Henry Crist

Neoadjuvant Concurrent Chemoradiation for Advanced Esthesioneuroblastoma: A Case Series and Review of the Literature

Esthesioneuroblastoma (ENB) is a rare malignancy arising from the olfactory epithelium of the nasal vault. ENB accounts for 3% to 6% of all intranasal tumors and has the best prognosis among sinonasal malignancies with neuroendocrine differentiation. The optimal treatment continues to be controversial, but the benefit of adjuvant therapy, particularly radiotherapy, has been well described in the literature. The largest reported series evaluated neoadjuvant radiotherapy of 50 Gy, with or without neoadjuvant chemotherapy, and found improved resectability with improved patient survival. We present two cases of advanced ENB at our institution treated with a preoperative concurrent radiochemotherapy in a manner akin to that of small-cell carcinoma of the lung.

Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer.

We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14-positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression.

Clinical comparison of noninvasive urine tests for ruling out recurrent urothelial carcinoma

OBJECTIVE Patients with urothelial carcinoma (UC) undergo rigorous surveillance for recurrence. Noninvasive urine tests are not currently recommended by guideline panels owing to insufficient clinical benefit. The objective of this study was to prospectively compare the performance of the Cxbladder Monitor test to other commonly available urine markers and cytology for surveillance of patients with UC. METHODS AND MATERIALS A total of 1,036 urine samples were collected from 803 patients undergoing surveillance for UC. Of these, 1,016 samples were directly assessed using cytology, NMP22 Bladderchek and NMP22 enzyme-linked immunosorbent assay (ELISA), and the clinically validated Cxbladder Monitor test. An exploratory analysis was also performed comparing data from 157 samples where UroVysion fluorescence in situ hybridization analysis was performed locally. RESULTS The sensitivity of Cxbladder Monitor (0.91) significantly outperformed cytology (0.22), NMP22 ELISA (0.26), and NMP22 BladderChek (0.11). The negative predictive value of Cxbladder Monitor was also superior at 0.96 compared with cytology (0.87), NMP22 ELISA (0.87), and NMP22 BladderChek (0.86). All false-negative results (n = 14) observed using Cxbladder Monitor were also negative for cytology, NMP22 ELISA, and NMP22 BladderChek. In the more limited set, UroVysion fluorescence in situ hybridization also had inferior sensitivity (0.33) and negative predictive value (0.92). CONCLUSIONS The Cxbladder Monitor test significantly outperforms current Food and Drug Administration-approved urine-based monitoring tests, as well as cytology, in a large representative population undergoing surveillance for recurrent UC. This supports using Cxbladder Monitor as a confirmatory negative adjunct to cystoscopy or to justify postponing cystoscopic investigations in patients with a low risk of recurrence.

Dedifferentiated Epithelial–Myoepithelial Carcinoma Analysis of a Rare Entity Based on a Case Report and Literature Review

Dedifferentiated epithelial–myoepithelial carcinoma (DEMC) is very rare salivary gland neoplasm with only anecdotal reports. We present an analysis of DEMC, based on a case and review of literature. Our patient, an 85-year-old woman, presented with a submandibular mass of 5 years duration that was increasing in size over a 5-week period. Histologically, there were areas of typical epithelial–myoepithelial carcinoma, with dedifferentiation of both components, manifesting morphologically as salivary duct carcinoma and areas of myoepithelial carcinoma. A review of literature revealed 21 previously reported cases of DEMC. DEMC occurs at an average age of 72 years, most often in the parotid gland (72%) followed by submandibular gland (17%). Dedifferentiation more often involves the epithelial component (13/15 cases) than the myoepithelial component (5/15 cases). Although typical epithelial–myoepithelial carcinomas are fairly indolent (average disease-free survival of 11.34 years), dedifferentiation confers a poor prognosis (survival reported from 1 to 72 months).

A comparative study of cell cycle mediator protein expression patterns in anaplastic and papillary thyroid carcinoma

Anaplastic thyroid carcinoma (ATC) is an extremely aggressive and rapidly fatal neoplasm. The aim of this study was to identify a limited cell cycle associated protein expression pattern unique to ATC and to correlate that pattern with clinical outcome. This represents one of the largest tissue micro-array projects comparing the cell cycle protein expression data of ATC to other well-differentiated tumors in the literature. Tissue microarrays were created from 21 patients with ATC and an age and gender matched cohort of patients with papillary thyroid carcinoma (PTC). Expression of epidermal growth factor receptor, cyclin D1, cyclin E, p53, p21, p16, aurora kinase A, opioid growth factor (OGF), OGF-receptor, thyroglobulin and Ki-67 was evaluated in a semi-quantitative fashion. Differences in protein expression between the cohorts were evaluated using chi-square tests with Bonferroni adjustments. Survival time and presence of metastasis at presentation were collected. The ATC cohort showed a statistically significant decrease (p < 0.05) in thyroglobulin expression and statistically significant increases (p < 0.05) in Ki-67 and p53 expression as compared with the PTC cohort. A trend toward loss of p16 and p21 expression was noted in the ATC cohort. A trend toward decreased survival was noted with p21 expression. These data indicate disruption of the normal cell cycle with aberrant expression of multiple protein markers suggesting increased proliferative activity and loss of control of cell cycle progression to G1 phase. These findings support the assertion that ATC may represent the furthest end of a continuum of thyroid carcinoma dedifferentiation.

Expression of Opioid Growth Factor (OGF)–OGF Receptor (OGFr) Axis in Human Nonmedullary Thyroid Cancer

BACKGROUND Although thyroid cancers are readily treatable with surgery and radioactive iodine, there are problems in managing recurring, as well as locally advanced, thyroid cancer. The opioid growth factor (OGF) and its receptor, OGF receptor (OGFr), form a tonically active, autocrine-paracrine loop that serves to inhibit cell proliferation in a wide variety of normal and abnormal cells and tissues. In the present study we examined the presence and distribution of OGF and OGFr in nonmedullary thyroid cancer, including papillary, follicular, and anaplastic, as well as thyroid tissue from patients with nonmalignant disease. METHODS Patient samples of thyroid cancers and goiter were collected at the time of resection and processed for immunohistochemistry of OGF and OGFr, as well as pharmacological binding assays for OGFr. RESULTS Both peptide and receptor were detected in the cytoplasm and nucleus of all nonmedullary thyroid cancers, as well as in goiter. Specific and saturable binding of OGFr was found in all thyroid samples. CONCLUSIONS The finding that a potent negative growth regulator and its receptor are present in nonmedullary thyroid cancers and thyroid tissues from patients with nonmalignant disease lead us to suggest that the OGF-OGFr axis serves as a regulator of cell proliferation in these tissues. Moreover, modulation of this biological system may be used to treat progression of nonmedullary thyroid neoplasias.

Frozen Section Interpretation of Pancreatic Margins: Subspecialized Gastrointestinal Pathologists Versus General Pathologists

Intraoperative assessment of pancreatic parenchymal margin during pancreatectomies is challenging and misinterpretation by the pathologist is a cause of incorrect frozen section (FS) diagnosis. Although the current literature supports that pancreatic margin FS diagnosis and its accuracy has no impact on the patient outcome for pancreatic ductal adenocarcinoma (PDAC) patients and reexcision in an attempt to achieve a negative intraoperative pancreatic margin after positive FS is not associated with increased overall survival; still it remains a routine practice in many institutions. To this end, we sought to assess the interobserver variation and accuracy of FS diagnosis between subspecialized gastrointestinal/pancreatobiliary (GI) and general pathologists. Seventy seven consecutive pancreatic parenchymal margin FSs performed on pancreatectomies for PDAC from 2010 to 2013 were retrieved at our institution. These were retrospectively evaluated by 2 GI and 2 general pathologists independently without knowledge of the original FS diagnosis or the final diagnosis. The specificity, sensitivity, positive predictive value, negative predictive value, and accuracy of GI versus general pathologist was 97.8% versus 87.5%, 61.1% versus 66.7%, 78.6% versus 41.4%, 95% versus 95.2%, and 93.5% versus 85.1%, respectively. The interobserver agreement between GI and general pathologists was fair (κ = .337, P < .001). The interobserver agreement between 2 GI pathologists was fair (κ = .373, P = .0005) and between 2 general pathologists was slight (κ = .195, P = .042). Although overall accuracy of subspecialized GI pathologists was higher than that of general pathologists, none had an accuracy of 100%. Our study reaffirms the challenging nature of these FSs.

Adenocarcinoma arising in a rectovaginal fistula in Crohn disease.

Adenocarcinomas occurring in the vagina are rare. Their correct classification may be very challenging to both the gynecologist and the pathologist, but it is essential for appropriate therapy. Although most adenocarcinomas in the vagina arise from other sites in the female genital tract, a significant minority reflects metastasis from a colorectal site. We report a very unusual occurrence of an adenocarcinoma that presented as a mass in the vagina protruding through the introitus. It arose in a rectovaginal fistula consequent to chronic Crohn disease, but it did not extend to involve the colonic mucosa. Neither the initial clinical examination nor the pathologic examination suggested the correct diagnosis. We report this case to remind the gynecologists of the potential complications of Crohn disease, and to highlight for the pathologists the difficulty that is often encountered in the correct identification of the source of carcinomas that are found in the vagina.

A Rare Soft Tissue Tumor Masquerading as a Parathyroid Adenoma in a Patient with Birt-Hogg-Dubé Syndrome and Multiple Cervical Endocrinopathies

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder that presents with renal tumors, pulmonary cysts with spontaneous pneumothoraces, and skin hamartomas. We present a case of a 67-year-old female with multiple endocrinopathies and a history of BHD syndrome. In 2011, a thyroidectomy with a four-gland parathyroidectomy was performed for toxic multinodular goiter (TMNG) and parathyroid hyperplasia. On frozen section, a tumor was identified next to a hypercellular parathyroid. After being worked up, this tumor was determined to be an adult rhabdomyoma. This represents the first time that both TMNG and parathyroid hyperplasia have been present in a BHD patient. Additionally, this is the first adult rhabdomyoma reported in a patient with BHD syndrome. Adult rhabdomyomas have no reported associations; however, potential colocation of the mutation in BHD syndrome and translocation in adult rhabdomyomas on chromosome 17p suggests a possible connection. Further work is needed to better understand this connection.

Frozen Section as a Rapid and Accurate Method for Diagnosing Acute Invasive Fungal Rhinosinusitis

Objective Identify methods to improve the frozen-section diagnosis of acute invasive fungal rhinosinusitis. Study Design Biopsies with frozen section for suspected acute invasive fungal rhinosinusitis were reviewed to identify causes for missed diagnoses and evaluate methods for potential improvement. Setting All aspects of the study were performed at the Penn State Milton S. Hershey Medical Center. Subjects and Methods All frozen sections performed for suspected acute invasive fungal rhinosinusitis between 2006 through 2017 were reviewed with their diagnoses compared to the final diagnoses. Sensitivity and specificity were determined for each biopsy specimen to evaluate the diagnostic method and for each patient for its effectiveness on outcome. Causes for frozen-section failures in diagnosis were identified. A periodic acid–Schiff stain for fungus (PASF) was modified for use on frozen tissue (PASF-fs) and applied both retrospectively and prospectively to frozen sections to determine its ability to identify undetected fungus and improve diagnostic sensitivity. Results Of 63 biopsies positive for acute invasive fungal rhinosinusitis, 51 were diagnosed on frozen section, while 61 were identified by including the novel PASF-fs stain, reducing the failure rate from 19% to 3%. Of 41 cases that were positive, 34 were diagnosed on frozen section. Of the 7 that were not, 5 were identified by including the PASF-fs, reducing the failure rate from 17% to 5%. Conclusions Frozen section interpretation of biopsies for suspected acute invasive fungal rhinosinusitis using a PASF-fs stain should enable a rapid and accurate diagnosis with improved outcomes by shortening the time to surgery.