Delayed haemolytic and serologic transfusion reactions: pathophysiology, treatment and prevention.

PURPOSE OF REVIEW: The aim of this study was to summarize the basic epidemiology, pathophysiology and management of delayed serologic and delayed haemolytic transfusion reactions (DHTRs), as well as recent developments in our understanding of these adverse events. RECENT FINDINGS: Several studies have identified risk factors for DHTRs, including high alloantibody evanescence rates among both general patient groups and those with sickle cell disease (SCD). Antibody detection is also hampered by the phenomenon of transfusion record fragmentation. There have also been enhancements in understanding of what may contribute to the more severe, hyperhaemolytic nature of DHTRs in SCD, including data regarding 'suicidal red blood cell death' and immune dysregulation amongst transfusion recipients with SCD. With growing recognition and study of hyperhaemolytic DHTRs, there have been improvements in management strategies for this entity, including a multitude of reports on using novel immunosuppressive agents for preventing or treating such reactions. SUMMARY: Delayed serologic and haemolytic reactions remain important and highly relevant transfusion-associated adverse events. Future directions include further unravelling the basic mechanisms, which underlie DHTRs and developing evidence-based approaches for treating these reactions. Implementing practical preventive strategies is also a priority.

Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas.

Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal ß-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion.

von Meyenburg complexes are more frequently associated with cholangiocarcinoma.

AIM: There is some evidence that von Meyenburg complexes (VMCs) can progress to cholangiocarcinoma (CC). This study aimed to evaluate the prevalence of VMCs in CC cases. METHODS: All hepatic resections and explants with intra-hepatic CC (I-CC) and hilar-CC (H-CC) from 1985 to 2020 were studied. Hepatic resections (n=68) for benign lesions or metastatic colonic carcinoma and 15 cases with cirrhosis without any cancer were used as controls. RESULTS: A total of 118 cases of CC (88 I-CC, 30 H-CC) were identified. Of these, 61 (52%) patients had no known background liver disease, and 20 (17%) had cirrhosis. Associated liver disorders included metabolic dysfunction-associated steatohepatitis (23), chronic viral hepatitis B or C (13), biliary disease (primary or secondary sclerosing cholangitis) (8), polycystic kidney disease (6), cryptogenic cirrhosis (5) and others miscellaneous disorders (7). VMCs were present in 34 (39%) of 88 I-CC cases and 7 (23%) of 30 H-CC cases. VMCs were present within the tumour (20 cases), outside the cancer (21 cases) or at both locations (10 cases). VMCs with dysplasia/carcinoma in situ were seen in 19 of 41 (46%) cases with CC and VMCs. In addition, bile duct adenomas were identified in 6 (5%) of CC. 7% of controls showed the presence of VMCs compared with 35% of CC cases (p<0.05). CONCLUSIONS: VMCs are seen far more frequently in patients with CC than in the control group. The findings support the hypothesis that VMCs could represent a precursor of CC or a marker for a higher risk of developing CC.

KRAS mutations are associated with specific morphologic features in colon cancer.

BACKGROUND: Mutations in the KRAS gene occur at an early stage in the development of colorectal carcinoma. Importantly, KRAS mutation predicts resistance to anti-epidermal growth factor receptor therapy in stage IV disease. GOALS: The aim of the current study is to correlate histologic features of colon cancer with the presence of KRAS mutations. STUDY: Tumor tissue from 145 colon cancer resections was tested for KRAS mutations. KRAS mutation status was correlated with demographic and histologic characteristics. Statistical analysis was performed using the Pearson χ2 test and multivariate analysis. RESULTS: KRAS mutations were present in 55/145 cases (37.9%), consistent with reported rates. KRAS mutations were significantly associated with usual adenocarcinoma morphology (multivariate P=0.014), peritumoral lymphocytic response (χ2, P=0.028; multivariate P=0.017), T3-T4 status (χ2, P=0.012; multivariate P=0.015), right-sided location (multivariate P=0.027), absence of lymphovascular invasion (multivariate P=0.008), and metastases at the time of resection (multivariate P=0.034). No association was found between KRAS mutation status and other factors. CONCLUSIONS: Specific morphologic features in colon cancer suggest a higher likelihood of the presence of KRAS mutations. These morphologic features overlap partially with those associated with DNA mismatch repair gene mutations. If confirmed, these results may suggest a paradigm for directed KRAS testing.

An update on ductal plate malformations and fibropolycystic diseases of the liver.

A variety of cystic and fibrocystic lesions can occur in the liver, which may be single or multiple and etiologically can be acquired or have genetic underpinnings. Although the morphology of ductal plate development and various associated malformations has been well described, the genetic etiologies of many of these disorders are still poorly understood. Multiple clinical phenotypes in the liver are proposed to originate from ductal plate malformations: congenital hepatic fibrosis, Caroli's disease, Von Meyenburg complex, and the liver cysts of autosomal dominant polycystic kidney and liver diseases. Although many of the patients with these disorders, particularly with isolated liver involvement remain asymptomatic, some develop portal hypertension or symptoms from cyst enlargement. Development of hepatocellular malignancy is a risk in a small subset. Recent advances have made it now possible for some of these phenotypes to be genetically defined, and intriguingly animal models of adult polycystic liver disease suggest that abnormal organ development is not required. This review describes the current understanding, genetic underpinning, and key clinicopathologic and imaging features of these fibropolycystic liver diseases.

Intermedin is overexpressed in hepatocellular carcinoma and regulates cell proliferation and survival.

Angiogenesis is one of the hallmarks of tumor growth and metastasis. Identification of tumor angiogenic factors has been a critical component in understanding cancer biology and treatment. Intermedin (IMD) has been reported to promote angiogenesis in a rat ischemic model and human umbilical vascular endothelial cells. Our study sought to determine the role of IMD in human hepatocellular carcinoma tumor progression. High IMD mRNA expression levels were observed in human hepatocellular carcinoma tumors, even in early stage disease, by real-time RT-PCR. Immunohistochemical analysis of hepatocellular carcinoma clinical samples demonstrated that the tumor regions were significantly more immunoreactive for IMD than adjacent benign liver. Inhibition of IMD expression using RNA interference reduced cell proliferation in SK-Hep-1 and SNU-398 cells. Blockage of IMD signaling using either an antagonist peptide or a neutralizing antibody inhibited growth in a dose-dependent manner with concomitant induction of apoptosis, causing cleavage of caspase-8 and downregulation of Gli1 and Bcl2. Conversely, addition of IMD active peptide increased the phosphorylation level of extracellular signal-regulated kinase. Thus, IMD might play an important role in cell proliferation and survival of hepatocellular carcinoma. Our data suggests that IMD is a potential biomarker and therapeutic target for hepatocellular carcinoma.

Hematuria and decreased kidney function as initial signs of acute B-cell lymphoblastic leukemia.

We report the case of a 14-year-old boy who presented with hematuria and decreased kidney function as initial manifestations of acute lymphoblastic leukemia (ALL). Computed tomography of the abdomen showed extensive retroperitoneal lymphadenopathy and bilateral nephromegaly. The patient's kidney biopsy specimen showed a dense monomorphous interstitial infiltrate of small round blue cells with significant nuclear atypia. Immunohistochemical workup showed positive staining for CD20, CD10, and terminal deoxynucleotidyl transferase (TdT), consistent with ALL. The patient underwent induction chemotherapy, attained remission 4 weeks after induction, and presently is stable in the consolidation phase of chemotherapy. This is an unusual case of ALL involving both kidneys with initial presenting signs of hematuria and decreased kidney function.

Acute vancomycin-dependent immune thrombocytopenia as an anamnestic response.

Drug-related thrombocytopenia is a well-described but relatively rare complication of antibiotic therapy. In this entity, platelet destruction is immune-mediated, often resulting in a precipitous drop in platelet count over a short period of time. Most of these cases of thrombocytopenia are drug-dependent, as discontinuation of the offending agent frequently results in a timely return to baseline, pre-exposure platelet levels. We report the case of a 61-year-old male patient receiving vancomycin and ceftazidime for lower extremity wet gangrene who experienced a marked, acute reduction in platelet count 12 to 15 hours after starting antibiotic therapy. There was no readily apparent clinical or laboratory explanation for his thrombocytopenia. Pre- and post- antibiotic serum samples were preserved and sent for drug-dependent platelet antibody analysis. The pre-exposure specimen revealed the presence of IgG vancomycin-dependent platelet antibodies, while the post-exposure specimen demonstrated both IgG and IgM vancomycin-dependent platelet antibodies. Ceftazidime-dependent platelet antibodies were not identified in either sample. These findings indicate prior sensitization to vancomycin, with subsequent acute production of IgM anti-platelet antibodies after re-exposure to the antibiotic. The patient's antibiotics were held after the acute-onset of thrombocytopenia with subsequent restoration of normal platelet counts within 4 days of drug withdrawal, and the patient at no time experienced significant adverse bleeding events. Antibiotic therapy with vancomycin is a rare and perhaps overlooked cause for new-onset thrombocytopenia in hospitalized patients. This case illustrates that the development of severe thrombocytopenia within hours of vancomycin administration does not rule out drug-related immune clearance, as the rapid platelet destruction may indicate an anamnestic antibody response to the drug after previous exposure. In such a scenario, immediate discontinuation of vancomycin is recommended to improve platelet counts. From a laboratory perspective, retrieval of serum both pre- and post-administration of vancomycin is most helpful in determining a patient's drug-immunization status and can help guide safe drug use during future infections.

Adult nesidioblastosis. Clinicopathologic correlation between pre-operative selective arterial calcium stimulation studies and post-operative pathologic findings.

CONTEXT: Adult nesidioblastosis, a rare form of abnormal islet cell proliferation arising from the pancreatic ductal epithelium, is usually associated with severe hyperinsulinemic hypoglycemia. Overall, seventy-three cases of nesidioblastosis have been described in the English literature since the entity was first described by Laidlaw in 1938, and only a minute fraction of these have occurred in children. CASE REPORT: We present the case of a previously healthy 45-year-old woman with new-onset severe hypoglycemia 4 and seizures. The differential diagnosis at presentation included factitious hypoglycemia and insulinoma. Extensive imaging and laboratory examination, including repeated CT and MRI scans, toxicology assays, and insulin-based chemical studies, were either inconclusive or negative. Subsequent testing involved stimulation of the pancreas through cannulation of the pancreatic vascular supply by interventional radiology. This testing revealed marked insulin release to low-level calcium challenge across multiple pancreatic segments. Based on these functional radiological findings, the patient underwent subtotal pancreatectomy. Gross and histologic examination of the resected tissue revealed no evidence of a pancreatic mass. Diffuse islet cell hyperplasia was noted in a pattern consistent with nesidioblastosis. The patient remained normoglycemic in the months following partial pancreatectomy. CONCLUSIONS: Nesidioblastosis, while exceedingly rare in adult populations, should be considered in the differential diagnosis of severe hypoglycemia. This diagnosis cannot be easily made through routine diagnostic laboratory or radiological procedures and likely requires a histological tissue diagnosis.

Identification of lymphatics within the colonic lamina propria in inflammation and neoplasia using the monoclonal antibody D2-40.

CONTEXT: Lymphatic vessels are believed to be absent in the colon above the level of the mucularis mucosae. However, in our experience, lymphatic vessels are sometimes identifiable within the lamina propria in the setting of inflammation and neoplasia. OBJECTIVE: We sought to assess the presence of lymphatics within the colonic lamina propria in neoplastic and inflammatory conditions using the lymphatic endothelium-specific immunohistochemical marker D2-40. DESIGN: Representative sections of normal colon, inflamed colon, hyperplastic polyps, inflammatory polyps, adenomatous polyps, adenomatous polyps containing intramucosal carcinoma, and invasive colonic adenocarcinomas were subjected to immunohistochemical staining with D2-40. The presence of immunopositive lymphatic vessels was assessed. Lymphatic density within the lamina propria was calculated quantitatively, and the presence of inflammation was graded subjectively on a four-tiered scale (0-3). RESULTS: Lymphatics were not identified within the lamina propria of normal colon. However, lymphatics were identified within the lamina propria in the majority of cases with neoplasia and/or inflammation. Additionally, there was a non-significant trend toward higher lymphatic vessel density in cases with increasing inflammation. CONCLUSIONS: Lymphatic vessels are present within the lamina propria of colon in pathologic states, including cases of intramucosal carcinoma. This "aberrant" lymphangiogenesis is likely to be driven by inflammation and/or neoplasia.

Solid variant of aneurysmal bone cyst with a novel (X;9) translocation.

Aneurysmal bone cysts (ABC) are locally destructive bone lesions occurring predominantly in young adults. There has been debate as to the neoplastic nature of these lesions. In recent years, however, compelling evidence of clonal chromosomal abnormalities has indicated a likely neoplastic origin. Although relatively few ABC have been assessed cytogenetically, many of those which have been studied have shown abnormalities of chromosome 17, particularly t(16;17)(q22;p13). We present a case of ABC in a 4-year-old female, which demonstrated the novel translocation t(X;9)(q26;q32).

Chromosomal rearrangements in lipofibromatosis.

Lipofibromatosis is a relatively rare pediatric neoplasm, which usually manifests as an ill-defined soft tissue mass involving the upper and lower distal extremities, the trunk, and, less frequently, the head. To date, no cytogenetic abnormalities have been reported in this uncommon neoplasm. We present a case of lipofibromatosis featuring a three-way t(4;9;6) translocation in a 5-year-old boy.

Primary malignant melanoma of the transverse colon: report of a case and review of the literature.

Gastrointestinal involvement by malignant melanoma is predominantly a metastatic phenomenon. Although primary malignant melanoma of the gastrointestinal tract has been documented in the esophagus, stomach, small bowel, and anorectum, the incidence of primary melanoma of the colon is rare and remains controversial in most cases. We present a case of solitary malignant melanoma of the transverse colon occurring in a 64-year-old African American male patient. Complete dermatologic and ophthalmologic examinations revealed no evidence of a cutaneous or an ocular primary lesion. Microscopic examination of the resection specimen revealed malignant melanoma, which was confirmed by immunohistochemical positivity for S100 and melan-A. We believe that this tumor represents a primary colonic malignant melanoma.

Minichromosome Maintenance Expression Defines Slow-Growing Gastroenteropancreatic Neuroendocrine Neoplasms.

BACKGROUND: Small intestinal neuroendocrine neoplasm (SI-NEN) proliferation is quantified by Ki67 measurements which capture G1-G2M phases of the cell cycle. G0 and early G1 phases, typical of slow-growing cells, can be detected by minichromosome maintenance protein (MCM) expression. We hypothesized that these replication licensing markers may provide clinically relevant information to augment Ki67 in low-grade neuroendocrine neoplasia. METHODS: Immunohistochemical staining (IHC), Western blot analysis, quantitative polymerase chain reaction, and copy number variations of MCM2, MCM3, and Ki67 were undertaken in SI-NENs (n = 22). MCM and Ki67 expression was compared by Kaplan-Meier survival analysis (tissue microarray, independent set [n = 55]). Forty-three pancreatic NENs and 14 normal tissues were included as controls. RESULTS: In SI-NENs, MCM2 (mean: 21.2%: range: 16%-25%) and MCM3 (28.7%: 22%-34%) were detected in significantly more cells than Ki67 (2.3%: 0%-7%, P < .01). MCM2 mRNA correlated with Ki67 IHC (P < .05). MCM3 protein expression was higher in metastases (38-fold) than in normal small intestine (P = .06) and was largely absent in normal neuroendocrine cells. There was considerable variation at the MCM copy number level (0-4 copies). MCM3 expression in proliferating cells significantly predicted overall survival (P < .002). Combinations of Ki67 and MCM2/3 in algorithms differentiated low and higher proliferative lesions (overall survival: 12 vs 6.1 years, P = .06). MCM expression was not informative in pancreatic NENs. CONCLUSION: MCMs are expressed in a higher proportion of NEN cells than Ki67 in slow-growing small intestinal lesions and correlate with survival. Assessment can be used to augment Ki67 to improve prognostic classification in these low-grade tumors.

Expression of p27, COX-2, MLH1, and MSH2 in young patients with colon carcinoma and correlation with morphologic findings.

Despite an overall decrease in colorectal carcinoma incidence, rates of colorectal carcinoma have increased substantially in patients aged less than 40 years. Several authors have characterized morphologic features of colorectal carcinoma in young patients, with variable results. To date, there has been 1 detailed molecular and immunohistochemical study in young patients with colorectal carcinoma. We sought to expand the data regarding young patients with colorectal carcinoma by a detailed assessment of morphologic features and by assaying expression of p27, COX-2, MLH1, and MSH2, markers with prognostic or therapeutic implications in colorectal carcinoma. We searched our pathology database from 1985 to 2009 and, after exclusion of cases with insufficient data or neoadjuvant therapy, identified a study population of 23 patients aged 40 or younger, 35 patients between 41 and 49 years of age, and a control group of 83 colorectal carcinoma patients aged 50 or older. Younger patients had higher tumor grade (P = .0085), with a trend toward mucinous differentiation and lymphovascular and perineural invasion. Loss of MSH2 was more prominent in younger patients (P = .02). Loss of p27 expression was not associated with age, but was associated with higher tumor stage (P = .0278), mucinous/signet ring differentiation (P = .0185), loss of either MLH1 or MSH2 (P = .0035), and larger tumor size (P = .0019). There was a trend toward lower COX-2 expression in younger patients, with less COX-2 expression relative to previously published data. Our findings support some prior reports regarding morphologic features in colorectal carcinoma in young patients and provide novel data on expression of several markers in this population.

Comparison of PCR-based detection of chromogranin A mRNA with traditional histological lymph node staging of small intestinal neuroendocrine neoplasia.

BACKGROUND: Accurate neuroendocrine neoplasia (NEN) staging is vital for determining prognosis and therapeutic strategy. The great majority of NENs express chromogranin A (CgA) which can be detected at a protein or transcript level. The current standards for lymph node metastasis detection are histological examination after Hematoxylin and Eosin (H&E) and CgA immunohistochemical (IHC) staining. We hypothesized that detection of CgA mRNA transcripts would be a more sensitive method of detecting these metastases. FINDINGS: We compared these traditional methods with PCR for CgA mRNA extracted from formalin fixed paraffin embedded slides of lymph nodes (n = 196) from small intestinal NENs, other gastrointestinal cancers and benign gastrointestinal disease. CgA PCR detected significantly more NEN lymph nodes (75%) than H&E (53%) or CgA IHC (57%) (p = 0.02). PCR detected CgA mRNA in 50% (14 of the 28) of SI-NEN lymph nodes previously considered negative. The false positive rate for detection of CgA mRNA was 19% in non-neuroendocrine cancers, and appeared to be due to occult neuroendocrine differentiation or contamination by normal epithelium during histological processing. CONCLUSIONS: Molecular pathological analysis demonstrates the limitations of observer-dependent histopathology. CgA PCR analysis detected the presence of CgA transcripts in lymph nodes without histological evidence of tumor metastasis. Molecular node positivity (stage molN1) of SI-NEN lymph nodes could confer greater staging accuracy and facilitate early and accurate therapeutic intervention. This technique warrants investigation using clinically annotated tumor samples with follow-up data.

Gastric antrum hypertrophy causing outlet obstruction in an infant with congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is associated with multiple congenital anomalies affecting several organ systems, including the gastrointestinal system. Pyloric stenosis and bands are known and previously reported etiologies of gastric outlet obstruction in infants with CDH. We report the first case of gastric antrum hypertrophy causing gastric outlet obstruction in an infant with CDH.

Primary peritoneal carcinoma in complete remission: a case report.

Primary peritoneal carcinoma (PPCa) is a relatively uncommonly diagnosed tumor. It has a similar presentation to ovarian cancer. PPCa has a poor prognosis with survival ranging from 12-18 months. PPCa spreads mainly transperitoneally, but lymphatic and hematological metastases have also been reported. It is a diagnosis of exclusion made after pathological report. Here, a case of a 71-year-old female who presented with early satiety, fatigue, weight loss and left cervical lymphadenopathy and was diagnosed with metastatic PPCa, is reported. The patient was treated with chemotherapy and achieved a complete remission. The management of this rare tumor is discussed herein.

Pseudointraductal papillary mucinous neoplasia caused by microscopic periductal endocrine tumors of the pancreas: a report of 3 cases.

Intraductal papillary mucinous neoplasms constitute histologically distinctive pancreatic tumors characterized by cystically dilated pancreatic ducts lined by papillary epithelium, often with extensive mucin production. With increasing awareness of and vigilance for these tumors, there has been a surge in the incidence of intraductal papillary mucinous neoplasms in the last few decades. However, resections of presumed intraductal papillary mucinous neoplasms sometimes reveal other types of cystic lesions. Here we describe 3 cases of small, incidentally identified pancreatic endocrine tumors that focally compressed the main pancreatic duct and presented clinically, radiologically, and grossly as intraductal papillary mucinous neoplasm. The histology of the dilated ducts in all cases lacked convincing features of intraductal papillary mucinous neoplasm, prompting more careful examination of the specimens and eventual identification of small well-differentiated endocrine neoplasms. The constellation of findings represented by pancreatic endocrine neoplasm-associated duct stricture and dilatation can mimic intraductal papillary mucinous neoplasm clinically and pathologically. Awareness of this phenomenon can potentially avoid misdiagnosis of intraductal papillary mucinous neoplasm in such cases.