSE technique was 97.4% (111/114 passes) compared to 92.1% (105/114 passes) with the conventional technique, p = 0.06. The accuracy increased according to the MOSE score evaluation: it was 43.5%, 65.5% and 78.3% in patients with score 1, score 2, and score 3, respectively. Moreover, if in the first two passes the MOSE score was 2 or 3, the accuracy was 82.6% (20/23), and upon adding a third pass, the accuracy increased to 87% (20/23), which was not significantly different from the general accuracy of the MOSE samples (86.8%) (p = 0.86). Conclusions: The MOSE score showed a comparable diagnostic accuracy to the conventional technique. However, MOSE allows endoscopists to perform an inspective evaluation of the material, tends to perform better than the conventional technique in terms of diagnostic adequacy, and may potentially reduce the number of passes.

Natural history of widespread high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: should we rebiopsy them all?

OBJECTIVE: To evaluate the premalignant potential of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP). METHODS: Patients diagnosed with monofocal HGPIN (mHGPIN), widespread HGPIN (≥4 cores, wHGPIN) and/or ASAP who underwent at least one rebiopsy during their follow-up, were enrolled. All enrollment biopsies underwent central pathologic revision. Risks for PCa were estimated using Fine and Gray method for competing risk. RESULTS: Pathologic revision changed the original diagnosis in 32.3% of cases. Among 336 cases enrolled, PCa was diagnosed in 164 (48.8%), and more specifically in 20 (30.3%) mHGPIN, 10 (34.5%) wHGPIN, 101 (54.0%) ASAP, and 33 (61.1%) HGPIN + ASAP (mean follow-up 124 months). Most PCa were Gleason score 6(3 + 3) (51.0%) and 7(3 + 4) (34.3%). On multivariate analysis, HGPIN + ASAP (HR 2.76, p < 0.001) and ASAP alone (HR 2.41, p < 0.001) were the only lesions significantly associated with PCa development. Of all cancers detected, 64.3% were at first rebiopsy. A rebiopsy performed within 3 months after ASAP diagnosis had a 45% chance of finding PCa. At Kaplan-Meier survival curves, median PCa-free survival was 48.1 months for HGPIN + ASAP and 64.9 months for ASAP (p 0.0005 at Log-rank test). At 1 year, 70% of HGPIN + ASAP, 73% of ASAP, 89% of wHGPIN, and 84% of mHGPIN were PCa-free. CONCLUSION: The diagnosis of ASAP and HGPIN strongly relies on the expertise of dedicated uro-pathologists. Finding of ASAP is a strong risk factor for a subsequent PCa diagnosis, advising a rebiopsy, possibly within 3 months. m/wHGPIN should not be routinely rebiopsied.

A Simplified Ultrasonographic Score for the Prediction of Cytologically Suspicious Thyroid Nodules.

PURPOSE: The major aim of ultrasound (US)-based risk stratification systems is to reduce unnecessary thyroid biopsies without losing the ability to recognize nodules with clinically significant malignancy. Each of the classic suspicious features of a thyroid nodule detected on US scan (hypoechoic pattern, microcalcifications, irregular margin, taller than wide shape, irregular vascularization) is significantly independently associated with the probability of malignancy, but none of them has good diagnostic accuracy. Thus, we evaluated the predictive value of a binary score simply based on the combination of these US features, regardless of the specific predictive value of each US feature, against the outcome of suspected malignancy at cytological diagnosis (TIR3 to TIR5 categories by SIAPEC-IAP [TIR+]). MATERIALS AND METHODS: 1009 thyroid nodules from 1081 patients were considered. The US features of suspicion of all nodules were categorized in 5 binary scores (U1 to U5), each including from 1 to 5 of those features. RESULTS: U2 (at least 2 US suspicious features) was the most balanced predictor of TIR+ (PPV 0.48, NPV 0.93, LR+ 3.05 and LR- 0.24). Weighting the predictivity of the single features did not improve the estimate. Using U2 as the criterion to send nodules to FNAC would have reduced the number of biopsies by 60 % (604 patients) and the false negatives would have only accounted for 41 cases out of 237 TIR+ (17 %) with 39 cases of TIR3 and 2 cases of TIR4, including only 6 malignant nodules on histological examination. U2 performed much better than the ATA recommendations for detecting those nodules, resulting in TIR+ at cytology. CONCLUSION: This simple and reproducible sonographic score based on 2 US features of suspicion of malignancy has quite a good performance with respect to identifying thyroid lesions categorized by cytology as medium-high risk of malignancy and could allow us to reduce cytology costs for low-risk nodules.

Amyloid-Rich Pancreatic Neuroendocrine Tumors: a Potential Diagnostic Pitfall in Endoscopic Ultrasound-Guided Fine Needle Aspiration Cytology (EUS-FNAC).

Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms that include even rarer variants that may pose different diagnostic problems, especially in fine needle aspiration cytology (FNAC). We describe the diagnostic clues of the amyloid-rich variant of PanNETs in endoscopic ultrasound (EUS)-guided fine needle aspiration cytology (EUS-FNAC). Three cases of PanNETs with an amyloid-rich stromal component were retrieved and retrospectively reviewed. For every case, the pancreatic lesion was investigated by a EUS-FNAC procedure. The final diagnosis was supported by immunocytochemistry and Congo red staining. All cases had similar EUS-FNAC features: neoplastic cells were entrapped in an eosinophilic, homogeneous dense and amorphous matrix. The neuroendocrine nature was confirmed by immunoexpression of synaptophysin and chromogranin A, while the amorphous stroma was characterized as amyloid based on positive Congo red staining. Regarding the hormonal profile, no insulin or proinsulin reactivity was observed, but all cases were diffusely positive for amylin. The diagnosis of uncommon variants of PanNETs, such as the amyloid-rich, is challenging especially in EUS-FNAC procedures because of a unique and misleading morphology, potentially mimicking fibrotic conditions and amyloid deposition within systemic amyloidosis. In cytology specimens, the presence of amorphous material requires amyloid deposition to be considered in the differential diagnosis of pancreatic neoplasms with neuroendocrine phenotype.

Retrospective analysis of the ultrasound features of resected thyroid nodules.

PURPOSE: Several ultrasound (US) risk stratification systems (US-RSSs) have been proposed to stratify the risk of malignancy (ROM) of thyroid nodules. This risk might be overestimated due to selection bias and comparison with the cytological report alone. Our study aimed to compare ROM and diagnostic performance of three guidelines (ATA, AACE/ACE/AME, EUTIRADS) and evaluate the changes in unnecessary biopsy according to the nodule size cutoff for biopsy, using histology as gold standard. METHODS: This retrospective observational study included 146 consecutive patients who underwent surgery after US and cytological characterization. We analyzed the effectiveness and accuracy of three US-RSSs. RESULTS: 46.6% of nodules were diagnosed as malignant. Applying US-RSS, the percentage of nodules that should have been analyzed by biopsy was 84.25% with ATA, 69.86% with EUTIRADS and 64.38% with AACE/ACE/AME systems. The ROM was 94.9%, 86.0%, 87.0% for high-risk category, 36.4%, 32.0%, 35.4% for intermediate-risk category and 22.9%, 0.0%, 22.9% for low-risk category by ATA, AACE/ACE/AME and EUTIRADS systems, respectively. EUTIRADS and AACE/ACE/AME systems were more accurate in differentiating malignant from benign cases. ATA score was the more sensitive US-RSS to identify malignant tumors within the high-risk category. About the unnecessary biopsies, in the intermediate-risk category, the application of the size criterion helps to increase specificity in all systems. CONCLUSIONS: The US categorization of low and high-risk thyroid nodules using current US-RSSs helps alone to determine the optimal treatment option. Nodule size remains relevant to recommend biopsy for the intermediate-risk category.

Mitochondrial DNA "common deletion" in post-fine needle aspiration infarcted oncocytic thyroid tumors.

Thyroid fine needle aspiration (FNA) can rarely induce morphological changes potentially hindering the histopathological diagnosis, especially in Hurthle cell tumors (HCTs), which may easily undergo post-FNA infarction or necrosis. HCTs contain mitochondrion (mt)-rich cells that may bear mtDNA mutations, the most frequent being the so-called common deletion (CD). The aim of this study was to determine the presence and extent of the mtDNA CD in a series of thyroid HCTs that underwent extensive infarction following FNA procedure in comparison with a control series of HCTs lacking post-FNA ischemic/hemorrhagic alterations. Of 257 HCTs with available matched FNA and surgical specimens, 8 cases showed extensive (≥80%) infarction or necrosis in the resected nodule (4 adenomas, 1 carcinoma, 3 HCTs undefined for malignancy). Noninfarcted tumors in the control series included 9 adenomas, 1 carcinoma, and 1 follicular tumor of uncertain malignant potential. These lesions were significantly (P = .03) larger than infarcted nodules. The mtDNA CD was identified using semiquantitative real-time polymerase chain reaction in 2 of 8 (25%) infarcted tumors. In HCTs lacking infarction/necrosis of the control series, the CD was significantly (P = .05) more common (8/11 cases, 72.7%). In 7 of the 10 deleted cases, the CD was present also in the adjacent nonneoplastic parenchyma. In conclusion, the rare oncocytic tumors undergoing extensive infarction are smaller than those lacking ischemic changes and bear the mtDNA CD in a significantly lower proportion compared with control noninfarcted HCTs. This may suggest that mtDNA deletion confers a survival advantage to oncocytic cells in stress conditions, including FNA procedures.

Single-Tube Flow Cytometry Assay for the Detection of Mature Lymphoid Neoplasms in Paucicellular Samples.

OBJECTIVES: Flow cytometry (FC) has become a useful support for cytomorphologic evaluation (CM) of fine-needle aspirates (FNA) and serous cavity effusions (SCE) in cases of suspected non-Hodgkin lymphoma (NHL). FC results may be hampered by the scarce viability and low cellularity of the specimens. STUDY DESIGN: We developed a single-tube FC assay (STA) that included 10 antibodies cocktailed in 8-color labeling, a cell viability dye, and a logical gating strategy to detect NHL in hypocellular samples. The results were correlated with CM and confirmed by histologic or molecular data when available. RESULTS: Using the STA, we detected B-type NHL in 31 out of 103 hypocellular samples (81 FNA and 22 SCE). Of these, 8 were not confirmed by CM and 2 were considered to be only suspicious. The FC-negative samples had a final diagnosis of benign/reactive process (42/72), carcinoma (27/72), or Hodgkin lymphoma (3/72). CONCLUSIONS: The STA approach allowed obtainment of maximum immunophenotyping data in specimens containing a low number of cells and a large amount of debris. The information obtained by STA can help cytomorphologists not only to recognize but also to exclude malignant lymphomas.

The strange case of a hematocele mistaken for a neoplastic scrotal mass.

Hematoceles are usually associated with a history of scrotal trauma, are usually painful and rarely have an idiopathic origin. We describe the peculiar case of a hematocele mistaken for a testicular cancer.

Flexible lab-tailored cut-offs for suitability of formalin-fixed tumor samples for diagnostic mutational analyses.

The selection of proper tissues from formalin-fixed and paraffin-embedded tumors before diagnostic molecular testing is responsibility of the pathologist and represents a crucial step to produce reliable test results. The international guidelines suggest two cut-offs, one for the percentage and one for the number of tumor cells, in order to enrich the tumor content before DNA extraction. The aim of the present work was two-fold: to evaluate to what extent a low percentage or absolute number of tumor cells can be qualified for somatic mutation testing; and to determine how assay sensitivities can guide pathologists towards a better definition of morphology-based adequacy cut-offs. We tested 1797 tumor specimens from melanomas, colorectal and lung adenocarcinomas. Respectively, their BRAF, K-RAS and EGFR genes were analyzed at specific exons by mutation-enriched PCR, pyrosequencing, direct sequencing and real-time PCR methods. We demonstrate that poorly cellular specimens do not modify the frequency distribution of either mutated or wild-type DNA samples nor that of specific mutations. This observation suggests that currently recommended cut-offs for adequacy of specimens to be processed for molecular assays seem to be too much stringent in a laboratory context that performs highly sensitive routine analytical methods. In conclusion, new cut-offs are needed based on test sensitivities and documented tumor heterogeneity.

Diagnostic performance of elastography in cytologically indeterminate thyroid nodules.

Cytological examination of material from fine-needle aspiration biopsy is the mainstay of diagnosis of thyroid nodules, thanks to its remarkable accuracy and scarcity of complications. However, follicular lesions (also called indeterminate lesions or Thy3 in the current classification), a heterogeneous group of lesions in which cytology is unable to give a definitive diagnosis to, represent its main limit. Elastography has been proposed as a potential diagnostic tool to define the risk of malignancy in the aforementioned nodules, but at present there is no conclusive data due to the small number of specifically addressed studies and the lack of concordance among them. The objective of our study was to evaluate the role of real-time elastography (RTE) for refining diagnosis of Thy3 nodules, by integrating diagnostic information provided by traditional ultrasound (US). The study included 108 patients with Thy3 nodules awaiting for surgery, which were evaluated by US (considering hypoecogenicity, irregular margins, microcalcifications, halo sign, and intranodular vascularization) and RTE. Nodules were classified at RTE using a four-class color scale. At histologic examination, 75 nodules were benign and 33 malignant. As expected, none of the ultrasound parameters alone was adequate in predicting malignancy or benignity of the nodules; in the presence of at least two US risk factors, we obtained 61 % sensitivity, 83 % specificity, and 77 % accuracy with 6.8 OR (95 % CI 2.4-20.4). RTE scores 3 and 4 showed 76 % sensitivity, 88 % specificity, 74 % PPV, and 89 % NPV with diagnostic accuracy of 84 %; the data are statistically significant (p < 0.0001) with a OR of 21.9 (95 % CI 7.1-76). By combining RTE with US parameters, the presence of at least 2 characters of suspicion had 88 % sensitivity and 94 % NPV with 23.8 OR (95 % CI 7-106.3). The use of combined RTE and US leads to the identification of two patients subpopulations which have a significantly different malignancy risk (6 vs. 63 %); further studies are needed to verify if it is possible to send only the first group to thyroidectomy and the other to follow-up.

Utilility of flow cytometry as ancillary study to improve the cytologic diagnosis of thyroid lymphomas.

BACKGROUND: To evaluate the efficacy of the use of flow cytometry (FC) immunophenotyping together with fine-needle aspiration cytology (FNAC) in the diagnosis of thyroid lymphoma. METHODS: FC was performed in parallel with FNAC in 35 samples of suspected thyroid lymphoma over a 12 years period. Results were correlated with histological or molecular findings and follow-up, when available. RESULTS: A final diagnosis of lymphoma was given in 13 of 35 (37.1%) specimens. Among the 22 cases considered negative for lymphoma by FC, 11 were diagnosed as thyroiditis by cytology, 7 as reactive, 2 were anaplastic carcinoma, and 2 cases were considered cytologically suspicious for lymphoma but were not confirmed by further investigations. Histology on core biopsy or molecular analysis was available in 12 of 13 lymphoma cases (92.3%). Data obtained by the combination cytology/FC were confirmed in all cases on histology biopsies. Correlation with histology showed a sensitivity and a specificity of 100% for the combination cytology/FC. CONCLUSIONS: FC is an important additional test that can contribute with cytology to the identification of lymphomas of the thyroid. FC can detect the presence of small neoplastic lymphocyte populations and may contribute to the diagnosis of cases in which the lymphoid infiltrate is difficult to interpret on cytology alone.

Italian consensus guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms.

This report contains clinically oriented guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms in patients fit for treatment. The statements were elaborated by working groups of experts by searching and analysing the literature, and then underwent a consensus process using a modified Delphi procedure. The statements report recommendations regarding the most appropriate use and timing of various imaging techniques and of endoscopic ultrasound, the role of circulating and intracystic markers and the pathologic evaluation for the diagnosis and follow-up of cystic pancreatic neoplasms.

Prognostic factors of 'high-grade' Ta bladder cancers according to the WHO 2004 classification: are these equivalent to 'high-risk' non-muscle-invasive bladder cancer?

OBJECTIVE: To determine the impact of prognostic factors of a series of high-grade Ta non-muscle-invasive bladder cancers (NMIBCs) according to the new International Society of Urological Pathology (ISUP) 1998/WHO 2004 grading system (previously classified as either TaG2 or TaG3). METHODS: One hundred and thirty-one high-grade Ta (105 G2 and 26 G3) cases were identified after independent review by two pathologists. Univariable and multivariable Cox regression models addressed recurrence and progression-free survival. Progression was defined as appearance of any T ≥1 recurrence after complete TUR (type 1) or occurrence of T ≥2 (type 2). RESULTS: Ten-year recurrence, type-1 and type-2 progression-free survival were 60, 75 and 95%, respectively. The previous grading system (G3 vs. G2) significantly predicted type 1 progression in the univariate model only. In the multivariate model, Ki67 was the only independent predictor of progression according to both definitions (HR = 5.25, p = 0.002 and HR = 6.16, p = 0.03, respectively). CONCLUSIONS: High-grade Ta NMIBC as defined by the WHO 2004 grading system cannot be equated with high-risk NMIBC. The risk of progression to muscle-invasive disease (type 2) is low, more in keeping with an intermediate-risk category of NMIBC. The previous WHO 1973 subcategorization into G2 and G3 is of little help in the prediction of outcome. Ki67 is a strong independent predictor of progression worthy of consideration for a clinical setting.

Cytomorphologic and molecular features of hobnail variant of papillary thyroid carcinoma: case series and literature review.

Recent reports indicate that hobnail papillary thyroid carcinoma (HPTC) is a rare, but very aggressive variant of papillary thyroid carcinoma. The authors describe the cytological features of five HPTC on fine-needle aspiration biopsies (FNAB). Moreover, their immunophenotype and the presence of B-RAF mutation by pyrosequencing were investigated. The patients' (three females and two males) age ranged from 27 to 86 (mean 65) years. Tumor size ranged from 2 to 9 cm (mean 4.2 cm). FNAB were highly cellular with a bloody background and scant colloid. The cells were arranged in papillary-like clusters or in micropapillary groups. The cell population consisted of medium-sized cells with "tear-drop" cytoplasm, apically placed nuclei that produced a surface bulge leading to a hobnail appearance. At higher magnification, nuclei showed variable degrees of atypia, occasional pink intranuclear pseudoinclusions, and grooves. Nuclear stratification and atypical mitotic figures were usually present. Immunocytochemistry revealed positive staining for thyroglobulin, thyroid transcriptor factor-1, Hector Battifora Mesothelial Antigen-1, partial loss of E-cadherin expression, and nuclear expression of p53 protein. B-RAF mutation was present in three out of five cytological cases. Immunohistochemical and molecular results were confirmed on histological sections. Recognizing the unique cytological features of HPTC should help to avoid misdiagnosis of this rare variant.

Two cases of retroperitoneal metastasis from a completely regressed burned-out testicular cancer.

INTRODUCTION: Primary extragonadal germ cell tumors (EGCT) are rare and it is still a matter of debate if they have to be considered as primary extragonadal issues or metastases from a primary testicular neoplasm. We describe two cases of the so-called burned-out seminoma, a primary testicular germ-cell tumor that spontaneously regressed after demonstration of retroperitoneal metastases. CASES PRESENTATION: Two patients (35 and 50 years old, respectively) presented with CT findings of retroperitoneal masses. In both cases physical examination of the testis was not suspicious, and only scrotal ultrasound (SUS) showed parenchymal alterations such as scarring, calcifications and nodular lesions. Left orchiectomy and chemotherapy were then performed in both cases. Currently, they are both free of disease. CONCLUSIONS: Although primary germ cell tumors may be of retroperitoneal origin, the likelihood of metastasis from a testicular primary origin should always be carefully considered in order to avoid misdiagnosis and to apply the best treatment schedule for the patients. Therefore, a testicular ultrasonography is mandatory in patients presenting CT findings of retroperitoneal adenopathy, even if patients are completely asymptomatic and their physical examination appears normal.

Assessing the risk of false-negative fine-needle aspiration cytology and of incidental cancer in nodular goiter.

OBJECTIVE: In cases of multinodular goiter with negative cytologic result, reasonable management options include surgical treatment, simple follow-up, or more recently introduced conservative therapies such as laser or radiofrequency ablation, and recombinant human thyroid-stimulating hormone-augmented radioiodine. For patients who are eligible for follow-up or nonsurgical treatments, the possibility that they may have an undiagnosed malignancy (false-negative [FN]-fine-needle aspiration cytology [FNAC] result or incidental thyroid cancer [ITC]) should be considered. The aim of our study was to assess the risk of malignancy in patients known to have presumably benign thyroid disease. METHODS: Surgical series of patients who underwent total thyroidectomy for benign disease between 2000 and 2010 at two Italian centers were reviewed. Patients with any preoperative suspicion of malignancy were excluded. RESULTS: Histologic examination revealed that 84 of 970 (8.6%) thyroidectomized patients had malignancy (5% ITC and 3.6% FN-FNAC), with 89.8% of ITCs having a diameter <10 mm, and 65.7% of FN-FNAC cancers having a diameter >30 mm. Sixty-seven thyroid malignancy patients (79.8%) had stage I disease (American Joint Committee on Cancer criteria). The risk of FN-FNAC increases with increasing size of the nodule, while the risk of ITC increases as nodule size decreases. CONCLUSION: The risk of malignancy in presumably benign thyroid disease cannot be overlooked, but can be minimized through skillfully performed ultrasonography (US) examination and FNAC. Once a patient with multinodular goiter is referred for follow-up or nonsurgical therapy, careful US surveillance is mandatory.