Architectural Atypia Research Articles

An Insight into the Utility of Sub-Categorisation of Atypia of Undetermined Significance for Risk Stratification: A Retrospective Study on an Indian Cohort with Histopathological Correlation

Background: Atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) criterion in thyroid fine-needle aspirates (FNAs) has been a heterogeneous entity with much inter-observer variation. Sub-categorisation of AUS/FLUS has been observed to play an effective role in risk stratification. We aimed to validate AUS/FLUS sub-categorisation in correlation with the spectrum of malignancy. Study Design: Subjects included patients with AUS/FLUS diagnosed between January 2015 and December 2016. AUS/FLUS cases were sub-categorised into those exhibiting (1) architectural atypia, (2) cytological atypia, (3) architectural and cytological atypia, (4) AUS with Hürthle cells, and (5) AUS not otherwise specified (AUS-NOS). Each sub-category was correlated with their corresponding incidence of malignancy in surgical resections. Result: The overall incidence of AUS/FLUS in our centre was 13% (132/1,018). On retrospective review of 117 patients with AUS/FLUS, smears with cytological atypia showed a higher incidence of malignancy (78.3%) than those with architectural atypia (75.3%). AUS/FLUS cases with both cytological and architectural atypia had a malignancy rate of 71.4%. Conclusion: AUS/FLUS cases with cytological atypia had a higher risk of malignancy than those with architectural atypia. The sub-categorisation of AUS/FLUS is diagnostically important for the proper risk stratification of patients.

RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours

ObjectiveWe aimed at the identification of genetic alterations that may functionally substitute for CTNNB1 mutation in ß-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC).DesignLarge cohorts of HCA (n=185) and HCC...

Pigmented skin lesions displaying regression features: Dermoscopy and reflectance confocal microscopy criteria for diagnosis.

Melanomas and nevi displaying regression features can be difficult to differentiate. To describe reflectance confocal microscopy features in benign and malignant pigmented skin lesions characterized by regression features in dermoscopy. Observational retrospective study. Inclusion criteria were presence of dermoscopic features of regression; availability of clinical, dermoscopic and RCM imaging; definite histopathologic diagnosis. The study sample comprised 217 lesions; 108 (49.8%) melanomas and 109 were benign lesions, of which 102 (47.0%) nevi and 7 (3.2%) lichen planus-like keratosis (lplk). Patients with melanoma were significantly older than those with benign lesions (61.9±15.4 vs 46.1±14.8; P<0.001) and a higher proportion of melanomas displayed dermoscopic regression structures in more than 50% of lesion surface (n=83/108; 76.9%; P<0.001). On RCM examination, pagetoid cells were significantly more reported in melanoma group, than in benign lesions (86.1% vs 59.6%; P<0.001) and were more frequently widespread distributed (65.6% vs 20.0%; P<0.001) and both dendritic and roundish (36.6% vs 15.4%; P<0.001) in shape. Aspecific architecture at the dermo-epidermal junction (DEJ) was more commonly seen among melanomas than benign lesions (23.1% vs 11.9%; P=0.002) with higher presence of dendritic and both dendritic and roundish atypical cells at the DEJ (28.7% vs 18.3% and 19.4% vs 3.7%; P<0.001, respectively). Focal pagetoid infiltration and ringed or clod patterns were more commonly seen in benign lesion. In conclusion, the correct interpretation of regressing lesions remains a challenge, assessing carefully the extent and characteristics of architectural and cytologic atypia on RCM is an additional piece of the complex puzzle of melanoma diagnosis.

Risk of malignancy in Thyroid "Atypia of undetermined significance/Follicular lesion of undetermined significance" and its subcategories - A 5-year experience.

Atypia of undetermined significance/Follicular lesion of undetermined significance [AUS/FLUS] is a heterogeneous category with a wide range of risk of malignancy [ROM] reported in the literature. The Bethesda system for reporting thyroid cytopathology [TBSRTC], 2017 has recommended subcategorization of AUS/FLUS. To evaluate the ROM in thyroid nodules categorized as AUS/FLUS, as well as separate ROM for each of the five subcategories. Retrospective analytic study. A retrospective audit was conducted for all thyroid fine-needle aspiration cytology (FNAC) from January 2013 to December 2017. Slides for cases with follow-up histopathology were reviewed, classified into the five recommended subcategories, and differential ROM was calculated. z test for comparison of proportions was done to evaluate the difference in ROM among different subcategories of AUS/FLUS. The P value of less than 0.05 was taken as statistically significant. Total number of thyroid FNACs reported was 1,630, of which 122 were AUS/FLUS (7.5%). Histopathology was available in 49 cases, out of which 18 were malignant (ROM = 36.7%). The risk of malignancy (ROM) for nodules with architectural and cytologic atypia was higher (43.8%) than ROM for nodules with only architectural atypia (16.7%). The sub-classification of AUS/FLUS into subcategories as recommended by TBSRTC, 2017 may better stratify the malignancy risk and guide future management guidelines.

Prognostic importance of atypical endometriosis with architectural hyperplasia versus cytologic atypia in endometriosis-associated ovarian cancer.

ObjectivePatients with endometriosis are at increased risk of ovarian cancer. It has been suggested that atypical endometriosis is a precursor lesion of endometriosis-associated ovarian cancer (EAOC). The aim of this study is to evaluate if cytologic (cellular) atypia and architectural atypia (hyperplasia), histologic findings described as atypical endometriosis, play a different role in patients with EAOC.MethodsA prospective study was conducted between January 2014 and April 2017 at our institution with patients undergoing surgery with a histologic diagnosis of endometriosis, ovarian cancer, or EAOC. The prevalence and immunohistologic study (Ki-67, BAF250a, COX-2) of cases of cellular and architectural atypia in endometriosis were analyzed.ResultsTwo hundred and sixty-six patients were included: the diagnosis was endometriosis alone in 159 cases, ovarian cancer in 81, and EAOC in 26. Atypical endometriosis was reported in 23 cases (12.43%), 39.13% of them found in patients with EAOC. Endometriosis with cellular atypia was found mainly in patients without neoplasm (71.4%), and endometriosis with architectural atypia was seen in patients with ovarian cancer (88.9%) (p=0.009). Ki-67 was significantly higher in endometriosis patients with architectural atypia than those with cellular atypia.ConclusionThe diagnosis of endometriosis with architectural atypia is important because it may be a precursor lesion of ovarian cancer; therefore, pathologists finding endometriosis should carefully examine the surgical specimen to identify any patients with hyperplasia-type endometriosis, as they may be at higher risk of developing EAOC.

Tumor Growth Rate Does Not Predict Malignancy in Surgically Resected Thyroid Nodules Classified as Bethesda Category III with Architectural Atypia.

It is unknown whether the growth of thyroid nodules with a Bethesda category III cytology (atypia of undetermined significance [AUS]) is predictive of malignancy, especially in cases with architectural atypia (AUS-A). This study evaluated whether tumor growth rates can help distinguish malignant from benign nodules in the AUS-A subcategory. This retrospective, single-center cohort study included 172 patients who underwent diagnostic thyroid surgery because of a nodule with a cytological diagnosis of AUS-A. The growth kinetics of nodules was assessed by serial preoperative neck ultrasonography over a median follow-up of 52.6 months (range 12.7-198.3 months). Pathologic examinations showed that 112 (65%) and 60 (35%) patients had benign and malignant nodules, respectively. The largest diameter and volume of both benign and malignant nodules increased gradually (p < 0.001). However, there was no significant difference in the growth rates of benign and malignant nodules based on the largest diameter (p = 0.132) and volume (p = 0.200). The time to tumor growth curves and estimated median time to significant tumor growth from baseline were not significantly different in malignant nodules compared to benign nodules (p = 0.458 and p = 0.568, respectively). The relative risk (RR) of malignancy of growing and stable nodules did not differ significantly based on the largest diameter (RR = 0.5; p = 0.064) and volume (RR = 0.9; p = 0.748). The size of thyroid nodules classified as AUS-A increased linearly, regardless whether these nodules were benign or malignant. These results suggest that growth kinetics on serial preoperative neck ultrasonography cannot predict malignancy in the AUS-A subcategory.

Endoscopic and clinicopathological features of intramucosal, histologically mixed-type, low-grade, well-differentiated gastric tubular adenocarcinoma with the potential for late-onset lymph node metastasis

BackgroundIntramucosal, histologically mixed-type, low-grade (LG), well-differentiated gastric tubular adenocarcinomas (tub1s; LG-tub1s) have larger mean diameters and exhibit a higher frequency of the gastric mucin phenotype (G-phenotype) than pure LG-tub1s. In proportion to their increases in diameter, G-phenotype differentiated-type early gastric cancer (EGC) tumours reportedly grow to eventually contain (an) undifferentiated-type component(s) and LG-tub1s, which are included in differentiated-type EGCs, reportedly exhibit changes in their glandular architectural and cytological atypia grades from LG to high-grade (HG) and can grow to contain a moderately differentiated tubular adenocarcinoma (tub2) component and undifferentiated components. Because they generally show a higher frequency of malignancy relative to tumours with a higher atypia grade and lower differentiation degree, it is suggested that, among mixed-type LG-tub1s, G-phenotype LG-tub1s containing an HG-tub2 component (LG-tub1s > HG-tub2) with undifferentiated components might lead to late-onset metastasis to lymph nodes even after a successful endoscopic submucosal dissection (ESD). We aimed to clarify the endoscopic and clinicopathological features of these G-phenotype LG-tub1s > HG-tub2.MethodsOf the 13,217 oesophagogastroduodenoscopies performed at our institutions between September 2008 and March 2016, 185 EGC lesions were evaluated in this retrospective observational study. Among these EGC lesions, 60 intramucosal LG-tub1s were divided into 53 tub1 (44 pure LG-tub1s and nine LG-tub1s containing HG-tub1) lesions and seven LG-tub1 > tub2 (LG-tub1 containing LG- and HG-tub2) lesions.ResultsThe frequencies of the superficial depressed type (P = 0.026), reddish colour (P = 0.006), HG of contained tub2s (P = 0.006), and G-phenotype (P = 0.028) were significantly higher in the LG-tub1 > tub2 group than those in the tub1 group. However, the largest lesion of the LG-tub1 > tub2 group had a superficial flat appearance, an isochromatic colour, an HG-tub2 and an undifferentiated component, and a large diameter greater than 30 mm, and it exhibited a G-phenotype.ConclusionsIntramucosal G-phenotype LG-tub1s > HG-tub2 are potential premalignant stomach neoplasms that may have specific endoscopic and clinicopathological features. However, G-phenotype LG-tub1s > HG-tub2 with undifferentiated component, which potentially show higher malignancy than those without undifferentiated components might change from a reddish to isochromatic colour. Accurately diagnosing, treating, and following-up G-phenotype LG-tub1s > HG-tub2 might decrease the number of patients who experience late-onset metastasis after ESD.

Prevalence and associated malignancy of Bethesda category III cytologies of thyroid nodules assigned to the “cytological atypia” or “architectural atypia” groups

ObjectiveTo ascertain the prevalence of Bethesda category III cytologies and their malignancy rate, and to analyze differences in the second cytology, malignancy rate, type of carcinoma, and TNM stage between the cytological atypia (CA) and architectural atypia (AA) groups. Patients and methodA retrospective study of 973 biopsies. Bethesda category III cytologies were classified as CA when nuclear atypia was seen but they were not diagnostic or suspicious of malignancy, and as AA when smears had few cells but had a predominantly microfollicular pattern and minimal or absent colloid. The cytological and pathological results were correlated. ResultsThere were 87 (8.9%) Bethesda category III cytologies (34 CC, 53 AA). Second cytologies were performed in 23 patients (16 with CA, 7 with AA), and a benign result was found in 68.7% of CA and 71.4% of the AA group. Sixty-four patients (23 CA, 41 AA) underwent surgery and 15 of these (23.4%) had a malignant disease: 39.1% CA vs 14.6% AA (p=0.029). There was a false negative result in the CA group. The follicular variant of papillary thyroid carcinoma was the most common malignancy (60%). There were no differences in type of carcinoma or TNM stage between CA and AA patients. ConclusionsThe reported prevalence of Bethesda category III cytologies was as expected. The malignancy rate was significantly higher in the CA group, but there were no differences in the result of the second cytology, type of carcinoma found, or TNM stage. The division of Bethesda category III cytologies is useful to provide a better stratification of the risk of malignancy.

Both Ultrasound Features and Nuclear Atypia are Associated with Malignancy in Thyroid Nodules with Atypia of Undetermined Significance.

The optimal management of thyroid nodules that undergo fine-needle aspiration (FNA) with findings of atypia of undetermined significance (AUS) is unclear. Categorizing nodules by AUS subtype and ultrasound characteristics may improve risk stratification. Therefore, the purpose of this study is to evaluate the association between AUS subtype and ultrasound features on risk of malignancy (ROM). We performed a review of all patients with a thyroid nodule who underwent an FNA at our institution between January 2010 and November 2015. Patients with AUS were divided into groups with (1) nuclear atypia, (2) architectural atypia, or (3) Hurthle cell atypia. Their ultrasound features were assessed using the American Thyroid Association (ATA) thyroid nodule sonographic patterns. We conducted a univariate and multivariable analysis to determine the association between AUS subtype and other variables of interest with ROM. Of the 3428 thyroid nodules that underwent FNA, 237 (6.9%) had AUS. Of the 97 surgically resected nodules, 67 (69%) were benign and 30 (31%) were malignant. On univariate analysis nuclear atypia (p < 0.01) was associated with a thyroid malignancy. On multivariable analysis, both ATA high-risk ultrasound features (p = 0.04, odds ratio [OR] 3.68) and nuclear atypia (p < 0.01, OR 11.8) were independently associated with a final diagnosis of thyroid carcinoma. Nuclear atypia and ATA high-risk ultrasound features are useful in identifying patients with AUS that are at a higher risk of thyroid malignancy. Surgeons should take these factors into consideration when evaluating patients with AUS.

Prevalencia y malignidad asociada de las citologías de categoría Bethesda III de nódulos tiroideos según el grupo «atipia citológica» o «atipia arquitectónica»

ObjectiveTo ascertain the prevalence of Bethesda category III cytologies and their malignancy rate, and to analyze differences in the second cytology, malignancy rate, type of carcinoma, and TNM stage between the cytological atypia (CA) and architectural atypia (AA) groups. Patients and methodA retrospective study of 973 biopsies. Bethesda category III cytologies were classified as CA when nuclear atypia was seen but they were not diagnostic or suspicious of malignancy, and as AA when smears had few cells but had a predominantly microfollicular pattern and minimal or absent colloid. The cytological and pathological results were correlated. ResultsThere were 87 (8.9%) Bethesda category III cytologies (34 CC, 53 AA). Second cytologies were performed in 23 patients (16 with CA, 7 with AA), and a benign result was found in 68.7% of CA and 71.4% of the AA group. Sixty-four patients (23 CA, 41 AA) underwent surgery and 15 of these (23.4%) had a malignant disease: 39.1% CA vs 14.6% AA (P=.029). There was a false negative result in the CA group. The follicular variant of papillary thyroid carcinoma was the most common malignancy (60%). There were no differences in type of carcinoma or TNM stage between CA and AA patients. ConclusionsThe reported prevalence of Bethesda category III cytologies was as expected. The malignancy rate was significantly higher in the CA group, but there were no differences in the result of the second cytology, type of carcinoma found, or TNM stage. The division of Bethesda category III cytologies is useful to provide a better stratification of the risk of malignancy.

A Proposal for Separation of Nuclear Atypia and Architectural Atypia in Bethesda Category III (AUS/FLUS) Based on Differing Rates of Thyroid Malignancy.

Bethesda category III (atypia of undetermined significance/follicular lesion of undetermined significance) includes sparsely cellular specimens with nuclear atypia (3N) and/or architectural atypia (3A). This study investigates whether the two types of atypia have different rates of malignancy (ROMs). Cytologic and histologic diagnoses of resected thyroid nodules were recorded. ROM was calculated for all Bethesda categories and for 3N and 3A subcategories. Possible noninvasive follicular thyroid neoplasms with papillary-like nuclear features were reviewed and removed from malignancies, and ROM was recalculated. A total of 1,396 nodules were included. ROM of 3N (33.3%-26.0%) was higher than 3A (7.7%-5.0%) (P < .0001) and was similar to suspicious for follicular neoplasm (25.0%-20.3%) (P = .3). ROM of 3A approached benign (2.4%-1.5%) (P = .02). Strong consideration should be given to separating 3N (nuclear atypia with higher risk for papillary thyroid carcinoma) from 3A (architectural atypia with higher chance of being benign) to convey different ROMs.

Benign Hepatic Lesions Arising in Accessory Hepatic Lobes

Abstract An accessory hepatic lobe is an uncommon hepatic congenital anomaly that can sometimes mimic a mass lesion clinically and radiologically. Because accessory hepatic lobes are only rarely resected, detailed descriptions of their histologic features are sparse. We report the histologic and immunohistochemical features of 3 cases of resected accessory hepatic lobes, all of which contained benign hepatic lesions (2 hepatic adenomas [HAs] and 1 focal nodular hyperplasia). All accessory lobes were connected to the liver by a pedicle. Histologically, all lesions demonstrated no cytologic or architectural atypia. Based on immunohistochemical analysis, 1 HA was classified as inflammatory type (positive for C-reactive protein and serum amyloid A), and 1 was unclassified type (negative for C-reactive protein, serum amyloid A, glutamine synthetase, and β-catenin and positive for liver fatty acid–binding protein); the focal nodular hyperplasia showed the typical map-like staining pattern with glutamine synthetase. Interestingly, multiple foci of myelolipoma were identified within the unclassified-type HA. Of note, in all cases, the nonlesional hepatic parenchyma featured structural vascular abnormalities of the hepatic artery branches, including abnormal thickening of arterial branches and multiple arterial branches per single portal tract. Our findings describe, for the first time, benign hepatic lesions arising in accessory hepatic lobes and suggest that accessory lobes are perhaps prone to such benign lesions because of structural abnormalities in their vasculature.

Metachronous rectal metastasis from primary transverse colon cancer: a case report

BackgroundColorectal metastases from primary colorectal cancers are very rare, and little is known about their epidemiological aspects or the best diagnostic and therapeutic strategies. Herein, we report a case of a 65-year-old woman with suspected metachronous metastasis to the rectum from primary transverse colon cancer.Case presentationThe patient underwent a laparoscopic extended right hemicolectomy for primary transverse colon cancer. Histopathological examination showed moderately differentiated adenocarcinoma, and the tumor was diagnosed as stage IIA (T3, N0, M0). Fifteen months after her colectomy, a computed tomography scan demonstrated a rectal tumor and a right ovarian tumor. Colonoscopy revealed a superficial elevated lesion in the middle rectum, and histological analysis showed moderately differentiated adenocarcinoma. Laparoscopic low anterior resection preserving the left colic artery and bilateral adnexectomy were performed. Histological examination of the rectal tumor showed that adenocarcinoma was mainly present in the submucosa and muscularis propria, while the carcinoma-involved region of the mucosal layer had mucosal colonization representing the spread of metastatic tumor cells along the basement membrane of preexisting crypts and/or villi. The right ovarian tumor proved to be moderately differentiated adenocarcinoma that was positive for cytokeratin 20 and negative for cytokeratin 7 staining, indicating metastasis from the colorectal cancer. The rectal and ovarian tumors were similar to transverse colon cancer in architectural and cytological atypia. Both adenocarcinomas of the transverse colon and rectum were negative for p53 in immunohistochemical staining and RAS wild type in genetic assessment. These findings support a possible diagnosis of rectal and ovarian metastasis from the primary transverse colon cancer. The patient recovered well after surgery, and neither relapse nor metastasis was observed 18 months after surgery.ConclusionDistinguishing primary from metastatic colorectal cancer can be challenging, but a comprehensive evaluation of histological features, clinical history, and tumor distribution can enable making a correct diagnosis and implementing optimal treatment.

Intraductal Papillary Mucinous Neoplasms of Minor Salivary Glands With AKT1 p.Glu17Lys Mutation.

The spectrum of low-grade intraductal papillary proliferations of the salivary glands is heterogenous, and reproducible morphologic diagnostic criteria have not yet been established. Recognized types are sialadenoma papilliferum, inverted ductal papilloma, and intraductal papilloma, but some lesions have been possibly included in the morphologic spectrum of cystadenoma or low-grade intraductal carcinomas. We herein present detailed morphologic, immunophenotypic, and genotypic features of 3 minor salivary gland neoplasms affecting 2 men (aged 65 and 71 y) and 1 woman (aged 78 y). They ranged in size from 1 to 2.5 cm. All tumors showed atypical papillary intraductal growth that presented either as uninodular/unicystic lesions (intraductal papilloma-like; n=2) or as a discontinuous growth along the ductal system in a manner similar to pancreatic intraductal papillary mucinous neoplasm (n=1). Variable cytologic and architectural atypia was observed, ranging from bland intraductal papilloma-like features, to areas mimicking atypical ductal hyperplasia and low-grade ductal carcinoma in situ of the breast. Amplicon-based massive parallel sequencing revealed an identical AKT1 p.Glu17Lys mutation in all 3 cases, but absence of concurring mutations in other genes of the RAS or PI3K pathway. This small series represents the first genetic study on salivary intraductal papillary neoplasms. Our cases showed significant variation in the degree of cytologic and architectural atypia, which overlaps with intraductal papillomas at the one end and with low-grade intraductal carcinoma at the other end of the spectrum, suggesting a disease continuum. As the full biological and morphologic characteristics of these ductal papillary lesions remain to be defined, the noncommitted term "intraductal papillary neoplasms" might be more appropriate. Our novel genetic findings mirror similar activating mutations of AKT1 and other PI3K pathway members in intraductal papillary lesions of the breast and anogenital glands.

Web-based thyroid imaging reporting and data system: Malignancy risk of atypia of undetermined significance or follicular lesion of undetermined significance thyroid nodules calculated by a combination of ultrasonography features and biopsy results.

The purpose of this study was to construct a web-based predictive model using ultrasound characteristics and subcategorized biopsy results for thyroid nodules of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) to stratify the risk of malignancy. Data included 672 thyroid nodules from 656 patients from a historical cohort. We analyzed ultrasound images of thyroid nodules and biopsy results according to nuclear atypia and architectural atypia. Multivariate logistic regression analysis was performed to predict whether nodules were diagnosed as malignant or benign. The ultrasound features, including spiculated margin, marked hypoechogenicity, calcifications, biopsy results, and cytologic atypia, showed significant differences between groups. A 13-point risk scoring system was developed, and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve of the development and validation sets were 0.837 and 0.830, respectively (http://www.gap.kr/thyroidnodule_b3.php). We devised a web-based predictive model using the combined information of ultrasound characteristics and biopsy results for AUS/FLUS thyroid nodules to stratify the malignant risk.

Subclassification of Bethesda Atypical and Follicular Neoplasm Categories According to Nuclear and Architectural Atypia Improves Discrimination of Thyroid Malignancy Risk.

Although The Bethesda System for Reporting Thyroid Cytopathology has provided clinicians with a standardized classification scheme for the diagnosis of thyroid fine-needle aspiration cytology (FNAC) specimens, the indeterminate categories of Bethesda III (B3)-atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS)-and Bethesda IV (B4)-follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)-continue to pose challenges with regards to ideal diagnostic and therapeutic management. Having previously demonstrated the presence of nuclear atypia as a high-risk subgroup in B3, the objective of this study was to evaluate the malignancy rates in the B4 subgroup with nuclear atypia. A retrospective review of all thyroid FNACs diagnosed as B4 (FN/SFN) between 2008 and 2015 was conducted at a tertiary referral center in Singapore. Data on patient demographics, sonographic features, and final histological diagnosis were collected. This was compared to data from a previous analysis on all nodules diagnosed as B3 (AUS/FLUS) over a similar period. A total of 137/309 (44.3%) and 88/111 (79.3%) FNACs diagnosed as B3 and B4, respectively, underwent surgical excision yielding final histopathological diagnoses. The malignancy rate of B4 was 31/88 (35.2%) compared to B3, which was 37/137 (27.0%). Subclassification based on the presence of architectural versus nuclear atypia showed significantly higher malignancy rates in B4 nodules with nuclear atypia (21.8% vs. 57.6%; p < 0.01). These findings corroborate previous results within the B3 category (malignancy rate of 14.7% vs. 36.8%; p < 0.01). The only sonographic features predictive of malignancy were the presence of macrocalcifications in B4 compared to irregularity of margins in B3. The presence of nuclear atypia identifies subgroups with significant differential malignancy risks within both the B3 and B4 categories. This supports the notion that subclassification is a useful risk stratification tool that can guide diagnostic and therapeutic management of indeterminate thyroid nodules with heterogenous risk profiles.

Different qualifiers of AUS/FLUS thyroid FNA have distinct BRAF, RAS, RET/PTC, and PAX8/PPARg alterations.

The Bethesda System for Reporting Thyroid Cytopathology category of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) includes fine-needle aspiration (FNA) specimens that cannot straightforwardly be classified as benign or malignant. To determine whether morphological subcategorization based on atypia qualifiers and molecular testing could improve malignancy risk stratification of AUS/FLUS patients, this study assessed the correlation between these qualifiers and the molecular alterations commonly harbored by thyroid neoplasms. A total of 162 AUS/FLUS cases were subcategorized by atypia qualifiers (Hürthle cell changes, architectural atypia, and cytologic atypia [CyA]) and were tested for BRAF, N-H-KRAS, RET/PTC, and paired box 8 (PAX8)/peroxisome proliferator activated receptor γ (PPARg) mutations. CyA was observed more frequently in mutation-positive AUS/FLUS (14 of 37 [37.84%]) than mutation-negative AUS/FLUS (20 of 125 [16.00%]; P < .0084), and it specifically harbored the BRAFV600E point mutation. Malignancy was confirmed in the available follow-up. Conversely, although RAS was the most frequent mutation identified in AUS/FLUS FNA specimens (26 of 37 cases [70.27%]; P < .0001), it was distributed across various AUS/FLUS subcategories and was not significantly associated with a specific atypia qualifier or malignant outcome according to the available follow-up. Rearrangements of both RET/PTC (n = 1) and PAX8/PPARg (n = 3) were rarely retrieved in the FNA samples. BRAF and RAS mutations are associated with different AUS/FLUS qualifiers and hence have different risks of malignancy. Consequently, a hybrid molecular and morphological subcategorization system could improve the malignancy risk stratification of thyroid FNA samples diagnosed as AUS/FLUS. Cancer Cytopathol 2018;126:317-25. © 2018 American Cancer Society.

High-grade prostatic intraepithelial neoplasia, PIN-like carcinoma, ductal carcinoma, and intraductal carcinoma of the prostate

Many prostate lesions have ‘large gland’ morphology with gland size similar to or larger than benign glands, complex glandular architecture including papillary, cribriform, and solid, and significant cytological atypia in glandular epithelium with nucleomegaly, prominent nucleoli, or anisonucleosis. The most common and clinically important lesions with ‘large gland’ morphology include high-grade prostatic intraepithelial neoplasia (HGPIN), PIN-like carcinoma, ductal adenocarcinoma, and intraductal carcinoma. These lesions have diverse clinical significance and management implications. HGPIN refers to proliferation of glandular epithelium that displays severe cytological atypia within the confines of prostatic ducts and acini. A HGPIN diagnosis in biopsies connotes ~25% risk of detection of cancer in repeat biopsies. It has been accepted as the main precursor lesion to invasive carcinoma. PIN-like carcinoma is a variant of acinar carcinoma that is morphologically reminiscent of HGPIN and is composed of large cancer glands lined with pseudostratified epithelium. Its clinical outcome is similar to that of usual acinar carcinomas and is graded as Gleason score 3+3=6. Ductal adenocarcinoma comprises large glands lined with tall columnar and pseudostratified epithelium. It is more aggressive than acinar carcinomas and is associated with higher stage disease and greater risk of PSA recurrence and mortality. Intraductal carcinoma is an intraglandular/ductal neoplastic proliferation of glandular epithelial cells that results in marked expansion of glandular architecture and nuclear atypia that often exceeds that in invasive carcinomas. In majority of cases, it is thought to represent retrograde extension of invasive carcinoma into pre-existing ducts and acini. Rarely it may represent a peculiar form of carcinoma with predilection for intraductal location. It is considered an adverse pathological feature and is seen almost always in high-grade and volume carcinoma and harbingers worse clinical outcomes. This article reviews ‘new’ information on the clinical and pathological features of HGPIN, PIN-like carcinoma, ductal carcinoma, and intraductal carcinoma, and focuses morphological features that aid the differential diagnosis.

The variegated histopathological features of atypical lentiginous melanocytic nevi: a single institution experience.

Atypical lentiginous melanocytic nevi (ALMNs) are atypical pigmented lesions with histopathological features similar to those of dysplastic nevi, with a lentiginous pattern. Variable histopathological features of ALMNs were observed in our practice. We described the histopathological features of ALMNs diagnosed in the period 2009-2015. Our cases were divided into 2 groups: Group 1: ALMNs showing the same histopathological features as previously described in the literature; Group 2: ALMNs with different features. Twenty-nine ALMNs were diagnosed; 2 groups of ALMNs were identified. Group 1 ALMNs showed a constant, mild epidermal acanthosis; frequently, an inflammatory infiltrate and dermal fibrosis, cytological atypia and mild architectural atypia. Group 2 ALMNs showed a constant psoriasis-like acanthosis with a hypercellularity of the rete ridges; cytological atypia was rare, whereas architectural atypia was constantly observed. Immunohistochemistry (MART-1 staining) revealed that the melanocytes were localized at the dermo-epidermal junction in both groups. ALMNs showed a broad spectrum of histopathological features. Our main finding was a constant architectural atypia in all lesions of Group 2. The identification of a unique type of ALMN seems no longer possible. The correct recognition of such benign, though atypical, melanocytic lesions is important in order to avoid an overdiagnosis of cutaneous melanoma and to prevent their potential evolution to the latter.

Cancer Risk Stratification of Indeterminate Thyroid Nodules: A Cytological Approach.

Management recommendations for thyroid nodules rely primarily on the cytological diagnosis. However, 25% of biopsies render an indeterminate cytology for which management decision is more challenging due to heterogeneity of the specimens. This study aimed to stratify the cancer risk through subcategorization of indeterminate cytology. The indeterminate cytological specimens (Bethesda-III or IV) of 518 thyroid nodules consecutively evaluated at our academic cancer center between October 2008 and September 2015, blinded to the histological outcome, were retrospectively reviewed. Cytological specimens were subclassified into four groups: aspirates exhibiting nuclear atypia (n = 158; 31%); architectural atypia (n = 222; 43%); oncocytic features (n = 120; 23%); or other types of atypia (n = 18; 3%). The prevalence of malignancy and odds ratio for malignancy were calculated in 323 nodules with histological confirmation. The prevalence of malignancy was 26% overall (20% in Bethesda-III and 29% in Bethesda-IV; p = 0.07), and 47%, 12%, 24%, and 25% for aspirates with nuclear atypia, architectural atypia, oncocytic features, or other types of atypia, respectively. The OR of nuclear atypia over architectural atypia was 6.4 (3.4-12.2; p < 0.001), and 2.7 over oncocytic features (1.4-5.1; p = 0.01), whereas the OR of architectural atypia over oncocytic features was 0.4 (0.2-0.9; p = 0.03). Results were similar for Bethesda-III and IV aspirates when analyzed independently. Furthermore, cytological subcategories improved cytology-histology correlation, as they were associated with distinct profiles of histological diagnoses (p < 0.001). Cytological subcategories can effectively stratify the risk of malignancy of thyroid nodules with indeterminate cytology and improve cytology-histology correlation.