Andrew Ricci

Immunocytochemical analysis of estrogen and progesterone receptors in benign stromal lesions of the breast. Evidence for hormonal etiology in pseudoangiomatous hyperplasia of mammary stroma.

Five cases of pseudoangiomatous hyperplasia of mammary stroma, together with seven examples of mammary hamartoma, were probed with monoclonal antibodies H222 and KD68 to investigate the possible role of estrogen and progesterone receptor expression in the pathogenesis of these benign stromal proliferations. All five cases of pseudoangiomatous hyperplasia showed patchy, intense labelling of the stromal cells with progesterone receptor antibodies, a pattern contrasting markedly with the absence of immunoreactivity in normal (nongestational) mammary stroma or the stromal component of common juvenile mammary hyperplasia. The stroma of the hamartoma group labeled inconsistently, with the notable exception of three myoid hamartomas. Stromal immunoreactivity was diffuse and intense in two of these, and patchy and distinct in the remaining case. These findings (a) support the contention that pseudoangiomatous hyperplasia represents a localized form of stromal overgrowth with a hormonal (primarily progestagenic) etiology and (b) further highlight the heterogeneity of socalled mammary hamartomas by demonstrating dramatically different progesterone receptor immunoreactivity patterns in myoid lesions as compared with other hamartoma variants.

Clinical and Laboratory Correlates of Esophagitis in Young Children

To develop clinical and laboratory criteria to identify young children with gastroesophageal reflux (GER) who are at particular risk for esophagitis and then to monitor their clinical course we have prospectively studied 40 subjects (ages 2-22 months, mean 8 months) with persistent symptoms of GER with 18 h intraesophageal pH monitoring, endoscopy, and grasp and suction esophageal biopsies. Esophagitis was found in 16 of 20 patients under 7 months, 12 of 14 between 7 and 12 months, and five of six between 12 and 24 months. Esophagitis was equally frequent in those patients with or without poor weight gain, wheezing, or irritability. Only 15% of patients with esophagitis had occult blood in their stool. No parameter of intraesophageal pH monitoring was both sensitive and specific in identifying patients who were ultimately found to have either mild or severe esophagitis. Follow-up data (37 patients) revealed that fundoplication was eventually required in four of eight patients with severe esophagitis, three of 22 with mild esophagitis, and none of seven without esophagitis. Currently used clinical and laboratory assessments of GER have limited value in identifying those children with either normal esophageal mucosa or at risk for varying degrees of esophagitis. Preliminary observations suggest that the presence of severe histologic esophagitis at the time of initial evaluation may have prognostic value in identifying those patients most likely to fail medical therapy and require fundoplication.

Early-Stage Invasive Breast Cancers: Potential Role of Optical Tomography with US Localization in Assisting Diagnosis

PURPOSE To investigate the potential role of optical tomography in the near-infrared (NIR) spectrum with ultrasonographic (US) localization as a means of differentiating early-stage cancers from benign lesions of the breast. MATERIALS AND METHODS The protocol was approved by the institutional review boards and was HIPAA compliant; all participants signed an informed consent. One hundred seventy-eight consecutive women (mean age, 52 years; range, 21-89 years) who underwent US-guided biopsy were imaged with a hand-held probe consisting of a coregistered US transducer and an NIR imager. The lesion location provided by coregistered US was used to guide optical imaging. Light absorption was measured at two optical wavelengths. From this measurement, tumor angiogenesis was assessed on the basis of calculated total hemoglobin concentration (tHb) and was correlated with core biopsy results. For patients diagnosed with carcinomas and followed up with subsequent excision, the tHb was correlated with pathologic parameters. RESULTS There were two in situ carcinomas (Tis), 35 T1 carcinomas, 24 T2-T4 carcinomas, and 114 benign lesions. The mean maximum and mean average tHb of the Tis-T1 group were 102.0 micromol/L +/- 28.5 (standard deviation) and 71.9 micromol/L +/- 18.8, and those of the T2-T4 group were 100.3 micromol/L +/- 26.4 and 67.0 micromol/L +/- 18.3, respectively. The mean maximum and mean average tHb of the benign group were 55.1 micromol/L +/- 22.7 and 39.1 micromol/L +/- 14.9, respectively. Both mean maximum and mean average tHb levels were significantly higher in the malignant groups than they were in the benign group (P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value for Tis-T1 cancers were 92%, 93%, 81%, and 97%. The corresponding values for T2-T4 tumors were 75%, 93%, 69%, and 95%. CONCLUSION The angiogenesis (tHb) contrast imaged by using the NIR technique with US holds promise as an adjunct to mammography and US for distinguishing early-stage invasive breast cancers from benign lesions.

Breast Cancer: Assessing Response to Neoadjuvant Chemotherapy by Using US-guided Near-Infrared Tomography

PURPOSE To assess initial breast tumor hemoglobin (Hb) content before the initiation of neoadjuvant chemotherapy, monitor the Hb changes at the end of each treatment cycle, and correlate these findings with tumor pathologic response. MATERIALS AND METHODS The HIPAA-compliant study protocol was approved by the institutional review boards of both institutions. Written informed consent was obtained from all patients. Patients who were eligible for neoadjuvant chemotherapy were recruited between December 2007 and May 2011, and their tumor Hb content was assessed by using a near-infrared imager coupled with an ultrasonography (US) system. Thirty-two women (mean age, 48 years; range, 32-82 years) were imaged before treatment, at the end of every treatment cycle, and before definitive surgery. The patients were graded in terms of their final pathologic response on the basis of the Miller-Payne system as nonresponders and partial responders (grades 1-3) and near-complete and complete responders (grades 4 and 5). Tumor vascularity was assessed from total Hb (tHb), oxygenated Hb (oxyHb), and deoxygenated Hb (deoxyHb) concentrations. Tumor vascularity changes during treatment were assessed from percentage tHb normalized to the pretreatment level. A two-sample two-sided t test was used to calculate the P value and to evaluate statistical significance between groups. Bonferroni-Holm correction was applied to obtain the corrected P value for multiple comparisons. RESULTS There were 20 Miller-Payne grade 1-3 tumors and 14 grade 4 or 5 tumors. Mean maximum pretreatment tHb, oxyHb, and deoxyHb levels were significantly higher in grade 4 and 5 tumors than in grade 1-3 tumors (P = .005, P = .008, and P = .017, respectively). The mean percentage tHb changes were significantly higher in grade 4 or 5 tumors than in grade 1-3 tumors at the end of treatment cycles 1-3 (P = .009 and corrected P = .009, P = .002 and corrected P = .004, and P < .001 and corrected P < .001, respectively). DISCUSSION These findings indicate that initial tumor Hb content is a strong predictor of final pathologic response. Additionally, the tHb changes during early treatment cycles can further predict final pathologic response.

Activated eosinophils in esophagitis in children : A transmission electron microscopic study

BACKGROUND Esophagitis in infants and children is often characterized by eosinophilic inflammation. The underlying pathophysiologic mechanisms leading to this type of inflammation, and the role of eosinophils in the clinical expression of esophagitis, are unknown. The purpose of this study was to demonstrate the ultrastructural activation state of eosinophils in esophagitis in infants and children. METHODS Standard transmission electron microscopy was used to examine endoscopic esophageal biopsy material from patients with and without esophagitis, as defined by standard histologic criteria. RESULTS Twelve esophagitis and three control cases were studied. In patients with esophagitis, electron microscopy revealed numerous eosinophils throughout the mucosa and invariably demonstrated signs of activation, including inversion of core-to-matrix densities and lucency of granule core protein. Eosinophils in an activated state were seen in active diapedesis through vascular endothelium into the mucosa. Eosinophils were sometimes seen in proximity to lymphocytes. Biopsies of control patients did not demonstrate eosinophils. CONCLUSIONS Eosinophils present in esophagitis are activated by electron microscopic criteria, and can been seen in an activated state entering into the mucosa. This suggests that eosinophils play an active role in the pathophysiology of this disorder, and that proinflammatory factors are present that selectively recruit and activate eosinophils in esophagitis in children.

PAGET'S DISEASE OF THE NIPPLE-AREOLA COMPLEX

The histogenesis of Pagets disease has been hotly debated, and only recently has epidermotropic theory become widely accepted. With the evolution of our understanding of breast cancer, it became apparent that the prognosis of Pagets disease was more a reflection of that of the underlying carcinoma, be it intraductal or infiltrating. The standard treatment of Pagets disease remains mastectomy with or without axillary dissection. In this era of breast-conserving surgery, however, there is much evidence to suggest that conservative treatment of Pagets disease of the breast is possible. A breast-conserving algorithm for the treatment of Pagets disease of the breast is proposed. Further refinements or modifications to the algorithm should be made as data from ongoing trials redefine our understanding of breast pathology and treatment.

Intractable Diarrhea From Cytomegalovirus Enterocolitis in an Immunocompetent Infant

Infection with cytomegalovirus (CMV) in infants can be congenital or perinatal. Infected infants may be asymptomatic or present with pneumonia, rash, hepatosplenomegaly, or encephalitis.1 In the presence of an immunodeficiency, severe and sometimes fatal disease may occur. To our knowledge, CMV has not been identified previously as a cause of intractable diarrhea of infancy. We report the case of a 5-week-old immunocompetent infant with intractable diarrhea attributable to CMV-induced enterocolitis. Recognition of this infection and initiation of ganciclovir therapy was associated with a rapid improvement and resolution of the diarrhea.

Clinical and pathologic prognostic variables in oropharyngeal squamous cell carcinoma

Eighty-five patients with squamous cell carcinoma of the oropharynx were studied to assess the value of histopathologic parameters related to their survival. The overall survival was 58 percent at 3 years and 51 percent at 5 years. Stepwise logistic regression analysis was used to determine the prognostic value of each of the histopathologic features. The extent of in situ carcinoma and presence of multifocality were positive predictors of survival, and perineural invasion and nodal involvement on clinical examination were negative predictors. None of the other parameters used in this study attained statistical significance. We conclude that the histologic grade traditionally used to predict clinical behavior may not be useful. Clinical stage, particularly nodal status; perineural invasion; and the multifocal or in situ disease, should be considered in pathologic reports to provide better prognostic profile in oropharyngeal carcinoma.

A clinicopathologic and immunohistochemical study of 16 patients with small intestinal leiomyosarcoma: limited utility of immunophenotyping

Clinicopathologic data including immunophenotypic expression of 16 new cases of small intestinal leiomyosarcoma are presented. Patient age ranged from 27 to 87 years (mean, 61 years) with a 2.2:1 male‐female ratio. Eighty‐eight percent of tumors occurred distally, i.e., in the jejunoileum. Considerable histologic heterogeneity was noted including epithelioid, myxoid, and sclerotic variants. Stratification by histologic grade suggests important clinical subsets. Only in grade I tumors is surgical extirpation alone potentially curative. Grade II tumors are associated with meaningful survival usually measured in years, however, nearly all patients can be expected to die from their tumors. Grade III sarcomas are fully malignant and rapidly progressive: except for one case with limited follow‐up, all patients with Grade III sarcomas died of disease with a mean survival of only nine months (median, 2 months). Immunostaining with antibodies directed against vimentin, muscle‐specific actin, desmin, and S‐100 protein were performed. Only antivimentin was uniformly reactive. Sixty‐three percent of cases tested showed actin immunoreactivity, and no tumors revealed immunohistochemically detectable desmin or S‐100 protein. Although many small bowel stromal sarcomas appear “poorly differentiated” by immunohistochemical methods presently available, that they are indeed leiomyosarcomas seems most likely from their intramural location and light histologic study. The limited utility of immunophenotyping and the importance of histologic grading are stressed.

p185HER2 Overexpression in Human Breast Cancer Using Molecular and Immunohistochemical Methods

Abstract With the successful clinical trials of the engineered antibody Herceptin(tm) (in advanced-stage breast cancer) and adriamycin-based chemotherapy regimens (in the adjuvant setting), the need to detect pi85HER2 overexpression or associated amplification of the coding gene HER2 in breast cancer patients is escalating. Twenty to 30% of breast carcinomas have overexpression of p185HEK2. This condition correlates with poor patient prognosis and predicts response to chemotherapy in lymph node-positive patients. In this study we compare quantisation of p185HER2 in breast cancer at the gene and protein levels using differential polymerase chain reaction (PCR) and immunohistochemistiy, respectively. To assign HER2 gene copy numbers, a calibration curve was constructed using normal breast epithelia and breast carcinoma cell lines having known dosages of amplified HER2. We found corresponding molecular and immunohistochemical results in 85% of the 13 paraffin-embedded breast carcinoma cases examined. Two cases were found to have minimum gene amplification but marked p185HER2 overexpression, suggesting an alternative mechanism to overexpression such as transcriptional activation. although the differential PCR assay exhibits saturation approaching 20 HER2 gene copies, this may not be clinically significant because the immunohistochemical assay also appears to saturate in this gene copy number range.