SWI/SNF chromatin remodeling complex in pancreatic ductal adenocarcinoma: Clinicopathologic and immunohistochemical study.

The SWItch/Sucrose Non-Fermentable (SWI/SNF) complex is a multimeric protein involved in transcription regulation and DNA damage repair. SWI/SNF complex abnormalities are observed in approximately 14-34 % of pancreatic ductal adenocarcinomas (PDACs). Herein, we evaluated the immunohistochemical expression of a subset of the SWI/SNF complex proteins (ARID1A, SMARCA4/BRG1, SMARCA2/BRM, and SMARCB1/INI1) within our PDAC tissue microarray to determine whether SWI/SNF loss is associated with any clinicopathologic features or patient survival in PDAC. In our cohort, 13 of 353 (3.7 %) PDACs showed deficient SWI/SNF complex expression, which included 11 (3.1 %) with ARID1A loss, 1 (0.3 %) with SMARCA4/BRG1 loss, and 1 (0.3 %) with SMARCA2/BRM loss. All cases were SMARCB1/INI1 proficient. The SWI/SNF-deficient PDACs were more frequently identified in older patients with a mean age of 71.6 years (SD = 7.78) compared to the SWI/SNF-proficient PDACs which occurred at a mean age of 65.2 years (SD = 10.95) (P = 0.013). The SWI/SNF-deficient PDACs were associated with higher histologic grade, compared to the SWI/SNF-proficient PDACs (P = 0.029). No other significant clinicopathologic differences were noted between SWI/SNF-deficient and SWI/SNF-proficient PDACs. On follow-up, no significant differences were seen for overall survival and progression-free survival between SWI/SNF-deficient and SWI/SNF-proficient PDACs (both with P > 0.05). In summary, SWI/SNF-deficient PDACs most frequently demonstrate ARID1A loss. SWI/SNF-deficient PDACs are associated with older age and higher histologic grade. No other significant associations among other clinicopathologic parameters were seen in SWI/SNF-deficient PDACs including survival.

Clinicopathologic features and diagnostic challenges of small cluster pattern appendiceal neuroendocrine tumors.

Appendiceal neuroendocrine neoplasms (NENs) can present with various growth patterns including the traditional triad of histologic patterns-insular, trabecular and tubular. A small cluster pattern was also found in this study and the literature on this specific morphology is limited. In this study, we conducted a comprehensive review of appendiceal NENs from our institution over a ten-year period. Clinical and demographic data were obtained from medical records. Immunohistochemical stains were performed with antibodies specific for synaptophysin, chromogranin, INSM1, CD56, serotonin and peptide YY. The small cluster pattern was found in 29.4 % of all cases evaluated. The tumor cells in these cases were predominantly located at the distal tip of the appendix, associated with fibrous obliteration. These tumors were smaller in size and tended towards less advanced tumor stage, with reduced incidence of lymphovascular and/or perineural invasion. Chromogranin expression was identified in 76 % of these cases. There is a heterogeneous hormone profile with 46.7 % serotonin and 33.3 % peptide YY. In conclusion, the small cluster pattern NENs present with unique histological features and hormone expression profile. Among the various neuroendocrine markers, INSM1 showed superior diagnostic performance, with high sensitivity and minimal non-specific staining.

Primary Colonic Medullary Carcinoma With Exclusive Squamous Differentiation.

BACKGROUND/AIM: Medullary carcinoma (MC) of the colon is a rare subtype of colorectal adenocarcinoma (CRC) with unique histomorphology and frequent mismatch repair (MMR) deficiency. MC with exclusive squamous differentiation has not been reported. We report an unusual case of MC with squamous differentiation and tested this differentiation potential in other MMR-deficient CRC cases. CASE REPORT: A 68-year-old woman presented with a large ascending colon mass and biopsy showed squamoid tumor morphology with immunoprofile concerning for squamous cell carcinoma (SCC). She underwent right hemicolectomy. Immunohistochemistry and next-generation sequencing (NGS) were performed for tumor classification. Macroscopically, the tumor was large and locally advanced. It metastasized to the lung without lymph node metastasis. Microscopically, the tumor cells were monotonous with cytological features of both MC and SCC. Immunostains were diffusely positive for p40 and CK5/6, but negative for other lineage markers including CDX2, CK20, and SATB2. The tumor was MMR deficient with loss of MLH1 and PMS2. NGS confirmed BRAF V600E mutation. In comparison, a tissue microarray comprising 64 previously diagnosed MMR deficient CRC was tested for squamous differentiation, and only 1 case showed focal CK5/6 expression, but none was positive for p40. CONCLUSION: MC with exclusive squamous differentiation not only posed significant diagnostic challenges, but also unveiled unrecognized differentiation plasticity in this tumor type.

Clinicopathologic Features of Low-grade Appendiceal Mucinous Neoplasm: A Single-institution Experience of 117 Cases.

Low-grade appendiceal mucinous neoplasm (LAMN) is an enigmatic tumor that lacks the capacity for classic invasion but can dissect through the appendiceal wall, causing pseudomyxoma peritonei (PMP). Most large studies of the histologic spectrum of LAMN and its rate of associated PMP include cases submitted from outside institutions, potentially skewing their findings. We identified 117 cases of LAMN at our institution. Hematoxylin and eosin-stained slides from each were reviewed, and clinical and pathologic parameters were noted. The patients were 76 females and 41 males, with a mean age of 60 years. Presenting symptoms were available for 113 patients; the majority (56%) were symptomatic, typically with abdominal pain. Ninety-one tumors (78%) were grossly dilated, and the entire appendix was submitted in 88 (75%) cases. Median lesion size was 5.5 cm. Ninety-two cases (79%) demonstrated epithelial denudation; these were often markedly dilated and contained intraluminal or mural microcalcifications. Thirty-two (27%) had a mucosal Schwann cell proliferation. On the basis of the American Joint Committee on Staging eighth edition cancer staging manual, of 117 cases, 66% were staged as pTis, 9% as pT3, 24% as pT4a, and 2% as pT4b. Ten cases (9%) were associated with histopathologic evidence of disseminated PMP. Only 1 patient died of disease, while 3 were alive with disease at last follow-up. Previous LAMN studies have utilized both departmental and extradepartmental material; our single-institution review demonstrated lower rates of PMP than some prior studies. Some LAMNs may be markedly dilated with extensive denudation, making the diagnosis difficult to confirm microscopically and ultimately requiring submission of the entire appendix for histologic evaluation.

Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes. METHODS: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and IGF1R genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors. RESULTS: Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; P trend = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; P trend = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m2 (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; P interaction = 0.032). KRAS-mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in IGF1R were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, P < 0.001). CONCLUSIONS: Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC. IMPACT: IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.

Invasive pulmonary aspergillosis in a patient with cirrhosis.

Aspergillus molds are ubiquitous environmental molds that can cause devastating invasive infections in immunocompromised patients. These infections often go unrecognized in critically ill patients. This case describes a 68 year-old female resident of a long-term nursing facility with history of dementia, nonalcoholic fatty liver disease with cirrhosis, chronic kidney disease stage III and insulin-dependent type 2 diabetes who presented with vomiting, diarrhea and leg swelling. She developed hypotension and was treated for sepsis but found to have negative routine infectious workup. Chest imaging showed nodular densities and bilateral opacities. She developed acute renal failure and hypoxic respiratory failure followed by acute decompensated cirrhosis with refractory volume overload and hypotension and was eventually transitioned to comfort care measures. Autopsy ultimately showed invasive pulmonary aspergillosis. Here we review the diagnosis and management of invasive fungal infections in critically ill patients without typical risk factors or clinical findings for invasive fungal disease. Invasive fungal infections are frequently missed and carry high mortality rates, therefore warranting consideration in critically ill populations.

Incidence and Significance of GATA3 Positivity in Pancreatic Ductal Adenocarcinoma and Cholangiocarcinoma.

GATA3 is a transcription factor involved in the development and differentiation of lymphocytes, breast, and hair follicles. The protein is a useful immunohistochemical (IHC) marker for supporting diagnoses of breast or urothelial carcinoma. This can be especially helpful in metastatic neoplasms to help delineate site of origin. GATA3 is also reportedly positive in a percentage of pancreatic ductal adenocarcinomas (PDACs) and cholangiocarcinomas (CCs), but no study has closely evaluated this relationship with respect to clininopathologic features or patient outcome. Using tissue microarrays, we analyzed 240 PDACs and 60 CCs with GATA3 IHC and compared expression to various clinical and pathologic parameters. Overall, GATA3 positivity was seen in 16% of PDACs and 5% of CCs. GATA3 positivity in PDAC cases was more common in male patients (P=0.013). GATA3-positive PDACs trended toward worse survival on multivariate analysis (P=0.074). The only 3 GATA3-positive CCs were poorly differentiated (P=0.069); low case number precluded multivariate survival analysis for CCs. GATA3 positivity can occur in carcinomas of the pancreatobiliary system, which should be considered during IHC workup of neoplasms of unclear origin. This positivity seems to have minimal relevance to patient outcome.

Hepatic sclerosing cavernous haemangioma can mimic the nodular elastosis stage of segmental atrophy.

AIMS: Segmental atrophy (SA) of the liver is a recently described pseudotumour that can show a broad spectrum of histological changes. The previously described histological differential diagnosis of SA has included cystic disease of the liver, amyloid, cancer-associated elastosis, and epithelioid haemangioendothelioma. We have observed that sclerosing cavernous haemangiomas (SCHs) can mimic the nodular elastosis stage of SA; the aim of this study was to explore this differential diagnosis. METHODS AND RESULTS: We identified 20 SCHs and 12 SAs, excluding haemangiomas with treatment effect. Several clinical and morphologic characteristics were examined, and elastin and CD34 staining was performed on cases with available tissue. SA was always asymptomatic, whereas SCH caused symptoms in 56% of patients (P = 0.026); SCH also tended to be larger (mean size: SCH, 47 mm; SA, 16 mm; P = 0.027). Thick-walled blood vessels were more common in SA than in SCH (92% versus 45%, P = 0.011), as was ductular reaction (50% versus 5%, P = 0.0057). The two lesions had similar rates of border irregularity, residual entrapped hepatocytes, matrix oedema, and at least mild elastic fibrosis as seen on special staining, although staining was typically dense and diffuse in SA. CD34 immunostaining demonstrated at least scattered vessels in all cases of SA and SCH. CONCLUSIONS: SCH can mimic SA, although it is generally larger and more often symptomatic. Elastin staining provides a useful adjunct to standard haematoxylin and eosin histological examination in resolving this differential diagnosis.

Cecal Mucosal Myxoma: The First Report of a New Type of Mesenchymal Colon Polyp.

Myxomas are benign mesenchymal neoplasms of unknown etiology that most commonly occur in the cardiac atrium; however, other reported sites include the skin, joints, skeletal muscles, maxillofacial bones, and sinonasal tract. Myxomas involving the gastrointestinal (GI) tract are rare and are limited to a few published case reports. We are presenting, to our knowledge, the first case report of a mucosal myxoma in the colon presenting as a colonic polyp. A 49-year-old woman underwent a screening colonoscopy and was found to have a 0.2-cm sessile polyp in the cecum. Histologically, the polyp was composed of bland spindled cells in the lamina propria set in a hypocellular, myxoid stroma. The lesion was relatively well-demarcated from the surrounding mucosa. The overlying colonic epithelium showed no dysplasia. S-100 immunohistochemical stain showed only focal nonspecific positivity, while CD34, CD117, SMA, EMA, and desmin were all negative. Alcian blue special stain showed positive staining, supporting the diagnosis of myxoma. Myxomas in the GI tract are very rare, with this being the first reported case of a polypoid colonic mucosal myxoma. Previous reports of GI myxomas are limited to examples in the stomach, small bowel, and one recently reported case in the colon, all of which were submucosal lesions and not limited to the mucosa. In some of the prior reports, the patients had synchronous cardiac atrial myxomas. Mucosal colonic myxoma represents a newly identified mesenchymal polyp of the colon and pathologists should be aware of this diagnostic entity.

Unexpectedly High Prevalence of Cystoisospora belli Infection in Acalculous Gallbladders of Immunocompetent Patients.

Objectives: Indications for cholecystectomy have changed dramatically over the past three decades. Cystoisospora belli has been reported in cholecystectomy specimens of immunocompetent patients. The present study was designed to determine the prevalence and clinical association of C belli in the gallbladder. Methods: The study included retrospective review of cholecystectomy specimens (n = 401) removed for various indications, and a prospective cohort of cholecystectomy specimens (n = 22) entirely submitted for histologic evaluation. Correlations of presence of C belli with age, sex, clinical indication, and abnormalities of preoperative laboratory values were assessed by Fisher exact test. Results: C belli was identified in 39/401 (9.7%) of the retrospective cohort, and 6/22 (27.3%) of the entirely submitted specimens. The presence of C belli showed no correlation with age, sex, clinical indication, or laboratory abnormalities. Conclusions: C belli resides in a latent state in the gallbladder and may be best considered a commensal organism.

Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.

PURPOSE: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. METHODS: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. RESULTS: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05). CONCLUSION: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

Dystrophic Adipocytes Mimicking Metastatic Signet Ring Cell Adenocarcinoma: A Diagnostic Pitfall in a Cachectic Patient.

Cachexia is a debilitating condition and complex syndrome commonly associated with a variety of chronic diseases. It is caused by metabolic dysregulation and characterized by profound loss of adipose tissue and skeletal muscles. While pathological changes of cachectic conditions on adipose tissue have been studied and documented in tumor-bearing animal models, similar morphological changes in human surgical specimens are rare. Here we report a case of a cachectic patient with pancreatic adenocarcinoma whose adipocytes underwent dramatic lipodystrophy mimicking signet ring cell adenocarcinoma. The patient had presented with a large bowel obstruction, a mass extending between the pancreas and colon, and radiographic concern for carcinomatosis. A moderately differentiated adenocarcinoma was identified invading externally into the colon, with extensive signet ring-like cells throughout the specimen, including those adjacent to the colon and lymph nodes and around nerves. These signet ring-like cells were round with variably clear to eosinophilic cytoplasm and a peripherally displaced round to oval nucleus. Immunohistochemical staining demonstrated that these signet ring-like cells were negative for AE1/AE3, CD138, or Kreyberg staining, while they were positive for S-100 staining, confirming these as dystrophic adipocytes. Here we examine dystrophic adipocytes in a cachetic patient, examining the differential diagnosis and potential ancillary studies.

Esophageal Mucosal Calcinosis: A Rare Site of Gastrointestinal Mucosal Calcinosis.

BACKGROUND Gastrointestinal tract mucosal calcinosis (MC) tends to affect the gastric mucosa, while esophageal involvement is rare. Gastric MC may be seen with solid organ transplantation, use of aluminum-containing antacids or sucralfate, malignancy, and chronic renal failure. While the incidence of gastric MC in renal transplant patients undergoing gastric biopsy is common (between 15-29%), to our knowledge esophageal MC has only been previously reported 3 times. CASE REPORT A 68-year-old male dialysis-dependent end stage renal disease status-post deceased donor kidney transplant underwent an esophagogastroduodenoscopy (EGD) for dysphagia and diffuse esophageal wall thickening seen on imaging studies. EGD demonstrated diffuse, circumferential thick white esophageal plaques and mucosal friability. Esophageal biopsies demonstrated erosive esophagitis with basophilic calcium deposits within the fibrinopurulent exudate and squamous mucosa. Stains for fungal organisms and viruses were negative. A diagnosis of esophageal MC was made. Although the patient had a protracted postoperative course after transplantation, he had improvement of the esophageal wall thickening on imaging after transplantation. CONCLUSIONS Esophageal MC is a rare phenomenon and all of the previously reported cases of esophageal MC, including our case, have been in patients with end stage renal disease who were on dialysis. Although prolonged hypercalcemia and hyperphosphatemia, an elevated calcium-phosphorus product, and associated underlying inflammation are likely key etiologic factors, the pathogenesis of esophageal MC is not fully understood and is likely due to multiple collective etiologies. Likewise, more reported cases are likely to increase our understanding of the clinical significance and management of this rare disorder.

IMP3 Immunohistochemical Expression Remains Consistent Among All Grades of Gastrointestinal Neuroendocrine Tumors.

Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3), is an oncofetal protein whose aberrant expression has previously been detected in multiple malignant neoplasms. Pulmonary neuroendocrine carcinomas demonstrate increased expression compared with pulmonary carcinoid tumors, but this relationship has not been studied in gastrointestinal neuroendocrine tumors (GINETs). This study examined IMP3 expression in GINETs, with a focus on correlation with established grading criteria. Fifty-four GINETs were immunohistochemically studied using a monoclonal antibody against IMP3. Using established World Health Organization criteria, the cases were stratified by grade and included 31 grade 1 neuroendocrine tumors (G1 GINETs), 15 grade 2 neuroendocrine tumors (G2 GINETs), and 8 neuroendocrine carcinomas (GINECs). The majority (51/54, 94.4%) of GINETs demonstrated IMP3 staining. Thirty cases (55.6%) showed IMP3 cytoplasmic/membranous staining in 60% or greater of tumor cells, with moderate to strong staining in nearly all of these cases (29/30; 96.7%). Of the remaining 24 cases, 3 cases showed no staining, whereas 17 (81%) demonstrated weak staining. When stratified by grade, there was no statistically significant difference in IMP3 staining among the 3 grades of GINETs; of the G1 GINETs, 14 (45.2%) demonstrated staining in at least 60% of tumor cells, compared with 10 (66.7%) G2 GINETs and 6 (75%) GINECs. Hindgut neoplasms of any grade were the most likely to show significant IMP3 staining. Unlike what has been demonstrated in neuroendocrine neoplasms in the lungs, GINETs appear to have a consistent IMP3 expression profile among all tumors grades, which may be reflective of their unique tumor biology.

Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma.

IMPORTANCE: Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes. OBJECTIVE: To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection. DESIGN, SETTING, AND PARTICIPANTS: This study analyzed protein expression and DNA alterations for the KRAS, CDKN2A, SMAD4, and TP53 genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women's Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjustment for age, sex, tumor characteristics, institution, and perioperative treatment. Data were collected September 9, 2012, to June 28, 2016, and analyzed December 17, 2016, to March 14, 2017. MAIN OUTCOMES AND MEASURES: The DFS and OS among patients with resected pancreatic adenocarcinoma. RESULTS: Of the 356 patients studied, 191 (53.7%) were men and 165 (46.3%) were women, with a median (interquartile range [IQR]) age of 67 (59.0-73.5) years. Patients with KRAS mutant tumors had worse DFS (median [IQR], 12.3 [6.7 -27.2] months) and OS (20.3 [11.3-38.3] months) compared with patients with KRAS wild-type tumors (DFS, 16.2 [8.9-30.5] months; OS, 38.6 [16.6-63.1] months) and had 5-year OS of 13.0% vs 30.2%. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had a median (IQR) OS of 15.3 (9.8-32.7) months. Patients whose tumors lacked CDKN2A expression had worse DFS (median, 11.5 [IQR, 6.2-24.5] months) and OS (19.7 [10.9-37.1] months) compared with patients who had intact CDKN2A (DFS, 14.8 [8.2-30.5] months; OS, 24.6 [14.1-44.6] months). The molecular status of SMAD4 was not associated with DFS or OS, whereas TP53 status was associated only with shorter DFS (HR, 1.33; 95% CI, 1.02-1.75; P = .04). Patients had worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 4 altered genes had worse DFS (HR, 1.79 [95% CI, 1.24-2.59; P = .002]) and OS (HR, 1.38 [95% CI, 0.98-1.94; P = .06]). Five-year OS was 18.4% for patients with 0 to 2 gene alterations, 14.1% for those with 3 alterations, and 8.2% for those with 4 alterations. CONCLUSIONS AND RELEVANCE: Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.

Lymph node metastases in resected pancreatic ductal adenocarcinoma: predictors of disease recurrence and survival.

BACKGROUND: Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC). METHODS: In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy. RESULTS: Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all Ptrend<0.01). American Joint Committee on Cancer 8th edition effectively predicted DFS and OS, while minimising model complexity. Lymph node metastases had weaker prognostic value in patients with positive margins and distal resections (both Pinteraction<0.03). Lymph node metastases by AJCC 7th and 8th editions did not predict the likelihood of local disease as the first site of recurrence. CONCLUSIONS: American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.

Distinction between inflammatory hepatocellular adenoma and mass effect on liver sampling.

Inflammatory hepatocellular adenoma (IHA) is characterized by sinusoidal dilation, inflammation, and bile ductular reaction. However, these changes can also be seen in nonneoplastic liver tissue adjacent to a mass lesion. This differential may arise in biopsy tissue attempting to sample a liver mass. Serum amyloid A (SAA) immunostaining is useful for the diagnosis of IHA but is not entirely specific. In addition, the histologic pattern of mass effect (ME) has received little formal scrutiny. We compared the clinical, morphologic, and immunohistochemical findings in 18 IHA and 36 livers with ME. Several histologic findings were evaluated in all cases. SAA and CD34 staining were also performed. Patients with IHA were younger (P<.0001) and more often female (P=.0044) than patients with specimens showing ME, but lesions were multifocal on imaging in two-thirds of patients in each category. Unpaired arteries were only seen in IHA (P<.0001), whereas ductular reaction was more common in ME (P=.012). Strong SAA immunostaining was observed in 100% of IHAs and 56% of ME cases (P=.0004), and CD34 staining was seen in 95% of IHAs and 6% of ME cases (P<.0001). Unpaired arteries and staining for SAA and CD34 best distinguish IHA from ME. However, unpaired arteries may be absent because of sampling, and SAA is not available in all laboratories. Ductular reaction can occur in IHA but is more common in ME.

Von Hippel-Lindau Disease.

Von Hippel-Lindau disease is an autosomal dominant syndrome which occurs secondary to germline mutations in the VHL tumor suppressor gene, located on chromosome 3. Clinically von Hippel-Lindau disease is characterized by an increased risk of developing simple visceral cysts, most commonly in the pancreas and kidneys, in addition to an increased risk of developing neoplasms, often with clear cell features, in a multitude of organ systems. The most common neoplasms are cerebellar and retinal hemangioblastomas, adrenal pheochromocytomas, clear cell renal cell carcinomas, pancreatic neuroendocrine tumors, pancreatic serous cystadenomas, and endolymphatic sac tumors. These lesions most commonly present during adulthood; however, screening and surveillance for the development of these lesions should begin in the pediatric years for patients with von Hippel-Lindau disease. In this review article, the genetics and most common neoplasms of von Hippel-Lindau disease are reviewed, with an eye towards implications for the pediatric patient.

High frequency of coexpression of maspin with p63 and p53 in squamous cell carcinoma but not in adenocarcinoma of the lung.

Maspin, a member of the serpin family of protease inhibitors, has been shown to inhibit tumor growth and suppress metastasis in several malignancies, including lung cancer. Previous studies have reported that p63 and p53 control maspin expression by transactivating the promoter. The present study analyzed immunohistochemical studies to determine the expression and coexpression patterns of maspin, p63 and p53 in non-small cell lung carcinoma, specifically squamous cell carcinoma and adenocarcinoma. The results showed that 83/86 cases (96.5%) of squamous cell carcinoma and 82/161 cases (50.9%) of adenocarcinoma included in this study were positive for maspin. There were 79/86 cases (91.9%) of squamous cell carcinoma and 16/161 cases (9.9%) of adenocarcinoma with positive expression for p63. In addition, 77/86 cases (89.5%) of squamous cell carcinoma and 99/161 cases (61.5%) of adenocarcinoma were positive for p53. Maspin, p63 and p53 expression were each significantly higher in squamous cell carcinoma than adenocarcinoma. Squamous cell carcinomas more highly coexpress maspin and p63, as well as maspin and p53, when compared with adenocarcinomas. The high frequency of coexpression of maspin and p63, as well as maspin and p53, in squamous cell carcinoma, suggests that p63 and p53 may be involved in the pathway to control maspin expression. Therapeutic targeting on maspin, p63 and p53 molecules might be beneficial in the management of patients with squamous cell carcinomas of the lung in the future.