Does Differentiated Squamous Intraepithelial Neoplasia Occur in the Cervix?

BACKGROUND: Invasive cervical cell squamous carcinoma (ICC) classically develops from high grade cervical intraepithelial neoplasia of usual type (uCIN). Differentiated cervical intraepithelial neoplasia (dCIN) analogue to differentiated vulvar intraepithelial neoplasia has not been described in the cervix. METHODS: A pilot case of ICC developing from dCIN with atypia limited to the basal/parabasal layers, focally associated with neoplastic spread above the parabasal layer (usual-like CIN pattern or u-like CIN) was identified. The previous cervical biopsy was under-diagnosed as low grade CIN. A total of 33 consecutive cases of ICC were reviewed to identify dCIN, u-like CIN and uCIN. RESULTS: The ICC developed from dCIN/u-like CIN in 2 patients, 46 and 47-year-old (group 1), mixed dCIN/u-like CIN and uCIN in 7 patients, 36±3-year-old (group 2) and from uCIN in 24 patients, 47±9-year-old (group 3). In group 1, focal uCIN but not connected to ICC was also seen and Pap smears showed only hyper-keratinized cells with mildly atypical nuclei. Endocervical gland involvement by CIN was absent in group 1, focal in group 2 and extensive in group 3. All cases showed diffuse p16 staining. P53 reactivity was noted in basal/parabasal in dCIN, predominantly lower and upper parts of the epithelium in groups 2 and 3, respectively. CONCLUSIONS: Totally, 27% of ICC cases had associated dCIN/u-like CIN and in younger patients than in the uCIN group. Larger studies are needed to confirm dCIN/u-like CIN as significant precursor lesions of ICC.

Laryngeal Squamous Cell Carcinomas are Commonly Associated With Differentiated Squamous Intraepithelial Neoplasia With or Without an Admixture With Usual Type of Squamous Intraepithelial Neoplasia: Clinical and Pathologic Significance.

BACKGROUND: Differentiated squamous intraepithelial neoplasia (dSIN) is a pathway in the development of invasive squamous cell carcinoma (SCC) distinct from the usual-type squamous intraepithelial neoplasia (uSIN) and has not been described in the larynx. MATERIALS AND METHODS: Sixty-nine consecutive cases of SCC were identified which included 25 dSIN, 13 uSIN, and 31 mixed dSIN+usual-like SIN (u-like SIN) cases. RESULTS: dSIN was characterized by atypical squamous cells limited to the basal/parabasal layers and u-like SIN was characterized by cytologic atypia limited to less than full thickness. Despite the lack of neoplastic involvement of the full thickness of the epithelium, these types of SIN were commonly connected with invasive carcinoma. Prior biopsies demonstrating only dSIN, without the underlying invasive SCC, were underdiagnosed in 2 cases. Because of the frequent keratinization, u-like SIN likely represents the "keratinized dysplasia" and shows changes suggestive of dSIN with upward spread of neoplastic cells into the upper layer of the epithelium. CONCLUSIONS: Laryngeal dSIN represents an important but under recognized pathway of invasive SCC development. As moderate dysplasia of uSIN type are not associated with invasive SCC, labeling u-like SIN as dysplasia of grade 2 or 3 likely leads to the controversies in the current grading systems in the upper aerodigestive system and causes confusion for clinicians.

Plasmacytoid urothelial carcinoma (PUC): Imaging features with histopathological correlation.

INTRODUCTION: Plasmacytoid urothelial carcinoma (PUC) is a high-grade variant of conventional urothelial cell carcinoma. This study is the first to describe the imaging findings of PUC, which are previously unreported, using clinical and histopathological correlation. METHODS: With internal review board approval, we identified 22 consecutive patients with PUC from 2007-2014. Clinical parameters, including age, gender, therapy, surgical margins, and long-term outcome, were recorded. Baseline imaging was reviewed by an abdominal radiologist who evaluated for tumour detectability/location/morphology, local staging, and presence/location of metastases. Pelvic peritoneal spread of tumour (defined as >5mm thick soft tissue spreading along fascial planes) was also evaluated. Followup imaging was reviewed for presence of local recurrence or metastases. RESULTS: Median age at presentation was 74 years (range 51-86), with only three female patients. Imaging features of the primary tumour in this study were not unique for PUC. Muscle-invasive disease was present on pathology in 19/22 (86%) of tumours, with distant metastases in 2/22 (9%) at baseline imaging. Pelvic peritoneal spread of tumour was radiologically present in 4/20 (20%) at baseline. During followup, recurrent/residual tumour was documented in 16/22 (73%) patients and 7/16 (44%) patients eventually developed distant metastases. Median time to disease recurrence in patients who underwent curative surgery was three months (range 0-19). CONCLUSIONS: PUC is an aggressive variant of urothelial carcinoma with poor prognosis. Pelvic peritoneal spread of tumour as thick sheets extending along fascial planes may represent a characteristic imaging finding of locally advanced PUC.

Flat Intraurothelial Neoplasia Exhibiting Diffuse Immunoreactivity for CD44 and Cytokeratin 5 (Urothelial Stem Cell/Basal Cell Markers): A Variant of Intraurothelial Neoplasia Commonly Associated With Muscle-invasive Urothelial Carcinoma.

BACKGROUND: Immunoreactivity for CD44 and cytokeratin (CK)5 (urothelial stem/basal cell markers) are decreased/negative in the common type of intraurothelial neoplasia including urothelial carcinomas (UC) in situ. Recent studies also reveal that a majority of muscle-invasive UC are basal-like UC with large areas of positive CD44/CK5 immunoreactivity. In addition, approximately 80% of muscle-invasive UC develop de novo as nonpapillary invasive UC. In this study, we investigate the CD44/CK5 immunoreactivity of the flat intraurothelial neoplasia (FIUN) associated with nonpapillary invasive UC. MATERIALS AND METHODS: Consecutive cases of nonpapillary UC were submitted for immunostaining. Immunostaining for CK5/CD44 was scored as high for staining of >25% thickness of urothelium and low for lesser immunoreactivity. RESULTS: In total, 109 consecutive cases were grouped into: in situ UC [carcinoma in situ (CIS)] (n=11), pT1 (n=14), and pT2-4 (n=84) with surface urothelium available for study. Forty-four cases including CIS (n=9), pT1 (n=12), and pT2-4 (n=23) showed FIUN with low/negative CD44/CK5 reactivity; 40 cases showed strong CK20 reactivity. Sixty-two cases including CIS (n=2), pT1 (n=2), and pT2-4 (n=58) showed extensive FIUN exhibiting high CD44/CK5 reactivity; 30 cases showed reactive CK20. FIUN lesions with high CD44/CK5 reactivity scores were associated with mild (urothelial dysplasia) to moderate atypia (CIS) and were rarely preceded by papillary UC. Most invasive UC associated with FIUN with high CD44/CK5 reactivity also exhibited extensive CD44/CK5 reactivity. The remaining 3 cases showed only reactive urothelium. Of interest, 4 cases with FIUN showed negative CD44/CK5/CK20 reactivity. CONCLUSIONS: Existence of CD44/CK5-immunoreactive (or basal-like) FIUN is consistent with the recent distinction of basal and luminal subtypes of UC. This type of FIUN is often associated with UC with progression to high-stage disease not preceded by recurrent papillary UC.

Clear Cell Urothelial Carcinoma.

Clear cell urothelial carcinoma (CCUC) is a rare variant of urothelial carcinoma (UC) and its clinical significance has not been well elucidated. Consecutive cases of UC over a period of 5 years were reviewed. Histopathological tumor parameters, including the proportion of tumor cells with clear cell change, and patient outcomes were recorded. Expression of the following immunohistochemical markers was investigated: CK7, CK20, CK5, CD44, and PAX8. We also conducted a review of the literature for case reports/series of CCUC. Ten CCUCs were identified out of a total of 872 cases of UC. The clear cell component was characterized by prominent cytoplasmic membranes and voluminous clear cytoplasm, and accounted for 30% to 90% of the invasive tumor component. Of all the non-CCUC cases reviewed, at least 50% (noninvasive or invasive UC) showed focal areas of clear cell change that accounted for less than 5% of the neoplastic cells. Immunohistochemically, CCUC exhibited positive reactivity for CK5/CD44 (n = 9); CK20 (n = 5), PAX8 (very focal to extensive) (n = 6), and GATA3/CK7 (n = 10). Eight of 10 CCUC were of advanced clinical stage (pT3/pT4) and 6 of 10 experienced tumor recurrence and/or death due to disease. In conclusion, CCUC can be distinguished from non-CCUC by the extensive clear cell change in more than 30% of cells. This variant is associated with rapid progression to muscle invasion and metastasis, with an aggressive clinical course. Expression of CK5/CD44 may represent basal cell features in most CCUC cases, while PAX8 expression is suggestive of mesonephric derivation.

Perineural invasion on biopsy is associated with upstaging at radical prostatectomy in Gleason score 3 + 4 = 7 prostate cancer.

This study assesses if perineural invasion (PNI) detected on biopsy with Gleason score (GS) 3 + 4 = 7 prostate cancer (PCa) is associated with upstaging/upgrading of disease after radical prostatectomy (RP). 154 patients with GS 3 + 4 = 7 PCa diagnosed from biopsy who underwent RP were assessed for PNI. The percentage of biopsy sites with PNI (%PNI) was also calculated. Pattern 4 morphologies (ill-defined glands [IDG], fused, cribriform, and glomerulations) were also assessed. Clinical information, GS and stage after RP were retrieved from the medical records. 45 % (69/154) of patients were upstaged (≥pT3) and 29 % (44/154) were upgraded to GS >3 + 4 = 7 after RP. 37 % (57/154) of patients had PNI which was associated with upstaging (RR 1.4; P = 0.04) but not upgrading (RR 0.9; P = 0.7). There was higher %PNI in upstaged patients (12.1 % ± 1.8 vs. 7.1 % ± 1.5, P = 0.03) with a significant correlation between %PNI and ≥pT3 (r = 0.178, P = 0.027). After multivariate analysis, only cribriform formations were significantly associated with upstaging (P = 0.009). The presence of PNI in biopsies with GS 3 + 4 = 7 PCa is associated with upstaging at RP but is a weaker predictor of ≥pT3 disease than cribriform morphology.

Stromal tissue as an adjunct tool in the diagnosis of follicular thyroid lesions by fine-needle aspiration biopsy.

BACKGROUND: The stroma in fine-needle aspiration biopsy (FNAB) of thyroid lesions has not been well investigated. DESIGN: We studied 256 consecutive cases of thyroid FNAB prepared with traditional smear technique. The stroma was categorized: Type 1a consisted of long (more than 3 mm), broad bands composed of mesh containing collagen fibrils thickened by entrapped blood components and follicular cells. Type 1b consisted of dense strands/bands. Type 2 was similar to Type 1a but with shorter (<2 mm) and looser stromal strands. RESULTS: Types 1a and b showed straight/curved/circular branching patterns suggestive of incomplete frameworks of nodular/papillary architectures or fragments of capsule. Type 1b stroma likely represented thick/collagenized fibrous septae. Incomplete or complete rings of small encapsulated tumor were occasionally identified. These frameworks of stroma were frequently associated with multinodular goiters (MNGs) which are often hypocellular and follicular neoplasms/papillary thyroid carcinoma with increased cellularity. Type 2 was associated with microfollicles in encapsulated neoplasms or with macrofollicles in MNG. Follicular lesions of unknown significance (n = 41) either negative (n = 26) or positive (n = 15) for carcinoma in subsequent follow-up were frequently associated with stroma characteristic of MNG and carcinoma, respectively. CONCLUSION: The preservation of the in vivo architecture of Type 1 is likely due to its elasticity. Recognition of the stromal architecture will likely facilitate the diagnosis.

Utility of Gleason pattern 4 morphologies detected on transrectal ultrasound (TRUS)-guided biopsies for prediction of upgrading or upstaging in Gleason score 3 + 4 = 7 prostate cancer.

Selected patients with Gleason score (GS) 3 + 4 = 7 prostate cancer (PCa) detected on transrectal ultrasound (TRUS)-guided biopsies may be considered for active surveillance (AS); however, a proportion of these will harbor more aggressive disease. The purpose of this study was to determine if morphologies of Gleason pattern 4 PCa may predict upgrading and/or upstaging after radical prostatectomy (RP). A database search for men with GS 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsy that underwent RP between January 2010 and October 2015 identified 152 patients. Two blinded genitourinary pathologists independently reviewed the biopsies and assessed ill-defined glands (IDG), fused glands, small or large cribriform patterns, and glomerulations. Patient age, serum prostate-specific antigen (PSA), percentage (%) of biopsy sites involved by 3 + 4 = 7 PCa, and overall extent of pattern 4 were also recorded. GS and stage (presence or absence of extraprostatic extension [EPE]) were retrieved from RP reports. Data were compared using independent t tests and chi-square. Inter-observer agreement was calculated using Cohen's Kappa statistic. Percent of biopsy sites and extent of pattern 4 were compared to statistically significant morphologies using the Spearman correlation. 28.3 % (43/152) of patients were upgraded to GS >3 + 4 = 7 at RP (GS 4 + 3 = 7 [N = 17], GS 4 + 3 = 7 with tertiary pattern 5 [N = 25], and GS 4 + 5 = 9 [N = 1]) and 44.1 % (67/152) showed EPE after RP. PSA was associated with both upgrading (8.5 ± 5.4 vs. 6.9 ± 3.2 ng/mL, [p = 0.04]) and EPE (8.2 ± 4.6 vs. 6.7 ± 3.2 ng/mL, [p = 0.03]). IDG, fused glands, and glomerulations were not associated with upgrading or EPE (p > 0.05) with moderate to strong inter-observer agreement (K = 0.76-0.88). There was strong inter-observer agreement for small and large cribriform formations (K = 0.93 and 0.94, respectively) and both patterns were strongly associated with upgrading (p < 0.001) and EPE (p = 0.02) on RP. Strong associations were observed between increasing number of morphologies and both upgrading (p = 0.0.25) and EPE (p < 0.001). Overall extent of pattern 4 was associated with upgrading (p = 0.009) and EPE (p = 0.019) while percent of sites involved by GS 3 + 4 = 7 was only associated with EPE (p = 0.023). Cribriform morphology correlated to percentage of sites with 3 + 4 and overall extent of pattern 4 (rho = 0.25, p = 0.002, rho = 0.20, p = 0.015, respectively). Presence of cribriform morphology on TRUS-guided biopsy is strongly associated with upgrading and upstaging at RP and shows near-perfect inter-observer agreement whereas IDG, fused glands, and glomerulations were not useful. Cribriform morphology may be of importance when considering treatment plans for patients with intermediate risk PCa.

Noninvasive Papillary Basal-like Urothelial Carcinoma: A Subgroup of Urothelial Carcinomas With Immunohistochemical Features of Basal Urothelial Cells Associated With a High Rate of Recurrence and Progression.

BACKGROUND: We investigated the clinical and pathologic significance of a subgroup of noninvasive papillary urothelial carcinomas (UCs) expressing reactivity to urothelial basal cell markers. DESIGN: In total, 302 consecutive cases of noninvasive papillary UC were evaluated immunohistochemically with cytokeratin 5 (CK5)/CD44. Any UC that was reactive for greater than 25% thickness of the urothelium was designated as basal-like urothelial carcinoma (BUC); remaining UC cases were designated as non-BUC. The follow-up period was up to 3 years. Historical review of UC was extended for up to 3 retrospective years. RESULTS: Among 302 noninvasive UC, BUC was identified in 33 of 256 (12.9%) low-grade UC and 8 of 46 (17%) high-grade UC (P=0.041). Immunoreactivity for CD44 was similar to that of CK5, but displayed weaker and more diffuse staining. CK20 was reactive in 9 cases, primarily high-grade BUC. Other basal cell markers (34bE12, p63, bcl2, and EP4) were found to be neither sensitive nor specific in detecting UC with high CK5 expression. In comparison with non-BUC, BUC was associated with increased multifocality, larger tumor size, higher recurrence rate, and more frequent upgrading and stage progression. In the follow-up period of 3 years, distant metastasis occurred in 6 cases of which 5 were in the BUC subgroup. CONCLUSIONS: Our results showed that noninvasive papillary BUC represents a small subset associated with increased risk of tumor recurrence and progression. The aggressive behavior is likely associated with basal-like features of BUC, as seen in carcinomas with basal cell features in other body sites.

Differentiated squamous intraepithelial neoplasia associated with squamous cell carcinoma of the anal canal.

AIMS: Differentiated squamous intraepithelial neoplasia (DSIN) has been described in several sites, including the upper aerodigestive tract and vulva, so this study investigated whether it also occurred in the anal canal. METHODS AND RESULTS: All cases of squamous cell carcinoma (SCC) involving the anal canal diagnosed between 2009 and 2015 at our institution were reviewed. Eighty-six cases were included, and 13 (15%) showed features consistent with DSIN: 10 were 'pure' DSIN, and three were 'mixed' DSIN and squamous intraepithelial lesion. DSIN was characterized by atypical keratinocytes limited to the basal/parabasal layers, acanthosis, and a 'cobblestone' appearance. Among specimens with pure DSIN, the surface was flat in eight cases. In five cases, the DSIN was extensive, and associated with deeply invasive SCC requiring radical surgical resection. Immunohistochemically, the epithelia showing changes consistent with DSIN were p16-negative, whereas the invasive component was p16-positive in 12 cases. Both Ki67 and p53 showed strong nuclear positivity in the basal/parabasal layers of DSIN. CONCLUSIONS: Invasive SCC associated with DSIN often presents at an advanced stage of disease, requiring radical surgical treatment. The neoplastic changes in DSIN are limited to the basal/parabasal layers, which may account for the negative diagnoses by anal cytopathology and late clinical diagnosis. The recognition of anal DSIN is important in order to avoid underdiagnosis in superficial biopsies.

Prostatic ductal adenocarcinoma: An aggressive variant that is underdiagnosed and undersampled on transrectal ultrasound (TRUS)-guided needle biopsy.

INTRODUCTION: We sought to determine if prostatic ductal adenocarcinoma is undersampled and/or underdiagnosed at transrectal ultrasound (TRUS)-guided biopsy. METHODS: With institutional review board approval, we searched our pathology database between 2008 and 2014 for patients with a diagnosis of ≥10% ductal adenocarcinoma on radical prostatectomy and available TRUS-guided needle biopsy specimens. Three blinded genitourinary pathologists independently examined the biopsy slides. The presence or absence of ductal adenocarcinoma was determined. Diagnostic accuracy was calculated using consensus diagnosis as the reference standard. Inter-observer agreement was assessed using Cohen's kappa coefficient. RESULTS: Based on consensus review, 66.7% (12/18) biopsy specimens demonstrated ductal adenocarcinoma and 33.3% (6/18) demonstrated conventional acinar prostatic adenocarcinoma. The sensitivity/specificity for each reader (R) was: 83/100% (R1), 100/83% (R2) and 58/83% (R3) and the inter-observer agreement was only fair (K=0.32). Only two of the original needle-biopsy reports correctly identified ductal adenocarcinoma (sensitivity = 17%). The main limitations of the study are the relatively small sample size and the potential for selection bias since we could only examine patients who underwent radical prostatectomy. CONCLUSIONS: Prostatic ductal adenocarcinoma may be undersampled at TRUS-guided biopsy and in this study was under-reported in routine clinical practice. This highlights the importance of increased awareness of ductal adeoncarcinoma and the need for clear diagnostic criteria. These findings have significant clinical impact especially when determining candidacy for active surveillance protocols.

Cribriform morphology predicts upstaging after radical prostatectomy in patients with Gleason score 3 + 4 = 7 prostate cancer at transrectal ultrasound (TRUS)-guided needle biopsy.

Selected patients with transrectal ultrasound (TRUS)-guided biopsies containing Gleason score 3 + 4 = 7 prostate cancer (PCa) may be considered candidates for active surveillance (AS). The purpose of this study was to determine if there are features that predict PCa upstaging and/or upgrading after radical prostatectomy (RP) in patients with Gleason score 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsies. We searched our institution's database for patients with Gleason score 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsy who underwent subsequent RP between January 2010 and January 2015. Two blinded genitourinary pathologists independently reviewed and assessed the following on biopsies: (a) nuclear size, nucleolar size and distribution of macronucleoli of PCa, which were subjectively graded using a semi-quantitative scale from 1 to 3, and (b) PCa with cribriform morphology and the size of cribriform disease. Patient age, serum prostate-specific antigen (PSA) and PSA density (PSAD) were also recorded. The Gleason score and stage (presence or absence of organ-confined disease (OCD)) were retrieved from RP reports. Comparisons were performed between groups using the chi-square test and Spearman correlation. One hundred and four patients were identified to have met inclusion criteria. The mean age was 63 (±6.1) years. Mean PSA and PSAD at diagnosis were 7.5 (±4.2) and 0.25 (±0.15) ng/mL, respectively. Gleason scores were upgraded to greater than 3 + 4 = 7 in 26.9 % (28/104) of patients, and 44.2 % (46/104) of patients had no OCD after RP. There was no correlation between age, PSA, PSAD or percent of biopsies with Gleason pattern 4 for either Gleason score upgrading or absence of OCD at the time of RP (p > 0.05). Thirty patients had cribriform morphology on TRUS-guided biopsy of which 60 % (18/30) had no OCD at RP (p = 0.04) while 36.7 % (11/30) were upgraded to Gleason score ≥3 + 4 = 7 after RP (p = 0.15). There was no association between nuclear size, nucleolar size and/or distribution of macronucleoli with upgrading and/or absence of OCD (p > 0.05). The size of cribriform pattern was not associated with the absence of OCD (p = 0.43) or Gleason score upgrade (p = 0.28). A proportion of patients with Gleason score 3 + 4 = 7 PCa at needle biopsy do not have OCD or are upgraded to higher Gleason scores after RP. In our study, patients with Gleason score 3 + 4 = 7 PCa with the presence of cribriform pattern 4 had a significantly increased chance of being found to have no OCD at the time of RP. There were no clinical or pathologic parameters at the time of TRUS-guided biopsy that identified risk factors for Gleason score upgrading at RP in this study. Cribriform morphology detected on biopsy in patients with Gleason score 3 + 4 = 7 PCa is associated with tumour upstaging after RP and may be considered a contraindication to active surveillance.

Invasive urothelial carcinoma exhibiting basal cell immunohistochemical markers: A variant of urothelial carcinoma associated with aggressive features.

We characterize invasive urothelial carcinoma (UC) exhibiting urothelial basal cell immunohistochemical markers. Consecutive invasive UCs were immunostained with CK20 and urothelial basal cell markers, cytokeratin 5 (CK5)/CD44. Immunostaining for CK5 and CD44 was scored as follows: positive for staining of more than 25% thickness of the epithelial nest or epithelium and low for lesser immunoreactivity. Invasive urothelial carcinoma (UC) exhibiting positive CK5/CD44 staining was designated as basal-like UC (BUC). In this study, of 251 invasive UC (pT1 in 57% and pT2-4 in 43%), BUC accounted for 40% of cases (accounting for most pT2-4 UC) and often presented as non-papillary UC without previous history of UC. In addition, BUC exhibited uniform nuclei with lesser degree of atypia than non BUC and decreased or negative cytokeratin 20 reactivity. Nested and microcystic variants of UC immunohistochemically stained as BUCs. Invasive non-BUCs were often papillary with marked cytologic atypia and pleomorphism, and accounted for most pT1 UC. The rates of perivesical invasion, lymph node and distant metastases were higher for BUC than non-BUC. All nine cases with absent/minimal residual in situ UC in 102 radical cystectomy specimens were from invasive non-BUC. BUC is distinguished from non-BUC due to this aggressive behavior, distinct immunohistochemical profile, and predominant non-papillary architecture. Our findings are consistent with recent studies identifying a subtype of muscle-invasive UC with molecular expression of basal cell and luminal cell molecular profiles. Our study further supports categorizing invasive UCs into these subtypes with different biological behaviors, possibly contributing to better therapeutic strategies.

Lymphatic endothelial cancerization in papillary thyroid carcinoma: hidden evidence of lymphatic invasion.

We hypothesize that cystic structures in metastatic papillary thyroid carcinoma (PTC) develop along the framework of lymphatic channels. To investigate this phenomenon, different categories of PTC were immunostained for D2-40 and TTF1. In this study, reactivity for D2-40 was considered as positive when there is membranous staining as often seen in lymphatic endothelial cells. Thirty cases of PTC with lymph node metastasis or with potential for lymphatic invasion and 20 cases metastatic PTC in lymph nodes were reviewed and found to show double/mosaic immunoreactivity for TTF1/D2-40 in 40-100% of cases. PTC metastasis in lymph nodes with cysts and some branching lymphatic-like channels lined by follicular cells with or without nuclear features of PTC were diffusely reactive to TTF1, and focally to D2-40. For primary and metastatic PTC, focal membranous D2-40 reactivity was also demonstrated in cysts or cleft linings. For25 thyroid neoplasms with no known potential for lymphatic invasion, there was no such immunoreactivity. The mosaic or double immunoreactivity for TTF1/D2-40 suggests lymphatic cancerization and possible endothelial mimicry of follicular cells. Mosaic/double immunoreactivity is helpful to detect the hidden pattern of lymphatic invasion masquerading as 'benign-appearing' follicles and supports our hypothesis of malignant cells developing along the lymphatic framework.

Intracellular lipid in papillary renal cell carcinoma (pRCC): T2 weighted (T2W) MRI and pathologic correlation.

OBJECTIVE: To evaluate if pRCCs demonstrate intracellular lipid (i-lipid) at chemical-shift (CS) MRI, and assess T2W-MRI and pathologic characteristics. METHODOLOGY: Sixty-two patients with a pRCC diagnosis underwent MRI over 11 years (IRB-approved). Two radiologists independently assessed for presence of i-lipid on CS-MRI and homogeneity on T2W-MRI. Inter-observer agreement was assessed via an intraclass correlation and results were compared using the Chi-square test. Discordant cases were reviewed to establish consensus. T2W SI-ratios (SI.tumor/SI.kidney) and CS-SI index were compared using independent t-tests and Spearman correlation. Two pathologists re-evaluated the histopathology. RESULTS: Nine of the 62 pRCCs (14.5%) demonstrated i-lipid; agreement was moderate (ICC = 0.63). Pathology review depicted clear cells in four tumours and foamy histiocytes in five tumours. 25.8-35.4% (ICC = 0.65) of tumours were homogeneous on T2W-MRI. No pRCC with i-lipid was considered homogeneous (p = 0.01-0.04). Overall, T2W SI-ratio and CS-SI index were 0.89 (±0.29) and -3.63 % (-7.27 to 11.42). pRCC with i-lipid had significantly higher T2W SI-ratio (p = 0.003). There was a correlation between the CS-SI index and T2W SI-ratio, (r = 0.44, p < 0.001). CONCLUSIONS: Intracellular lipid is uncommonly detected in pRCCs due to clear cell changes and foamy histiocytes. These tumours are associated with heterogeneously-increased SI in T2W-MRI. KEY POINTS: • A minority of pRCCs demonstrate intracellular lipid in CS-MRI. • Quantitatively, intracellular lipid in pRCCs is minimal (<25%). • Intracellular lipid in pRCCs are from clear cell heterogeneity or foamy histiocytes. • pRCCs with intracellular lipid are heterogeneously hyperintense at T2W-MRI. • pRCCs that are homogeneously hypointense at T2W-MRI do not contain intracellular lipid.

Metastatic renal cell carcinoma mimicking a schwannoma in a dorsal root ganglion: case report.

Peripheral nerve tumors are soft-tissue tumors that can occur in any nerve throughout the body. The majority of peripheral nerve tumors arise from elements of the nerve sheath with the two most common being neurofibromas and schwannomas. More than 90% of all peripheral nerve tumors are benign. When there is peripheral nerve involvement in metastatic carcinoma, it is often via contiguous spread from the primary mass; hematogenous seeding to a peripheral nerve is seldom seen. In this report the authors describe the even rarer case of metastatic renal cell carcinoma mimicking a schwannoma in a dorsal root ganglion. Cases from the literature show the rarity of this finding and its late clinical appearance. Given that survival in patients with metastatic carcinoma continues to increase, dorsal root ganglion metastasis may become more common over time.

Novel technique of sampling the urinary bladder for urothelial carcinoma specimens.

Sampling of the urinary bladder (UB) in radical cystectomy specimens is usually performed by obtaining sections through the lesions taken in rather random planes. The technique is hindered by the difficulty in identifying the anatomical relationship of the tumor with the remaining urinary bladder. Fifty radical cystectomy specimens were bisected in the horizontal plane at the middle portion of the UB then fixed without tissue stretching in 10% buffered formalin for at least 24 hours. The UBs were serially sectioned in parallel horizontal planes from the UB neck to the dome into rings of 3 to 10 mm thickness. The sections were orderly arranged and photographed. At least one ring of tissue was entirely submitted along with areas of interest or representative areas. Our proposed technique of transverse sections results in a mild increase in the number of sections submitted for microscopic examination. The advantages of our methods are (a) consistency and ease of sampling that help the microscopic-macroscopic correlation, (b) suitability for gross examination and for determining depth of invasion and largest tumor diameter, (c) improved identification of satellite lesions, and (d) suitability for neoplastic mapping and suitability for reexamination. The technique was validated by comparing with results of current technique.

Multi-parametric (mp) MRI of prostatic ductal adenocarcinoma.

BACKGROUND: Prostatic ductal adenocarcinoma (DCa) is an aggressive variant of conventional adenocarcinoma (CCa) with mixed DCa and CCa tumors comprising up to 5% of all prostate cancers. DCa may be underestimated on T2-weighted (T2W) MRI. This study assessed the mp-MRI appearance of DCa as compared with CCa. METHODS: With research ethics board approval, we identified 38 patients who underwent mp-MRI (T2W, DWI, and DCE) and radical prostatectomy (RP) between 2012 and 2014. Eight DCa in 8 patients and 39 CCa tumor foci in 30 consecutive patients were identified. Tumor volume, apparent diffusion coefficient (ADC;10(-3) mm(2) /s), and time-signal intensity (SI) curves were calculated. Parametric data were compared using the Kruskal-Wallis test and univariate regression. Time-SI curves were compared using the chi-square test. RESULTS: Tumor volumes were: 1.62(±1.02) for DCa, 1.03(±0.54) for Gleason 9, 0.88(±0.93) for Gleason 7/8, and 0.26(±0.14) mL for Gleason 6. There was no difference in size between DCa and Gleason 9 (P = 0.22); however, DCa were larger than Gleason 7/8 (P = 0.03) and Gleason 6 (P = 0.003) tumors. ADC values were: 0.789(±0.22) for DCa, 1.01(±0.19) for Gleason 9, 0.992(±0.23) for Gleason 7/8 and 1.389(±0.41) 10(-3) mm(2) /s for Gleason 6 tumors. There was no difference in ADC between DCa and Gleason 9 (P = 0.14) or Gleason 7/8 (P = 0.055) tumors. There was a difference in ADC for DCa and Gleason ≥7 CCa compared to Gleason 6 tumors, (P < 0.001 and P = 0.012). All DCa demonstrated type III time-SI curves. Gleason ≥ 7 tumors demonstrated type II/III curves. Gleason 6 tumors demonstrated Type I/II time-SI curves. There was no difference in curve type between groups, (P = 0.18). CONCLUSION: Although DCa mimics Gleason score 3 + 3 = 6 tumor at T2W MRI; DCa resembles Gleason ≥7 CCa on mp-MRI.

Histopathogenesis of non-HPV-related differentiated oral squamous intraepithelial neoplasia.

INTRODUCTION: A study of immunohistopathologic and cytohistopathologic changes of the parabasal/basal layers in the differentiated squamous intraepithelial neoplasia (DSIN) may elucidate the histopathogenesis and reveal changes aiding early diagnosis and grading of the lesion. MATERIALS AND METHODS: A total of 55 consecutive resection specimens of nonbasaloid squamous cell carcinoma of the anterior oral cavity and 8 biopsies before resections displaying DSIN in the overlying squamous epithelium were examined. RESULTS: Squamous epithelium that is continuous/immediately adjacent to invasive squamous cell carcinoma (type 1) and the more peripheral (type 2) epithelium of resection specimens displayed consistent changes in the parabasal/basal layers: (A) cytologic atypia with proliferation of parabasal cells with downward expansion causing reactive proliferation of the basal cell layer in the early stage, invading the basal layer in the late stage; (B) disordered nuclear/cytoplasmic arrangement; (C) "Cobblestone" appearance. Immunoreactivity for TP53 and Ki67 was helpful in the diagnosis. The epithelial spectrum of changes decreased as one moved from type 1 to type 2 lesions. Five out of 8 biopsies showed type 1 lesions (followed by resection in a period of 11±6 mo) and 3 showed type 2 lesions (followed by resection in a period of 55±20 mo). In addition, resections were margin positive for type 2 lesions in 5 cases associated with recurrence at the site of resection during a period of 69±9 months. CONCLUSIONS: DSIN is characterized by a proliferation of neoplastic parabasal cells with dyskeratosis, downward expansion/pushing of the basal layer with elongation of rete ridges. We proposed grading of DSIN based on the changes of the parabasal/basal layers.

Nested and microcystic variants of urothelial carcinoma displaying immunohistochemical features of basal-like urothelial cells: an immunohistochemical and histopathogenetic study.

Nested/microcystic (NV/MV) urothelial carcinoma (UC) variants are associated with mild cytologic atypia and commonly present at high-stage disease. The histopathogenesis is investigated using urothelial basal cell markers. Archival 14 NV/MV and three inverted papilloma (IP) were immunostained for CD44, cytokeratin 5 (CK5), CK34bE12 and p63. Twenty consecutive cases of invasive high-grade UC including 14 superficial and 6 muscle-invasive UC cases were used as control. Immunostaining was scored as high for staining of full or more than 50% thickness of the epithelial nest or epithelium and low for lesser immunoreactivity and negative reactivity. All 14 NV/MV, 3 IP and 6 control cases showed a high score of immunoreactivity for CK5, CD44, CK34bE12 and focally for p63. The remaining control cases showed a high score of immunoreactivity for CK34bE12, while negative or low for CK5, CD44 and p63. In conclusion, immunoreactivity CK5 and CD44 commonly immunostained NV/MV and some invasive high grade UC. Other basal cell markers (CK34bE12 and p63) appear to be non specific or non sensitive. NV and MV and some UC likely represent a subset of UC displaying immunohistochemical features of urothelial basal cells. They had tendency of endophytic growth and early invasion despite the innocuous cytologic appearance.