Viral Hepatitis B Reactivation With Delayed Cholestatic Effect Secondary to Acalabrutinib.

One significant complication of hepatitis B virus includes reactivation (HBVr) in the context of the use of immunosuppressive agents, such as corticosteroids and rituximab, among others. Limited data exist on the topic of HBVr risk in the context of tyrosine kinase inhibitors for which there is no strong guidance recommendation. We describe the clinical characteristics, diagnostic challenges, and the clinical course of a single patient with recurrent mantle cell lymphoma who developed HBVr after treatment with acalabrutinib, a Bruton tyrosine kinase inhibitor.

Optimal Combination of Pitch, Modulation Factor and Dosimetric Considerations in Treatment Planning for Total Body Irradiation Using Helical Tomotherapy.

OBJECTIVE: The aim of this study is to makethe standard total body irradiation (TBI) protocol for Helical tomotherapy© (HT) and to analyze the optimal pitch and modulation factor (MF) with respect to dose homogeneity index (HI), target dose coverage, target overdose, beam on time (BOT) and mean lung dose. MATERIALS AND METHODS: Ten patients who underwent high-dose TBI were taken for this study. For each patient, 35 dose plans were created by different combination of pitch and MF. The optimal pitch and MF were deduced using scatter plot and regression methodology based on target coverage, HI, target volume receiving 103%(V103%), 105%(V105%) and 107% (V107%) of the prescription dose and BOT. Using these optimal pitch and MF, the final dose plan was made and the planning aim and achieved dose was compared using two tailed student's t-test. Radiochromic films and ionization chambers were used to measure the delivered dose using anthropomorphic phantom on various points for the head and pelvis regions to verify the skin flash margin and its effect on skin dose. RESULTS: The optimal pitch and MF value were 0.287 and 2.4 respectively. Based on optimal pitch and MF, the mean BOT was 1692 seconds with optimal inhomogeneity (7.4%). For target, D95 and D98 were 97.09% (range:94.7-99.6%, p=0.002) and 93.9% (range:91.5-94.4%,p=0.007) respectively, and mean D2 was within 107% with SD of ±1.22% (p=0.04). The mean of PTV receiving V103, V105 and V107 was 24.48% (range=7.7-36.6%, p=0.03), 5.76% (range=1.4-12.1%, SD=±3.3%), 1.93% (range=0.1-4.6%, p=0.008) respectively. Our measurements show that the flash margin did not increase the skin dose. CONCLUSION: In our study, the optimal combination of pitch value of 0.287 and MF value of 2.4 provided acceptable plans for all patients planned for TBI in HT. The flash margin can provide adequate coverage during patient position uncertainty without increasing the skin dose.

Mycophenolate Mofetil: A Friend or a Foe with Post-Transplantation Cyclophosphamide and Tacrolimus Prophylaxis in HLA-Matched Donors?

Adapted from the haploidentical hematopoietic stem cell transplantation (HCT) literature, post-transplantation cyclophosphamide (PTCy) is being used increasingly with HLA-matched donors, generally with a calcineurin inhibitor, such as tacrolimus (Tac), and with or without mycophenolate mofetil (MMF). Owing to its immunosuppressive and potentially antitumor and antimicrobial properties, MMF is an attractive drug; the benefit gained when it is used with PTCy/Tac remains unclear, however. To assess this, we compared PTCy/Tac (n = 242) and PTCy/Tac/MMF (n = 144) regimens in recipients of HLA-matched donor transplantation. In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.6 to 2.8; P < .001), and steroid-refractory/dependent aGVHD (HR, 4.8; 95% CI, 2.4 to 9.6; P < .001), yet a significantly lower risk of relapse (HR, .5; 95% CI, .3 to .9; P = .009) and better progression-free survival (PFS) (HR, .7; 95% CI, .5 to .9; P = .04). There were no differences in the risk of grade III-IV aGVHD, chronic graft-versus-host disease (cGVHD), nonrelapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days and an elevated risk of bacterial infection. In an exploratory stool microbiome analysis (n = 16), we noted a higher relative abundance of ß-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD. Our data suggest that the addition of MMF to PTCy/Tac for HLA-matched donor HCT does not provide any advantage for GVHD prevention. Further studies are needed to decipher this mechanism and understand its role with PTCy-based prophylaxis.

Metastatic nonhematopoietic neoplasms to the breast: a study of 238 cases.

The aim of this study was to review the clinicopathologic characteristics of metastatic nonhematopoietic malignancies to the breast, in order to identify salient features for practicing pathologists that are useful in distinguishing metastatic lesions from primary breast neoplasms. A total of 238 cases were identified during the period from January 2005 to January 2015. Clinicopathologic features of these cases were retrospectively reviewed. Primary tumors included melanoma (99, 42%), serous carcinoma (35, 15%), neuroendocrine neoplasm (32, 13%), sarcoma (23, 10%), and adenocarcinoma from various organs (47, 20%), and 2 others. Most metastases were unilateral (223, 94%) and unifocal (206, 87%) and were detected radiographically (167, 70%). Concurrent ipsilateral axillary metastasis occurred in 33 (14%) patients. Among 238 cases, 41 had metastatic disease to the breast concurrently or preceding the primary cancer diagnosis. Notably, in 39 (16%) cases, breast metastasis was the first clinical presentation of disease, and 16 (41%) of these cases were initially misdiagnosed as breast primaries. In contrast, with a known history of nonmammary primary tumors, only 4 of 197 (2%) cases were misdiagnosed (p < 0.0001). Metastatic tumors share many overlapping features with breast primary carcinomas. However, cases with a well-circumscribed tumor, lack of in situ component, estrogen receptor/progesterone receptor negativity, and unusual morphologic features should raise the consideration of metastatic disease. While clinical history is paramount for correct diagnosis, metastasis to the breast as the first clinical presentation is not uncommon.

Commissioning and Dosimetric Results of an Indigenously Developed Intra-Vaginal Template for Interstitial Plus Intracavitary High dose Rate Image-Guided Brachytherapy of Advanced Cervix Cancer.

Aim: The goal of this study is to discuss the commissioning and dosimetric parameters achieved during the clinical implementation of an indigenously developed intracavitary (IC) plus interstitial (IS) template for high dose rate (HDR) image-guided brachytherapy (IGBT) in cancer (Ca) cervix. We want to discuss our achieved values of cumulative equi-effective doses (EQD2) for high-risk clinical target volume (HRCTV) and organ at risk (OAR) and compare it with available published results. Materials and Methods: Medanta anterior oblique/lateral oblique template has a total of 19 needles including the central tandem. For commissioning the template with needles, the indigenously made acrylic phantom was used. Oblique and straight needles were placed inside the acrylic phantom and a computed tomography (CT) scan was performed. Sixteen patients were treated in HDR IGBT using this template after external-beam radiotherapy. The IGBT plans were evaluated based on EQD2 of target coverage i.e., dose received by 98% (D98%_HRCTV), 90% (D90%_HRCTV), and 50% (D50%_HRCTV) volume of HRCTV, and dose received by 2 cc (D2cc) and 0.1 cc (D0.1cc) of OAR using linear quadratic (LQ) radiobiological model. Results: The autoradiographic in radiochromic film shows that the distance between the needle tip and the middle of the source position is 6 mm. The mean D98%_HRCTV and D90%_HRCTV was 76.8 Gy (range: 70-87.7 Gy, P < 0.01) and 84.49 Gy (range: 76.6-96.7 Gy, P < 0.01), respectively. Mean EQD2 of D2cc of the bladder, rectum, and sigmoid was 85.6 Gy (range: 77.5-99.6 Gy, P < 0.03), 74.3 Gy (range: 70.9-76.7 Gy, P < 0.05), and 58.3 Gy (range: 50.6-67.9 Gy, P = 0.01), respectively. The mean total reference air kerma at a 1 m distance is 0.489cGy (range: 0.391-0.681cGy). Conclusions: The indigenously developed template could attain satisfactory standards in terms of set parameters for commissioning and acceptable dose volume relations in our clinical use for treating the advanced Ca cervix patients who need IC + IS type of HDR IGBT. The comparative analysis with contemporary applicators was acceptable.

Dosimetric Comparison of Robotic and Linear Accelerator Multi-Leaf Collimator-Based Stereotactic Radiosurgery for Arteriovenous Malformation.

PURPOSE: To investigate the dosimetric comparison of different collimators which are used in robotic radiosurgery (cyberknife-CK) and linear accelerator (LINAC) for stereotactic radiosurgery (SRS) in arteriovenous malformation (AVM). MATERIALS AND METHODS: Twenty-five AVM patients were planned in CK using FIXED cone, IRIS collimator, and multi-leaf collimator (MLC) based in LINAC. Dosimetric comparison was performed using Paddick conformity index (CIPaddick) and International Commission on Radiation Units and measurements (ICRU) homogeneity index (HIICRU), gradient score (GS), normal brain dose received by 10cc (D10cc) and critical structure (brain stem, optic chiasma, optic nerves) doses. Paired sample t-test was used for statistical analysis. RESULTS: Mean treatment volume was 3.16cc (standard deviation ± 4.91cc). No significant deviation (P =0.45, 0.237 for FIXED vs. IRIS and FIXED vs. MLC, respectively) was found in target coverage. For CIPaddick, the mean difference (MD) between FIXED- and MLC-based plans was 0.16(P = 0.001); For HIICRU, difference between FIXED and IRIS was insignificant (0.5, P = 0.823); but, when FIXED versus MLC, the deviation was 7.99% (P = 0.002). In FIXED- and MLC-based plans, significant difference was found in GS70 and GS40 (P < 0.041 and 0.005, respectively). MD between FIXED- and MLC-based plans for normal brain for 5Gy, 10Gy, 12Gy, and 20Gy were 36.08cc (P = 0.009), 7.12cc (P = 0.000), 5.84cc (P = 0.000) and 1.56cc (P = 0.000), respectively. AVM volume <0.7cc should be treated with CK FIXED and >0.7cc were treated by using FIXED or IRIS collimators. AVM volume > 1.4cc can be treated by either LINAC MLC-based SRS or CK. CONCLUSION: Our study shows CK collimator (IRIS and FIXED) could be able to treat brain AVMs in any size. Linac MLC-based SRS has some limitations in terms of conformity and low-dose spillage, and advantages like reduced treatment time and MU.

Passive and active immunity in infants born to mothers with SARS-CoV-2 infection during pregnancy: prospective cohort study.

OBJECTIVE: To investigate maternal immunoglobulins' (IgM, IgG) response to SARS-CoV-2 infection during pregnancy and IgG transplacental transfer, to characterise neonatal antibody response to SARS-CoV-2 infection, and to longitudinally follow actively and passively acquired antibodies in infants. DESIGN: A prospective observational study. SETTING: Public healthcare system in Santa Clara County (California, USA). PARTICIPANTS: Women with symptomatic or asymptomatic SARS-CoV-2 infection during pregnancy and their infants were enrolled between 15 April 2020 and 31 March 2021. OUTCOMES: SARS-CoV-2 serology analyses in the cord and maternal blood at delivery and longitudinally in infant blood between birth and 28 weeks of life. RESULTS: Of 145 mothers who tested positive for SARS-CoV-2 during pregnancy, 86 had symptomatic infections: 78 with mild-moderate symptoms, and 8 with severe-critical symptoms. The seropositivity rates of the mothers at delivery was 65% (95% CI 0.56% to 0.73%) and the cord blood was 58% (95% CI 0.49% to 0.66%). IgG levels significantly correlated between the maternal and cord blood (Rs=0.93, p<0.0001). IgG transplacental transfer ratio was significantly higher when the first maternal positive PCR was 60-180 days before delivery compared with <60 days (1.2 vs 0.6, p<0.0001). Infant IgG seroreversion rates over follow-up periods of 1-4, 5-12, and 13-28 weeks were 8% (4 of 48), 12% (3 of 25), and 38% (5 of 13), respectively. The IgG seropositivity in the infants was positively related to IgG levels in the cord blood and persisted up to 6 months of age. Two newborns showed seroconversion at 2 weeks of age with high levels of IgM and IgG, including one premature infant with confirmed intrapartum infection. CONCLUSIONS: Maternal SARS-CoV-2 IgG is efficiently transferred across the placenta when infections occur more than 2 months before delivery. Maternally derived passive immunity may persist in infants up to 6 months of life. Neonates are capable of mounting a strong antibody response to perinatal SARS-CoV-2 infection.

Passive and active immunity in infants born to mothers with SARS-CoV-2 infection during pregnancy: Prospective cohort study.

OBJECTIVE: To investigate maternal immunoglobulins' (IgM, IgG) response to SARS-CoV-2 infection during pregnancy and IgG transplacental transfer, to characterize neonatal antibody response to SARS-CoV-2 infection, and to longitudinally follow actively- and passively-acquired SARS-CoV-2 antibodies in infants. DESIGN: A prospective observational study. SETTING: A public healthcare system in Santa Clara County (CA, USA). PARTICIPANTS: Women with SARS-CoV-2 infection during pregnancy and their infants were enrolled between April 15, 2020 and March 31, 2021. OUTCOMES: SARS-CoV-2 serology analyses in the cord and maternal blood at delivery and longitudinally in infant blood between birth and 28 weeks of life. RESULTS: Of 145 mothers who tested positive for SARS-CoV-2 during pregnancy, 86 had symptomatic infections: 78 with mild-moderate symptoms, and eight with severe-critical symptoms. Of the 147 newborns, two infants showed seroconversion at two weeks of age with high levels of IgM and IgG, including one premature infant with confirmed intrapartum infection. The seropositivity rates of the mothers at delivery was 65% (95% CI 0.56-0.73) and the cord blood was 58% (95% CI 0.49-0.66). IgG levels significantly correlated between the maternal and cord blood (Rs= 0.93, p< 0.0001). IgG transplacental transfer ratio was significantly higher when the first maternal positive PCR was 60-180 days before delivery compared to <60 days (1.2 vs. 0.6, p=<0.0001). Infant IgG negative conversion rate over follow-up periods of 1-4, 5-12, and 13-28 weeks were 8% (4/48), 12% (3/25), and 38% (5/13), respectively. The IgG seropositivity in the infants was positively related to IgG levels in the cord blood and persisted up to six months of age. CONCLUSIONS: Maternal SARS-CoV-2 IgG is efficiently transferred across the placenta when infections occur more than two months before delivery. Maternally-derived passive immunity may protect infants up to six months of life. Neonates mount a strong antibody response to perinatal SARS-CoV-2 infection.

Idiopathic refractory ascites after allogeneic stem cell transplantation: a previously unrecognized entity.

At our center, we observed a series of patients who developed transudative refractory ascites secondary to noncirrhotic, non-veno-occlusive disease (VOD)-related portal hypertension after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients were considered to have idiopathic portal hypertension-related refractory ascites (IRA) if they developed ascites secondary to intrahepatic portal hypertension (serum ascites albumin gradient ≥1.1 g/dL or hepatic venous pressure gradient [HVPG] >5 mm Hg), but did not meet the clinical criteria for classical VOD/sinusoidal obstructive syndrome (SOS) and did not have any alternate etiology of portal hypertension. From our institutional database, we identified 40 patients who developed IRA after allo-HSCT between 2004 and 2018. The patients' median age at the time of allo-HSCT was 54 years (range, 21-73 years). The median time to development of IRA after allo-HSCT was 80 days (range, 16-576 days). The median number of paracentesis was 3 (range, 1-11), and 15 (38%) patients had an intraperitoneal catheter placed for continued drainage of the rapidly accumulating ascites. Portal pressures were measured in 19 patients; 6 (15%) had moderate portal hypertension (HVPG 6-9 mm Hg), and 13 (33%) had severe portal hypertension (HVPG ≥ 10 mm Hg). Liver biopsy was performed in 24 patients. None of the patients met the criteria for classical VOD/SOS (clinical/histological) or cirrhosis (histological). The cumulative incidence of nonrelapse mortality was 63%, and the median survival duration after the development of the IRA was 7 months (range, 0.8-125.6 months). IRA is a poorly understood and often fatal complication of allo-HSCT.

Diagnosis, grading, and treatment recommendations for children, adolescents, and young adults with sinusoidal obstructive syndrome: an international expert position statement.

Sinusoidal obstructive syndrome, also known as hepatic veno-occlusive disease, is a potentially life-threatening complication that occurs in children undergoing haemopoietic stem-cell transplantation (HSCT). Differences in the incidence of genetic predisposition and clinical presentation of sinusoidal obstructive syndrome between children and adults have rendered the historical Baltimore and Seattle diagnostic criteria insufficient for children. In 2017, the European Society for Blood and Marrow Transplantation (EBMT) proposed the first paediatric diagnostic and severity grading guidelines for sinusoidal obstructive syndrome, intended for implementation across European centres. However, universally accepted paediatric criteria are needed to ensure prompt diagnosis, definitive treatment, and improved outcomes for children, adolescents, and young adults with sinusoidal obstructive syndrome, and to facilitate international clinical research collaboration. We convened an international panel of multidisciplinary experts including physicians with expertise in HSCT, paediatric intensive care, nephrology, hepatology, radiology, pathology, and transfusion medicine; HSCT advanced-practice providers and medical trainees; pharmacists; and translational and basic science researchers from the Pediatric Acute Lung Injury and Sepsis Investigators Network, the EBMT, the Pediatric Blood and Marrow Transplant Consortia, and several other institutions with extensive experience in sinusoidal obstructive syndrome. Panellists convened at The University of Texas, MD Anderson Cancer Center (Houston, TX, USA) in February, 2019, to evaluate the available evidence. In this expert position statement paper, we provide consensus recommendations for the international implementation of guidelines for the diagnosis, severity grading, and treatment of sinusoidal obstructive syndrome among children, adolescents, and young adults. We endorse universal adoption of paediatric diagnostic guidelines for sinusoidal obstruction syndrome as proposed by the EBMT, and provide implementation guidance for standardisation across centres; we have further proposed adjunctive use of age-appropriate organ-specific toxicity criteria for severity grading and provided prophylaxis and treatment considerations among children and adolescent and young adult patients. Key recommendations include: (1) liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of sinusoidal obstructive syndrome in children, adolescents, and young adults; (2) platelet refractoriness can be defined as a corrected count increment of less than 5000-7500 following at least two sequential ABO-compatible fresh platelet transfusions; (3) hepatomegaly is best defined as an absolute increase of at least 1 cm in liver length at the midclavicular line; and if a baseline measurement is not available, hepatomegaly can be defined as greater than 2 SDs above normal for age; and (4) the presence and volume of ascites can be categorised as mild (minimal fluid by liver, spleen, or pelvis), moderate (<1 cm fluid), or severe (fluid in all three regions with >1 cm fluid in at least two regions).

Histologic Grade 1 Is Associated With Increased Nonrelapsed Mortality in Lower Gastrointestinal Graft Versus Host Disease.

Histologic confirmation is considered a standard practice to diagnose gastrointestinal graft versus host disease (GI GVHD) and is often used in making treatment decisions. A histologic grade is often determined in cases that are diagnosed with GI GVHD. Although extensive crypt loss (histologic grade 4) is associated with high nonrelapse mortality (NRM), the prognostic value for the more common grade 1 is poorly understood. As clinical decisions are made on the degree of histologic evidence, it is important to establish its prognostic significance. Therefore, we evaluated 309 patients who underwent endoscopic biopsy for suspected GI GVHD within 6 months posttransplant between 2009 and 2012. The presence of histologic grade 1 was associated with increased NRM (hazard ratio=2.7, P=0.02) when compared with one of negative biopsy in patients with lower but not isolated upper GI GVHD. Multivariate competing-risk regression analysis confirmed the independent impact of histologic grade 1 in patients with early clinical stages of lower GI GVHD (stage 0 to 2) (hazard ratio=2.7, P=0.044). When compared with advanced histologic grades, histologic grade 1 did not lessen the adverse outcome for patients with advanced lower GI GVHD (stage 3 to 4) (cumulative incidence NRM of 84%). In conclusion, the presence of histologic grade 1 is associated with increased NRM in patients presenting with lower GI GVHD (stages 0 to 2) and is sufficient evidence for decision to initiate therapy. At the same time, histologic grade 1 does not lessen the markedly adverse impact of advanced lower GI GVHD (stage 3 to 4) and is not synonymous with "mild" GVHD.

Cutaneous Metastasis of a Mucoepidermoid Carcinoma of the Pancreas: First Reported Case.

BACKGROUND: Mucoepidermoid pancreatic cancer is a rare entity with only 8 cases reported in the literature. On review of the literature, the authors found that cutaneous metastases in pancreatic cancer are rare and have not been associated with the mucoepidermoid subtype. The authors present the first reported case of cutaneous metastasis in a patient with mucoepidermoid carcinoma of the pancreas. CASE PRESENTATION: A 50-year old white male with a metastatic invasive poorly differentiated mucoepidermoid carcinoma of the pancreas was found to have a slow growing lesion in the skin over his left upper quadrant while undergoing active therapy. The lesion was biopsied and the pathology was consistent with pancreatic origin sharing similar morphologic features when compared with the primary pancreactectomy specimen. CONCLUSIONS: Mucoepidermoid pancreatic cancer is an exceedingly rare subtype of pancreatic cancer, with very little information regarding its diagnosis, treatment, and patterns of metastases. Here, the authors present the first reported case of cutaneous metastases of mucoepidermoid pancreatic cancer.

Malignant Solitary Fibrous Tumor of the Pancreas.

Solitary fibrous tumor (SFT) arising in the pancreas is exceedingly rare, with only 11 cases reported in the English literature. All cases described thus far have exhibited benign histology. We report the first case of malignant SFT of the pancreas. The patient was a 52-year-old woman who presented with obstructive jaundice and a 15-cm pancreatic head mass. The mass showed areas with typical histologic features for SFT including small fibroblastlike cells arranged in the well-characterized "patternless pattern" of architecture, hemangiopericytomalike vessels, areas with dense collagen and infrequent mitoses (0-2 per 10 high-power fields [HPFs]). In addition, multiple areas with an overtly sarcomatous morphology were present, containing large spindle and epithelioid cells with nuclear pleomorphism, marked cellularity, up to17 mitoses per 10 HPFs, and necrosis. Immunohistochemical stains were positive for CD34 and B-cell CLL/lymphoma 2 (Bcl-2) in both benign and malignant components and showed strong, diffuse p53 and p16 staining in the malignant component. At last follow-up (40 months), the patient was alive and well without evidence of disease. However, given that the presence of a malignant component in extrapancreatic SFT has been associated with recurrence/metastasis and death, complete surgical resection and close long-term follow-up is required.

Goblet cell carcinoid tumor, mixed goblet cell carcinoid-adenocarcinoma, and adenocarcinoma of the appendix: comparison of clinicopathologic features and prognosis.

CONTEXT: The prognosis of appendiceal goblet cell carcinoid tumors (GCTs) is believed to be intermediate between appendiceal adenocarcinomas and conventional carcinoid tumors. However, GCTs can have mixed morphologic patterns, with variable amount of adenocarcinoma. OBJECTIVE: To evaluate the behavior of GCTs and related entities with variable components of adenocarcinoma. DESIGN: We classified 74 cases of appendiceal tumors into 3 groups: group 1, GCTs or GCTs with less than 25% adenocarcinoma; group 2, GCTs with 25% to 50% adenocarcinoma; group 3, GCTs with more than 50% adenocarcinoma; and a comparison group of 68 adenocarcinomas without a GCT component (group 4). Well-differentiated mucinous adenocarcinomas were excluded. Clinicopathologic features and follow-up were obtained from computerized medical records and the US Social Security Death Index. RESULTS: Of the 142 tumors studied, 23 tumors (16%) were classified as group 1; 27 (19%) as group 2; 24 (17%) as group 3; and 68 (48%) as group 4. Staging and survival differed significantly among these groups. Among 140 patients (99%) with available staging data, stages II, III, and IV were present in 87%, 4%, and 4% of patients in group 1 patients; 67%, 7%, and 22% of patients in group 2; 29%, 4%, and 67% of patients in group 3; and 19%, 6%, and 75% of patients in group 4, respectively (P = .01). Mean (SD) overall survival was 83.8 (34.6), 60.6 (30.3), 45.6 (39.7), and 33.6 (27.6) months for groups 1, 2, 3, and 4, respectively (P = .01). By multivariate analysis, only stage and tumor category were independent predictors of overall survival. CONCLUSION: Our data highlight the importance of subclassifying the proportion of adenocarcinoma in appendiceal tumors with GCT morphology because that finding reflects disease stage and affects survival.

Squamoid cystosis of pancreatic ducts: a variant of a newly-described cystic lesion, with evidence for an obstructive etiology.

We describe a 40-year-old man who was found to have a cystic mass in the pancreatic tail during workup for weight loss and abdominal discomfort. Although computed tomography scan showed a single cyst associated with dilatation of the main pancreatic duct, gross and histologic examination of the distal pancreatectomy specimen actually revealed a central cyst that was surrounded by multiple smaller cystic spaces. This distinctive appearance was formed from extensive cystic dilatation and squamous metaplasia of the native pancreatic duct system. Further, a traumatic neuroma was discovered near the junction between normal and abnormal parenchyma. We believe that this case represents a variant of the newly-described squamoid cyst of pancreatic ducts which we term squamoid cystosis of pancreatic ducts. The presence of chronic pancreatitis and a traumatic neuroma supports the hypothesis that squamoid cysts are non-neoplastic lesions arising from prior duct obstruction.

Low-grade neuroendocrine tumors arising in intestinal adenomas: evidence for alterations in the adenomatous polyposis coli/ß-catenin pathway.

Low-grade neuroendocrine tumors (NETs) arising in intestinal adenomas are rare. They are occasionally observed in patients with familial adenomatous polyposis (FAP), suggesting a role for the adenomatous polyposis coli/ß-catenin pathway. We identified 25 composite adenoma/low-grade NETs from colorectum (21) and duodenum (4) and evaluated their clinicopathological features, survival, and nuclear ß-catenin expression by immunohistochemistry. ß-catenin staining was scored as % positivity × intensity (weak, 1; moderate, 2; and strong, 3), for a total possible score of 300. Control groups included 1781 adenomas without NET, 63 composite adenoma/high-grade neuroendocrine carcinomas (NECs), and 32 sporadic NETs. Among 25 adenoma/low-grade NETs, 4 (16%) occurred in patients with FAP. Size of the NET component ranged from 0.01 to 0.9 cm (mean, 0.32 cm). Most (84%) arose in "advanced" adenomas (size >1 cm, villous architecture [72%], or high-grade dysplasia [56%]). In contrast, villous architecture and high-grade dysplasia were present in only 14% (P < .001) and 7% (P < .001), respectively, of adenomas without NET. Overall survival with adenoma/low-grade NET was significantly higher than adenoma/high-grade NEC but significantly lower than sporadic NET (P < .001). Higher ß-catenin expression was seen in adenoma/low-grade NETs (mean score, 231) compared with sporadic NETs (mean score, 48; P < .0001) and adenoma/high-grade NEC (mean score, 173; P = .04). In summary, composite adenoma/low-grade NETs most commonly occur with advanced polyps, but the NET component itself is generally small and indolent. In contrast to sporadic NETs, the occurrence of these lesions in FAP and their high levels of nuclear ß-catenin expression support a pathogenic role for the adenomatous polyposis coli/ß-catenin pathway.

Molecular cytogenetic characterization of mammary neuroendocrine carcinoma.

Primary mammary neuroendocrine carcinoma (NEC) is an uncommon entity that accounts for 2% to 5% of breast carcinomas. Recent reports have shown that NEC of the breast is an aggressive subtype of mammary carcinoma that is distinct from invasive ductal carcinoma, not otherwise specified, and have suggested that these tumors have a poorer prognosis than invasive ductal carcinoma, not otherwise specified. In this study, we provide the first cytogenetic characterization of mammary NEC using both conventional G-banding and spectral karyotype on a group of 7 tumors. We identified clonal chromosomal aberrations in 5 (71.4%) cases, with 4 of them showing complex karyotypes. Of these, recurrent numerical aberrations included gain of chromosome 7 (n = 2) and loss of chromosome 15 (n = 2). Recurrent clonal structural chromosomal aberrations involved chromosomes 1 (n = 3), 3 (n = 2), 6q (n = 3), and 17q (n = 3). Of the 4 (57.1%) cases with complex karyotypes, 2 showed evidence of chromothripsis, a phenomenon in which tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. One of these had evidence of chromothripsis involving chromosomes 1, 6, 8, and 15. The other also had evidence of chromosome 8 chromothripsis, making this a recurrent finding shared by both cases. We also found that mammary NEC shared some cytogenetic abnormalities--such as trisomy 7 and 12--with other neuroendocrine tumors in the lung and gastrointestinal tract, suggesting trisomy 7 and 12 as potential common molecular aberrations in neuroendocrine tumors. To our knowledge, this is the first report on molecular cytogenetic characterization of mammary NEC.

Benign glandular downgrowth in gastric neuroendocrine neoplasms: a potential mimic of composite tumour.

AIMS: We have observed glandular downgrowth in some gastric neuroendocrine tumours (NETs), in which nonneoplastic appearing gastric glands are admixed with submucosal neuroendocrine nests, that could potentially be confused with composite tumours. METHODS AND RESULTS: We reviewed 68 gastric NETs with at least submucosal invasion, and evaluated associations between glandular downgrowth, clinical parameters (age, gender, NET setting) and tumour characteristics (size, depth of invasion, grade). Controls included 45 duodenal NETs. Glandular downgrowth was present in 28 (41%) gastric NETs but only 2 (4.4%) duodenal NETs (P < 0.0001). It was not related to age, gender, hypergastrinemia (downgrowth present in 43% of NETs arising in autoimmune gastritis, 41% of Zollinger-Ellison syndrome, 36% of sporadic NETs), tumour size, depth of invasion, or grade. Glandular downgrowth was confined to the submucosa even though 12 (18%) gastric NETs invaded muscularis propria. Submucosal gastric glands (pyloric type in 79%, intestinal in 50%, fundic in 29%) showed metaplastic changes similar to overlying mucosa, were usually mitotically inactive (64% of cases lacked mitotic figures), were geographically restricted to the NET, and never metastasized. CONCLUSIONS: Our findings support the frequent occurrence and nonneoplastic nature of glandular downgrowth in gastric NETs, which should not be mistaken for composite tumours.

Dysplasia-like epithelial atypia in ischemic bowel disease.

Inflammatory and reactive conditions are known to mimic dysplasia or malignancy in the gastrointestinal tract. Epithelial atypia that closely mimics low-grade dysplasia (LGD) or high-grade dysplasia (HGD) can sometimes be seen in ischemic bowel. To study this phenomenon, we evaluated surgical resections for ischemic enteritis (n = 65) and ischemic colitis (n = 99) that included sections of viable epithelium adjacent to necrosis. Viable epithelium was classified as normal, obviously reactive, LGD-like atypia or high-grade dysplasia (HGD)-like atypia. Cases with available paraffin blocks were characterized immunohistochemically with antibodies to p16, p53, and MIB-1. Fourteen dysplastic lesions in chronic ulcerative colitis served as controls. Dysplasia-like atypia was found in 13 small bowel resections (20%) and 15 colectomies (15%), most common near re-epithelializing erosions. Two colectomies had extensive dysplasia-like atypia, whereas the other 26 demonstrated focal or several foci of atypia. Nine cases contained HGD-like atypia, 15 contained LGD-like atypia, and 4 showed both HGD- and LGD-like atypia. Features indicating subacute-to-chronic ischemia were more frequent in LGD-like atypia (13/15, 87%) than HGD-like atypia (2/9, 22%; P = .003). Dysplasia-like atypia showed overexpression of p16 (73%), p53 (50%), and MIB-1 (92%), but these markers did not reliably distinguish dysplasia-like atypia from true dysplasia in chronic ulcerative colitis (P = .45 for p16, P = .51 for p53, P = .08 for MIB-1). These results underscore the frequency of dysplasia-like atypia in ischemic bowel, which can occasionally be an extensive and worrisome finding. Distinction from true dysplasia requires recognizing the context of the epithelial atypia because cell cycle markers were not helpful in classifying individual cases.