Syndrome of Inappropriate Antidiuretic Hormone Release Secondary to Ectopic Olfactory Neuroblastoma: Case Report and Review of Literature.

Ectopic olfactory neuroblastoma (ONB) is a rare neuroendocrine sinonasal malignancy which arises from sinonasal regions where olfactory neuroepithelium does not exist. Presentation of syndrome of inappropriate antidiuretic hormone release (SIADH) in patients with ectopic ONB is extremely rare. We report a case of a 22-year-old patient with ectopic ONB and paraneoplastic SIADH that was managed at our center. The ONB was arising from the left lamina papyracea and extending into the maxillary and ethmoid sinuses and filling the nasal cavity. Correction of sodium levels occurred within 24 hours of endoscopic resection via a combined trans-nasal transorbital approach. To avoid negative sequela secondary to rapid sodium correction, the patient was managed by desmopressin to obtain gradual sodium correction, which was achieved on the fourth postoperative day. Ectopic presentation of ONB with paraneoplastic SIADH is extremely rare with only 7 cases reported in the literature to date. Management via surgical resection and/or radiotherapy for these patients requires the managing clinician to be vigilant of serum sodium levels. A multidisciplinary approach is essential for optimal outcomes.

Management of rectal neuroendocrine tumours by transanal endoscopic microsurgery.

AIM: The objective of this study was to evaluate the safety and effectiveness of transanal endoscopic microsurgery for rectal neuroendocrine tumours. METHOD: A retrospective cohort study of all pathology-confirmed rectal neuroendocrine tumours treated by transanal endoscopic microsurgery from April 2007 to December 2020 at a tertiary care centre was performed. Demographic, clinical, radiographic and pathological data were collected. Characteristics of patients with recurrence were examined. Descriptive statistics were performed. RESULTS: There were 58 patients treated by transanal endoscopic microsurgery excision. Referrals were for primary excision (15, 25.9%), completion re-excision after incomplete endoscopic removal (38, 65.5%) or locally recurrent rectal neuroendocrine tumours (5, 8.6%). The mean age of patients was 56.4 ± 11.9 years and 26 patients were women (44.8%). Mean tumour size was 7.4 ± 3.8 mm (range 1.0-15.0 mm). Most (86.4%) were Grade 1 tumours. Mean operative time was 37.2 ± 17.2 min and 56 patients (96.6%) were discharged on the same day. All patients had negative margins on final pathology. Of the 38 patients who were referred for completion re-excision after incomplete endoscopic removal, eight (21.1%) had residual tumour on final pathology. Three recurrences were diagnosed at 2.1, 4.5 and 12.5 years after excision. All recurrences were from Grade 1 or 2 primary tumours, less than 2 cm, and diagnosed radiographically. CONCLUSION: To date, this is the largest North American study looking at transanal endoscopic microsurgery for rectal neuroendocrine tumours. This technique is effective in managing primary, incompletely excised and recurrent tumours with good clinical and oncological outcomes.

Identification of a Subset of Stage I Colorectal Cancer Patients With High Recurrence Risk.

BACKGROUND: A challenge in early-stage colorectal cancer (CRC) is identifying biomarkers that predict an increased risk for recurrence. A potential clinically adaptable biomarker is focal adhesion kinase (FAK), a tyrosine kinase that promotes invasion and metastasis. METHODS: An initial, single-institution, 298-patient cohort with all stages of CRC and long-term follow-up was assessed for FAK with tissue microarrays using immunohistochemistry. FAK expression was scored and dichotomized into high and low. Subsequently, a validation cohort of 517 early-stage CRCs from a separate institution was evaluated. All statistical tests were 2-sided. RESULTS: FAK overexpression did not correlate with any known histologic feature and was an early event in CRC, increasing from normal colon to stage I, and stage I to II, but not different at higher stages. High FAK was associated with decreased 10-year recurrence-free survival (RFS) among stage I patients (70.2% for high FAK vs 94.1% for low, P = .02), but not among higher stages in the initial cohort. The same finding was seen in the validation cohort (73.1% for high FAK vs 93.1% for low, P = .004). Multivariable survival analysis for stage I patients showed only two statistically significant factors predicting RFS: FAK (hazard ratio = 5.27, 95% confidence interval = 1.81 to 15.33, P = .002) and perineural invasion (hazard ratio = 7.38, 95% confidence interval = 1.01 to 53.96, P = .049). FAK was the only statistically significant factor in multivariable analysis across RFS, overall, and disease-specific survivals. CONCLUSIONS: High FAK expression identified a subset of stage I CRC patients with high incidence of recurrence and reduced survival, suggesting that FAK has important prognostic value. These patients would immediately benefit from more rigorous surveillance protocols for recurrent disease.

The safety of high-dose dexmedetomidine after cardiac surgery: a historical cohort study.

PURPOSE: The off-label use of dexmedetomidine beyond the monograph-recommended maximum dose of 0.7 µg·kg-1·hr-1 is common in postoperative cardiac surgical units; however, limited data exist on the association of higher doses and adverse hemodynamic effects. We sought to compare the rate of hypotension or bradycardia in cardiac surgery patients receiving peak infusion doses below and above 0.7 µg·kg-1·hr-1 for any indication or duration. METHODS: In this historical cohort study, we reviewed all patients who received dexmedetomidine infusion after cardiac surgery between June 2013 and July 2017 at a single centre. Regardless of the duration of exposure at the peak infusion dose, patients were categorized into high- or standard-dose groups using 0.7 µg·kg-1·hr-1 as the cutoff value. We compared rates of the primary composite outcome of hypotension or bradycardia, and secondary outcomes (i.e., arrhythmia and hyperglycemia) between groups using the two-proportion z test. Exploratory regression models were fitted to adjust for potential confounders. RESULTS: The median [interquartile range (IQR)] peak infusion dose was 1.0 [1.0-1.4] µg·kg-1·hr-1 in the high-dose group (N = 121) and 0.5 [0.4-0.7] µg·kg-1·hr-1 in the standard-dose group (N = 124). The rates of the primary composite outcome were 73% and 65%, respectively (absolute risk difference, 8%; 95% confidence interval, -3 to 20; P = 0.17). There was no significant difference in primary or secondary outcomes between groups. CONCLUSION: There was a high overall rate of hypotension or bradycardia in patients receiving dexmedetomidine after cardiac surgery; infusion rates below or above 0.7 µg·kg-1·hr-1 had similar rates of adverse hemodynamic events.

RéSUMé: OBJECTIF: L'utilisation non conforme (off-label) de la dexmédétomidine au-delà de la dose maximale recommandée dans la monographie de 0,7 µg·kg−1·h−1 est fréquente dans les unités de chirurgie cardiaque postopératoire; cependant, il n'existe que peu de données sur l'association entre des doses plus élevées et des effets hémodynamiques indésirables. Nous avons cherché à comparer le taux d'hypotension ou de bradycardie chez les patients de chirurgie cardiaque recevant des doses de perfusion maximales inférieures ou supérieures à 0,7 µg·kg−1·h−1 pour toute indication ou durée. MéTHODE: Dans cette étude de cohorte historique, nous avons passé en revue tous les patients qui ont reçu une perfusion de dexmédétomidine après une chirurgie cardiaque entre juin 2013 et juillet 2017 dans un seul centre. Quelle que soit la durée de l'exposition à la dose de perfusion maximale, les patients ont été classés en groupes à dose élevée ou standard selon une valeur seuil de 0,7 µg·kg−1·h−1. Nous avons comparé les taux d'hypotension ou de bradycardie, notre critère d'évaluation principal composite, et les taux des critères d'évaluation secondaires (soit l'arythmie et l'hyperglycémie) entre les groupes à l'aide du test z à deux proportions. Des modèles de régression exploratoire ont été ajustés pour tenir compte des facteurs de confusion potentiels. RéSULTATS: La dose de perfusion maximale médiane [écart interquartile (ÉIQ)] était de 1,0 [1,0­1,4] µg·kg−1·h−1 dans le groupe à forte dose (n = 121) et de 0,5 [0,4­0,7] µg·kg−1·h−1 dans le groupe à dose standard (n = 124). Les taux pour le critère d'évaluation principal composite étaient de 73% et 65%, respectivement (différence de risque absolue, 8%; intervalle de confiance à 95%, -3 à 20; P = 0,17). Aucune différence intergroupe significative n'a été observée dans les critères d'évaluation primaires ou secondaires. CONCLUSION: Nous avons observé un taux global élevé d'hypotension ou de bradycardie chez les patients recevant de la dexmédétomidine après une chirurgie cardiaque; les taux de perfusion inférieurs ou supérieurs à 0,7 µg·kg−1·h−1 ont entraîné des taux similaires d'événements hémodynamiques indésirables.

Topography, morphology, and etiology of lymphocytic gastritis: a single institution experience.

Lymphocytic gastritis (LG) is an uncommon reaction pattern of gastric injury characterized by intraepithelial lymphocytosis of the surface foveolar epithelium and chronic inflammation in the lamina propria. It most commonly occurs in association with gluten-sensitive enteropathy, Helicobacter pylori gastritis, non-steroidal anti-inflammatory drugs, and microscopic colitis. While the topography of LG has been described in gluten-sensitive enteropathy and H. pylori infection, no definite morphologic features have been used to further subcategorize LG based on possible etiologies. Furthermore, new immunotherapy agents have been associated with lymphocytic infiltrate in the gastrointestinal tract, but their association with LG has not been reported. Cases of LG were collected from our institution in the period between August 2011 and September 2017. The topography of LG and morphologic features such as glandular microabscesses, intestinal metaplasia, lymphoid aggregates, surface vs pit distribution of lymphocytes, and number of intraepithelial lymphocytes per 100 epithelial cells were assessed for each case using the updated Sydney System where applicable. Twenty-seven cases of LG were identified in the recent 6-year period at our institution. Gluten-sensitive enteropathy is the main reported cause of LG followed by NSAID injury. Cases of LG associated with gluten-sensitive enteropathy are antral predominant, those associated with H. pylori are body predominant, and those occurring in the setting of NSAID injury show pangastritis. Glandular microabscesses are observed in all cases of LG associated with H. pylori, and not in the setting of GSE or NSAID injury. In addition, a case of LG associated with melanoma immunotherapy has been identified. Topography and morphology of lymphocytic gastritis may point to the cause of injury, allowing for proper treatment of the underlying disease.

Colorectal carcinoma with double somatic mismatch repair gene inactivation: clinical and pathological characteristics and response to immune checkpoint blockade.

Double somatic mismatch-repair-gene mutation/alteration is a recently recognized molecular mechanism that underlies microsatellite instability-high in some colorectal carcinomas. It remains to be determined whether and how microsatellite instability-high tumors with this molecular defect differ from their counterparts caused by other mechanisms, specifically, Lynch syndrome-associated and MLH1-promoter hypermethylated. In this study, we evaluated the clinical and pathological characteristics of a series of 15 double somatic mutation/alteration-associated microsatellite instability-high colorectal carcinomas identified from our genetics service and 68 such cases reported in the literature. We observed that these cases presented at an age similar to MLH1-promoter hypermethylated (n = 20) and microsatellite-stable (n = 39) cases but older than Lynch syndrome-associated cases (n = 20, p < 0.05). While these tumors simulated other microsatellite instability-high tumors in their prevalent right-sided location, they appeared to differ in TNM stages at presentation (73% stage III/IV versus 25% stage III/IV in other microsatellite instability-high tumors, p = 0.04). Histologically, 40% of them had a dominant solid growth pattern. Inter-tumoral heterogeneity was a striking feature, spanning the spectrum from medullary type (with a tumor-infiltrating-lymphocyte/high-power-field count as high as 59) to conventional-type with only few tumor-infiltrating-lymphocytes (1/high-power-filed). As a group, these tumors seemed less likely to show robustly high lymphocytic infiltration than other microsatellite instability-high tumors (only 20% had ≥10 tumor-infiltrating-lymphocytes/high-power-filed, whereas this rate in Lynch syndrome-associated and MLH1-promoter hypermethylated tumors was 60% and 75%, respectively). Three double somatic mutation/alteration-associated tumors were treated with a PD1/PD-L1 checkpoint inhibitor. While all three had an elevated tumor-mutation-burden (>47 mut/megabase), only one had tumor-infiltrating-lymphocytes >10/high-power-field, yet all three exhibited measurable response. In summary, microsatellite instability-high colorectal carcinomas caused by double somatic mismatch-repair-gene mutation/alteration may have varied clinical and pathological characteristics, and some may have relatively low tumor-infiltrating-lymphocytes; response to immune checkpoint inhibitors can be achieved in this group even when the lymphocytic infiltration is not abundant.

SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance.

PURPOSE: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. RESULTS: The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. CONCLUSIONS: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.

Antipsychotic prescribing patterns on admission to and at discharge from a tertiary care program for treatment-resistant psychosis.

Retrospective data were collected from 330 individuals who were treated at a tertiary care program for treatment-resistant psychosis between 1994 and 2010. The main objectives were to compare the use of antipsychotic monotherapy to polypharmacy and to characterize within-individual changes in treatment and symptomatology between admission and discharge. At admission, individuals who were prescribed only one antipsychotic were comparable to those who were prescribed at least two antipsychotics with regard to demographics and symptom severity. The use of psychotropic medications other than antipsychotics was also similar between the two groups. However, the magnitude of antipsychotic utilization was greater in individuals who were receiving antipsychotic polypharmacy. In addition, a greater proportion received excessive doses at admission. Similar findings were observed when the two antipsychotic prescribing practices were compared at discharge. Three important patterns were identified when investigating within-individual changes. First, fewer individuals were prescribed more than one antipsychotic at discharge. This was accompanied by a general decrease in the magnitude of antipsychotic utilization. Second, the number of individuals who were prescribed clozapine had increased by discharge. Most who were already prescribed clozapine at admission had their doses increased. Third, improvements in symptomatology were observed across all of the subscales included in the Positive and Negative Symptom Scale (PANSS); 57.9% of individuals experienced a relative reduction in total PANSS scores exceeding 20%. Based on these findings, it is possible to alleviate symptom severity while reducing antipsychotic utilization when patients are treated at a tertiary care program for treatment-resistant psychosis.

Poorly Differentiated Clusters Predict Colon Cancer Recurrence: An In-Depth Comparative Analysis of Invasive-Front Prognostic Markers.

This study aimed to compare common histologic markers at the invasive front of colon adenocarcinoma in terms of prognostic accuracy and interobserver agreement. Consecutive patients who underwent curative resection for stages I to III colon adenocarcinoma at a single institution in 2007 to 2014 were identified. Poorly differentiated clusters (PDCs), tumor budding, perineural invasion, desmoplastic reaction, and Crohn-like lymphoid reaction at the invasive front, as well as the World Health Organization (WHO) grade of the entire tumor, were analyzed. Prognostic accuracies for recurrence-free survival (RFS) were compared, and interobserver agreement among 3 pathologists was assessed. The study cohort consisted of 851 patients. Although all the histologic markers except WHO grade were significantly associated with RFS (PDCs, tumor budding, perineural invasion, and desmoplastic reaction: P<0.001; Crohn-like lymphoid reaction: P=0.021), PDCs (grade 1 [G1]: n=581; G2: n=145; G3: n=125) showed the largest separation of 3-year RFS in the full cohort (G1: 94.1%; G3: 63.7%; hazard ratio [HR], 6.39; 95% confidence interval [CI], 4.11-9.95; P<0.001), stage II patients (G1: 94.0%; G3: 67.3%; HR, 4.15; 95% CI, 1.96-8.82; P<0.001), and stage III patients (G1: 89.0%; G3: 59.4%; HR, 4.50; 95% CI, 2.41-8.41; P<0.001). PDCs had the highest prognostic accuracy for RFS with the concordance probability estimate of 0.642, whereas WHO grade had the lowest. Interobserver agreement was the highest for PDCs, with a weighted kappa of 0.824. The risk of recurrence over time peaked earlier for worse PDCs grade. Our findings indicate that PDCs are the best invasive-front histologic marker in terms of prognostic accuracy and interobserver agreement. PDCs may replace WHO grade as a prognostic indicator.

Diagnostic value of histone 3 mutations in osteoclast-rich bone tumors.

Differentiating osteoclast-rich lesions of bone (giant cell tumor of bone [GCTB], chondroblastoma [CBA], and aneurysmal bone cyst [ABC]) can be challenging, especially in small biopsies or fine-needle aspirations. Mutations affecting codons 34 and 36 of either H3 Histone Family Member 3A (H3F3A) and/or 3B (H3F3B) are characteristically seen in GCTB and CBAs. We devised a simple assay to identify these mutations and evaluated its applicability for routine clinical diagnosis. One hundred twenty-four tissue specimens from 108 patients (43 GCTBs, 38 CBAs and 27 ABCs) were collected from the archives of the Calgary Laboratory Services/University of Calgary and Vanderbilt University Medical Center. Histology was reviewed by an expert orthopedic pathologist. A single base extension assay (SNaPshot) is used to interrogate each nucleotide in codons 34 and 36 of H3F3A and codon 36 of H3F3B. Final diagnoses were generated after re-reviewing cases and incorporating molecular findings. Of 43 GCTBs, 38 (88%) had an H3F3A G34W mutation; 35 of 38 CBAs (92%) had a K36M mutation in either H3F3B (N = 31; 82%) or H3F3A (N = 4; 11%); none of 27 ABCs had a tested mutation. Molecular findings changed the histomorphologic diagnosis in 5 cases (3 GCTB changed to ABC, and 2 ABC changed to GCTB). These findings support the diagnostic utility of mutational analysis for this differential diagnosis in certain challenging cases when clinicoradiologic and histomorphologic features are not definitive, particularly for distinguishing cellular ABC versus GCTB with secondary ABC.

Prevalence and Anatomic Distribution of Serrated and Adenomatous Lesions in Patients with Inflammatory Bowel Disease.

Background. Sessile serrated adenomas/polyps (SSA/Ps) and traditional serrated adenomas (TSAs) have not been well characterized in patients with inflammatory bowel disease (IBD). This study assesses the prevalence and anatomic distribution of SSA/Ps, TSAs, and conventional adenomas/dysplasia (Ad/Ds) in IBD patients. Methods. IBD patients with serrated, adenomatous, or hyperplastic lesions between 2005 and 2009 were identified in the regional tertiary-care hospital database. Clinicopathological information was reviewed and the histology of biopsies was reevaluated. Results. Ninety-six Ad/Ds, 25 SSA/Ps, and 4 TSAs were identified in 83 patients. Compared to Ad/Ds, serrated lesions were more prevalent in females (p = 0.046). The prevalence of Ad/Ds was 4.95%, SSA/Ps was 1.39%, and TSAs was 0.31%. No relationship was identified between lesion type and IBD type. Comparing all IBD patients, the distribution of lesion types was significantly different (p = 0.02) with Ad/Ds more common distally, SSA/Ps more common proximally, and TSAs evenly distributed. Among Crohn's disease (CD) patients, a similar distribution difference was noted (p < 0.001). However, ulcerative colitis (UC) patients had a uniform distribution of lesion types (p = 0.320). Conclusions. IBD patients have a lower prevalence of premalignant lesions compared to the general population, and the anatomic distribution of lesions differed between CD and UC patients. These findings may indicate an interaction between lesion and IBD pathogenesis with potential clinical implications.

Association Between Phosphorylated Histone H3 and Oncotype DX Recurrence Scores in Breast Cancer.

We investigate the association between phosphorylated histone H3 (PhH3) and Oncotype DX recurrence score (RS). All invasive breast carcinoma with RS results from our city between 2007 and 2010 (n=47) were reviewed. Whole-tumor sections were stained for PhH3. Mitotic and PhH3 counts were performed and clinical charts reviewed. PhH3 correlated well with RS (r=0.69, P<0.001). Other correlations were: PhH3 versus mitotic count (r=0.87, P<0.001), PhH3 versus mitotic score (r=0.71, P<0.001), PhH3 versus modified Bloom-Richardson-Elston (MBR) grade (r=0.65, P<0.001), RS versus mitotic count (r=0.62, P<0.001), RS versus mitotic score (r=0.44, P=0.002), and RS versus MBR grade (r=0.49, P=0.001). Significant correlation between PhH3 and RS remained after controlling for mitotic count (r=0.39, P=0.007), mitotic score (r=0.60, P<0.001), MBR grade (r=0.56, P<0.001), and all 3 (r=0.37, P=0.014) by partial correlation. Two patients died of metastasis at 12 and 38 months after diagnosis. One had intermediate RS, and 1 high RS; both were in the top-third of PhH3 count. All other patients are alive and recurrence free. Correlation between PhH3 and RS was statistically significant in our cohort, and remained significant after controlling for traditional measures of proliferation. Given that RS has an established strong relationship with prognosis and therapy responsiveness, PhH3 may thus also be an important prognostic/predictive marker in breast cancer.

Diagnosing colorectal medullary carcinoma: interobserver variability and clinicopathological implications.

Colorectal medullary carcinoma, recognized by the World Health Organization as a distinct histologic subtype, is commonly regarded as a specific entity with an improved prognosis and unique molecular pathogenesis. A fundamental but as yet unaddressed question, however, is whether it can be diagnosed reproducibly. In this study, by analyzing 80 colorectal adenocarcinomas whose dominant growth pattern was solid (thus encompassing medullary carcinoma and its mimics), we provided a detailed description of the morphological spectrum from "classic medullary histology" to nonmedullary poorly differentiated histologies and demonstrated significant overlapping between categories. By assessing a selected subset (n=30) that represented the spectrum of histologies, we showed that the interobserver agreement for diagnosing medullary carcinoma by using 2010 World Health Organization criteria was poor; the κ value among 5 gastrointestinal pathologists was only 0.157 (95% confidence interval, 0.127-0.263; P=.001). When we arbitrarily classified the entire cohort into "classic" and "indeterminate" medullary tumors (group 1, n=19; group 2, n=26, respectively) and nonmedullary poorly differentiated tumors (group 3, n=35), groups 1 and 2 were more likely to exhibit mismatch repair protein deficiency than group 3 (P<.001); however, improved survival could not be detected in either group compared with group 3. Our findings suggest that the diagnosis of medullary carcinoma, as currently applied, may only serve as a morphological descriptor indicating an increased likelihood of mismatch-repair deficiency. Additional evidence including a more objective classification system is needed before medullary carcinoma can be regarded as a distinct entity with prognostic relevance. Until such evidence becomes available, caution should be exercised when making this diagnosis, as well as when comparing results across different studies.

Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma.

Immune checkpoint blockade targeting the programmed death-1 (PD-1) pathway has shown efficacy in several types of cancers including mismatch-repair-deficient colorectal carcinoma. In some tumor types, programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry has shown utility as a predictive marker for response to anti-PD-1 therapies. This utility, however, remains to be determined in colorectal carcinoma. In addition, although tumor-infiltrating lymphocytes have been associated with better prognosis in colorectal carcinoma, the prognostic value of PD-1 expression in these lymphocytes and its interaction with PD-L1 expression still await investigation. To address these questions, we performed a pilot study to evaluate the patterns of PD-L1 and PD-1 immunohistochemical expression on colorectal carcinoma cells and their tumor-infiltrating lymphocytes, respectively. Using tissue microarray, we found that 5% (19/394) of colorectal carcinomas exhibited high tumor PD-L1 expression, and 19% (76/392) had elevated numbers of PD-1-positive tumor-infiltrating lymphocytes. PD-L1 levels correlated with PD-1 levels (P<0.001), and mismatch-repair-deficient tumors had significantly higher rates of high PD-L1 and PD-1 expression when compared with mismatch-repair-proficient tumors (18% vs 2% and 50% vs 13%, respectively; P<0.001 for both). Staining intensity was also stronger for both markers in mismatch-repair-deficient tumors. Furthermore, we observed that among patients with mismatch-repair-deficient colorectal carcinoma, PD-1/PD-L1 expression stratified recurrence-free survival in an inter-dependent manner: an association between high PD-1-positive tumor-infiltrating lymphocytes and improved recurrence-free survival (P=0.041) was maintained only when the tumors had low-level PD-L1 expression (P=0.006); patients whose tumors had both high PD-1-positive tumor-infiltrating lymphocytes and high PD-L1 expression had a significantly worse recurrence-free survival (P<0.001). Thus, our results not only provide a foundation for further assessment of PD-L1 immunohistochemistry as a predictive marker for anti-PD-1 therapy in colorectal carcinoma, they also shed light on the prognostic impact of tumor-infiltrating lymphocytes in different subsets of mismatch-repair-deficient colorectal carcinomas.

ARID1A expression in early stage colorectal adenocarcinoma: an exploration of its prognostic significance.

ARID1A is a chromatin remodeling gene that is mutated in a number of cancers including colorectal carcinoma (CRC). Loss of ARID1A has been associated with an adverse outcome in some types of cancer. However, literature data have not been consistent. Major limitations of some outcome studies include small sample size and heterogeneous patient population. In this study, we evaluated the prognostic value of ARID1A in a homogeneous group of early stage CRC patients, a population where prognostic markers are particularly relevant. We collected a retrospective series of 578 stage I or II CRCs. All patients underwent surgery with curative intent and without neoadjuvant or adjuvant therapy. ARID1A expression was analyzed by immunohistochemistry using tissue microarray. We found ARID1A loss in 49 of 552 analyzable tumors (8.9%). Compared with the ARID1A-retained group, cases with ARID1A loss were associated with female sex (P<.001), mismatch-repair protein deficiency (P<.001), poor differentiation (P<.001), lymphovascular invasion (P=.001), and higher pT stage (P=.047). However, at a median follow-up of 49months, ARID1A loss did not correlate with overall, disease-specific, or recurrence-free survival. This is the first systematic analysis to evaluate the prognostic significance of ARID1A in stage I/II CRCs, and our data indicate that ARID1A loss lacks prognostic significance in this population despite its association with other adverse features. Such data are clinically relevant, as efforts are ongoing in identifying markers that can detect the small but significant subset of early stage CRCs that will have a poor outcome.

Digital differentiation of non-small cell carcinomas of the lung by the fractal dimension of their epithelial architecture.

INTRODUCTION: In recent years, differences have emerged in the treatment of squamous and non-squamous non-small cell lung carcinomas (NSCLCs). This highlights the importance of accurate histopathologic classification. However, there remains inter-observer disagreement when making diagnoses based on histology. Fractal dimension (FD) is a mathematical measure of irregularity and complexity of shape. We hypothesize that the FD of carcinoma epithelial architecture can assist in differentiating adenocarcinoma (ADC) from squamous cell carcinoma (SCC) of the lung. METHODS: 134 resected (88 ADC and 46 SCC) cases of resected early-stage NSCLC were analyzed. Tissue micro arrays were generated from formalin-fixed paraffin-embedded tissue, stained with pan-cytokeratin, and digitally imaged and the FD of the epithelial structure calculated. Mean FD of ADC and SCC were compared using the independent t-test, partial correlations, and receiver operating characteristic (ROC) analyses. RESULTS: A statistically significant difference (p<0.001) between the mean FD of ADC (M=1.70, SD=0.07) and SCC (M=1.78, SD=0.07) was found. Significance remained (p<0.001) when controlling for several possible confounders. ROC analysis demonstrated an area-under-the-curve of 0.81 (p<0.001). CONCLUSIONS: The epithelial structure FD of NSCLC has potential as a reproducible and automated measure to help subtype NSCLCs into ADC and SCC. With further image analysis algorithm improvements, fractal analysis may be a component in computerized histomorphological assessments of lung cancer and may provide an adjunct test in differentiating NSCLCs.

Current breast cancer proliferative markers correlate variably based on decoupled duration of cell cycle phases.

Mitotic count, PhH3, and MIB-1 are used as measures of the proportion of proliferating malignant cells in surgical pathology. They highlight different stages of the cell cycle, but little is known about how this affects their counts. This study assesses the strength of their correlations and attempts to determine the relationship between them. Proliferation counts for forty-nine consecutive cases of invasive breast carcinomas were analyzed, with the same tumor area on each stain counted using digital image analysis. The integrated optical density (IOD) of nuclei was measured as an approximation of nuclear DNA content. PhH3 strongly correlated with mitotic count (r = 0.94). Weaker correlations were found between MIB-1 versus PhH3 (r = 0.79) and mitotic count (r = 0.83). Nuclear IOD showed stronger correlation with MIB-1 (r = 0.37) than to mitotic count (r = 0.23) and PhH3 (r = 0.34). With evidence from a literature review, it is suggested that the weaker correlations with MIB-1 are not explained by count imprecision or error, but relies on temporal decorrelation between cell cycle phases. Consequences on correlation between these proliferative markers are illustrated by mathematical models.

Solitary lesions with fibrosis and increased IgG4+ plasma cells: part of the expanding spectrum of IgG4-related disease or a nonspecific inflammatory response?

We assessed 6 cases acquired during routine surgical sign-out for IgG4-related disease (IRD) according to criteria from a recent consensus meeting. These cases fulfilled the morphologic criteria-that is, dense lymphoplasmacytic infiltrates, IgG4:IgG ratio greater than or equal to 0.4, and fibrosis (storiform in 4 cases-but were associated with malignancy or did not fulfill the criteria for a new site. These criteria include increased serum IgG4 (normal in the majority of IRD) and a response to glucocorticoids, which is not appropriate treatment for resectable lesions as in our cases. Until more is known about the natural history of the disease, we propose that the possibility of an early, localized, or forme fruste of IRD should be considered and that cases associated with malignancy should at least be documented. Although we acknowledge the value of the consensus criteria, their strict application may result in missed opportunities to study the disease.