Donna J. Lager

C-erbB-2 expression and codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas.

We evaluated the prognostic significance of p185c-erbB-2 expression and ras gene mutations in all patients diagnosed with a pulmonary adenocarcinoma between 1982 and 1985 at the University of Iowa. p185c-erbB-2 expression was detected in 15 cases (34%). A ras gene mutation was found in 16 cases (36%) and all were in codon-12 of K-ras. No N-ras mutations were identified. Both p185c-erbB-2 expression and a K-ras mutation were found only in codon-12 and present in six cases (14%). By univariate analysis p185c-erbB-2 expression was associated with shortened survival (P = 0.02) while the presence of a K-ras mutation was not (P = 0.16). Multivariate analysis by the Cox proportional hazards model, controlling for patient age and tumor stage, also continued to identify p185c-erbB-2 expression as an independent unfavorable prognostic factor (P = 0.01). In this model a K-ras mutation also approached significance as a poor prognostic indicator (P = 0.06). The impact of both p185c-erbB-2 expression and a K-ras mutation on survival was additive and highly significant (P = 0.004). This additive nature suggests that together these two markers identify a high-risk population of lung adenocarcinoma patients that may benefit from aggressive therapy.

Transplant-associated thrombotic microangiopathy : the role of IgG administration as initial therapy

Two transplant patients, one a renal-pancreas and the other a liver allograft recipient, are reported. Both developed clinical and histologic evidence of cyclosporine-associated thrombotic microangiopathy and responded favorably to intravenous IgG therapy. An additional 20 cadaveric renal transplant recipients who developed cyclosporine-associated thrombotic microangiopathy are reviewed. The clinical and laboratory presentation of posttransplant thrombotic microangiopathy varied. Elevated serum creatinine and lactic dehydrogenase (LDH) levels were the most consistent, albeit nonspecific, findings at diagnosis. Fourteen of 22 patients (64%) presented with thrombocytopenia and 19 (86%) had a hemolytic anemia verified on diagnosis. Histologic evidence of thrombotic microangiopathy was present in renal biopsies from each of the renal allograft recipients and a skin biopsy from the liver allograft recipient. Treatment included withdrawal or reduction of the cyclosporine dose, plasmapheresis, or administration of intravenous IgG. There was an overall renal allograft loss of 57%, which included five deaths. Symptomatic cytomegalovirus infection was more common than expected in this patient group (P = 0.038) and may, in combination with cyclosporine therapy, have predisposed these patients to develop clinically significant thrombotic microangiopathy. Transplant-associated microangiopathy appears to be a relatively common disorder associated with a substantial increase in early graft loss (P = 0.005) and mortality (P = 0.001).

Field cancerization: Why late 'recurrent' ovarian cancer is not recurrent

OBJECTIVEnLate recurrence of ovarian cancer may result from either regrowth of dormant tumor cells or from development of a new cancer caused by the phenomenon of field cancerization. Clinically, some recurrent ovarian cancers show the same therapeutic sensitivities to chemotherapy and surgery as did the primary disease, whereas others are refractory to all therapy. We hypothesize that recurrent ovarian cancers are distinguishable on the basis of a molecular genetic fingerprint and that some are actually new primary cancers of the peritoneum rather than recurrent ovarian cancer.nnnSTUDY DESIGNnWe constructed molecular genetic fingerprints of 13 paired primary and late recurrent ovarian cancers to study their clonal relationships. The tumor pairs were analyzed for p53 mutations and allelotypes, patterns of X-chromosome inactivation, loss of heterozygosity, and microsatellite instability at 12 different loci on 6 different chromosomes. Techniques used included single-strand conformational polymorphism mutation screening and polymerase chain reaction-based sequence analysis of the p53 locus, restriction digestion of the androgen receptor locus to determine X-chromosome inactivation, and polyacrylamide gel electrophoresis of highly polymorphic dinucleotide, trinucleotide, and tetranucleotide repeats.nnnRESULTSnThe average age at initial diagnosis for this cohort was 54.7 years (range 45.3 to 65.5). Mean interval to recurrence was 42.7 months (range 28 to 62). Molecular fingerprints were characterized for 4 to 8 informative loci per tumor pair. The fingerprints of 10 (77%) differed significantly, strongly suggesting that a second primary cancer had developed. The remaining 3 tumor pairs demonstrated identical allelotypes consistent with regrowth of dormant tumor cells.nnnCONCLUSIONnOur results are consistent with the field cancerization hypothesis of ovarian carcinogenesis but could also be explained by a polyclonal tumor origin, which contrasts with the currently accepted monoclonal theory of ovarian carcinogenesis. Late development of a new primary cancer may herald the proband as a member of a familial cancer phenotype. These studies provide a molecular genetic rationale that both explains and prognosticates the clinical course of recurrent ovarian cancer.

The optimal number of biopsy fragments to establish a morphologic diagnosis of eosinophilic esophagitis.

OBJECTIVES:Eosinophilic esophagitis (EoE) is characterized clinically by dysphagia, chest pain, and food impaction, and morphologically by increased numbers of intraepithelial eosinophils and marked basal hyperplasia of the squamous mucosa. The consensus criteria for a diagnosis of EoE include the presence of ≥15 eosinophils/HPF in biopsies from both proximal and distal esophagus in the absence of other causes of esophageal eosinophilia, and the lack of clinical response to proton pump inhibitor therapy. Because of the variability in the distribution of intraepithelial eosinophils among biopsy fragments and the lack of standardized biopsy practices, we sought to determine the optimal number of esophageal biopsies from the mid and distal esophagus needed to reach the minimum morphologic criteria of ≥15 eosinophils/HPF.METHODS:From 5 January 2009 to 26 September 2011, 771 patients were diagnosed with EoE at our institution. From that patient population, 102 sequential cases were chosen for further study, all of whom had biopsies taken from the mid and distal esophagus. Cases with only gastric mucosa present and biopsies taken from patients with a previous diagnosis of EoE were excluded. The original H&E-stained slides were reviewed, and the number of biopsy fragments containing squamous mucosa was recorded. By using a × 40 objective and × 10 oculars (field diameter=0.52u2009mm, field area=0.21u2009mm2), the number of eosinophils per high power field (EOS/HPF) in up to three HPFs was counted in each biopsy fragment.RESULTS:The EOS/HPF were counted in 1,342 biopsy fragments. The number of biopsy fragments obtained from the mid esophagus ranged from 1 to 20 (mean 7; median 7) and those obtained from the distal esophagus ranged from 1 to 18 (mean 6; median 5). There was no significant difference between the mean number of EOS/HPF from the mid (26) and lower (25) esophagus or between the mean peak number of EOS/HPF from the mid (69.1) and lower (60.4) esophagus. The probability of one, four, five, and six biopsy fragments containing >15 EOS/HPF was 0.63, 0.98, 0.99, and >0.99, respectively.CONCLUSIONS:From these data, at least four biopsy fragments should be submitted from the mid and/or proximal esophagus to optimize the chances of a positive diagnosis of EoE in populations not known to have undergone previous proton pump inhibitor therapy. However, the yield is not increased beyond six biopsy fragments. In order to morphologically exclude a diagnosis of reflux esophagitis as the cause of intraepithelial eosinophilia, distal esophageal biopsies, if obtained, must be accompanied by more proximal biopsies (i.e., mid esophagus or higher).

Lymphocytic gastritis is not associated with active Helicobacter pylori infection.

Lymphocytic gastritis (LG), characterized by marked intra‐epithelial lymphocytosis in the gastric mucosa, has been frequently associated with both celiac disease (CD) and H. pylori gastritis. The aim of this study was to review and correlate the morphology of LG with the presence of CD and H. pylori.

Incidence of Diagnostic Change in Colorectal Polyp Specimens After Deeper Sectioning at 2 Different Laboratories Staffed by the Same Pathologists

OBJECTIVESnTo calculate the incidence of nondiagnostic (ND) colorectal (CR) polyp cases in which deeper tissue sectioning rendered new diagnostic information--particularly adenomas--in 2 laboratories staffed by the same pathologists.nnnMETHODSnAfter initial diagnosis, 100 ND CR polyps from each laboratory were reexamined with 3 deeper levels to establish rates of diagnostic conversion based on biopsy specimen location and original observation(s).nnnRESULTSnDeeper sectioning rendered new diagnostic information in 43 (21.5%) of 200 biopsy specimens and specifically adenomas in 16 (8.0%) of 200 biopsy specimens.nnnCONCLUSIONSnThese results support routine ordering of deeper levels on ND CR polyps to improve adenoma detection rates, especially those cases without any histologic abnormality. If another biopsy in the same case already is adenomatous, examination of deeper levels may not be necessary, as it may not have any significant effect on the clinical management of the patient.

Correlative Light and Scanning Electron Microscopy of Intestinal Giardiasis, Cryptosporidiosis, and Spirochetosis

Cases of intestinal giardiasis, spirochetosis, and cryptosporidiosis were examined by scanning electron microscopy (SEM) using hematoxylin and eosin (H&E)-stained tissue sections from which the coverslips were removed and the sections coated with gold. The technique is simple and reliably provides excellent morphologic detail that is preserved in the deparaffinized 4 microsections. We present examples of nine intestinal parasites examined in this manner and compare this technique with standard H&E staining and special stains with regard to relative costs, turnaround time, labor input, and morphologic preservation. Scanning electron microscopy is a useful adjunct in providing confirmatory evidence in the diagnosis of intestinal giardiasis, spirochetosis, and cryptosporidiosis.

Diarrhoea and duodenal disease

A 27-year-old Caucasian male presented with a one-month history of diarrhoea, severe abdominal cramping, heartburn and weight loss. The symptoms began right after breakfast in the morning and continued with 3–4 watery stools throughout the day, but none during the night. Spicy foods, alcoholic beverages and excessive water intake seemed to exacerbate the pain, but soda seemed to alleviate it. The patient denied use of antibiotics, antispasmodics, or antihypertensive drugs, and drank minimal milk. The patient denied any recent international travel or contact with diapers or ill persons but confirmed that the symptoms started about a week after a river trip. There was no known family history of GI disease. …

Sa1870 Fundic Gland Polyps With Dysplasia

Fundic gland polyps (FGPs) are the most common type of gastric polyp and are seen in up to 5% of patients on endoscopy. Although considered benign, FGPs are more common in patients with familial adenomatous polyposis (FAP). FGPs occur sporadically in up to 1.9% of the general population and in 84% of patients with syndromic FAP. Dysplasia in FGP is reported in 53% of syndromic FGPs and in only 2.3% of sporadic FGPs. The aim of this study is to compare patients with FGPs with dysplasia and those with FGPs without dysplasia. The pathology files from two institutions were searched from 1/1/2009 to 10/1/2013 for FGPs with dysplasia (FGPD). A similar number of control cases of FGP with no dysplasia (FGPND) were also randomly retrieved. All biopsies were reviewed, and diagnoses were agreed upon by three pathologists. Patient demographic data was recorded and included age, gender, race, diagnosis of FAP, and PPI use. Twenty-five patients with FGPD were identified (Male: 15, Female: 10, mean age: 60). Five patients had a confirmed history of FAP (mean age: 36), 9 had a high probability of FAP based on family or personal GI history (mean age: 61), 3 had no indication of FAP (such as family or personal history of colon cancer or polyps) (mean age: 63), and in 8 patients the family or personal history was not recorded (mean age: 62). Seventeen patients (68%) were on a protein pump inhibitor (PPI). The mean age of FGPD patients with FAP is significantly lower than patients without FAP (p< 0.001). The 26 patients with FGPND included 10 males and 16 females (mean age: 60). None of the patients had a history of FAP, 12 had a high probability of FAP based on family or personal GI history (mean age: 61), 6 had no indication of FAP (mean age: 59), and in 8 patients the family or personal history was not recorded (mean age: 55). Eighteen patients (69%) were on a PPI. There were no ethnic/racial differences between the two groups of patients. Of all biopsies from patients with FGPD, 88% of all fragments were smaller than 5 mm2 and 5% were greater than10 mm2. In contrast, of all the biopsies from patients with FGPND, 68% of all fragments were smaller than 5 mm2 and 20% were greater than 10 mm2. These data show no correlation between PPI use and the presence of low grade dysplasia in FGP. FGPND tended to result in larger biopsy fragments than FGPD; however there was no significant difference in the number of polyps described endoscopically between the two groups. Patients who have low-grade dysplasia in FGP are more likely to have FAP or a high probability of FAP than those without dysplasia. Low grade dysplasia in FGP is seen at a younger age in patients with FAP than in those without FAP. Finding low grade dysplasia in FGP, particularly in patients younger than 40 years, should raise a suspicion for FAP.