Faculty Bibliography

Distinction of hydatidiform moles from nonmolar specimens (NMs) and subclassification of hydatidiform moles as complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) are important for clinical practice and investigational studies; however, diagnosis based solely on morphology is affected by interobserver variability. Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively. Eighty genotyped cases (27 CHMs, 27 PHMs, 26 NMs) were selected from a series of 200 potentially molar specimens previously diagnosed using p57 immunohistochemistry and genotyping. Cases were classified by 6 pathologists (3 faculty level gynecologic pathologists and 3 fellows) on the basis of morphology, masked to p57 immunostaining and genotyping results, into 1 of 3 categories (CHM, PHM, or NM) during 2 diagnostic rounds; a third round incorporating p57 immunostaining results was also conducted. Consensus diagnoses (those rendered by 2 of 3 pathologists in each group) were also determined. Performance of experienced gynecologic pathologists versus fellow pathologists was compared, using genotyping results as the gold standard. Correct classification of CHMs ranged from 59% to 100%; there were no statistically significant differences in performance of faculty versus fellows in any round (P-values of 0.13, 0.67, and 0.54 for rounds 1 to 3, respectively). Correct classification of PHMs ranged from 26% to 93%, with statistically significantly better performance of faculty versus fellows in each round (P-values of 0.04, <0.01, and <0.01 for rounds 1 to 3, respectively). Correct classification of NMs ranged from 31% to 92%, with statistically significantly better performance of faculty only in round 2 (P-values of 1.0, <0.01, and 0.61 for rounds 1 to 3, respectively). Correct classification of all cases combined ranged from 51% to 75% by morphology and 70% to 80% with p57, with statistically significantly better performance of faculty only in round 2 (P-values of 0.69, <0.01, and 0.15 for rounds 1 to 3, respectively). p57 immunostaining significantly improved recognition of CHMs (P<0.01) and had high reproducibility (kappa=0.93 to 0.96) but had no impact on distinction of PHMs and NMs. Genotyping provides a definitive diagnosis for the approximately 25% to 50% of cases that are misclassified by morphology, especially those that are also unresolved by p57 immunostaining.

It has been reported that the diagnosis of serous tubal intraepithelial carcinoma (STIC) is not optimally reproducible on the basis of only histologic assessment. Recently, we reported that the use of a diagnostic algorithm that combines histologic features and coordinate immunohistochemical expression of p53 and Ki-67 substantially improves reproducibility of the diagnosis. The goal of the current study was to validate this algorithm by testing a group of 6 gynecologic pathologists who had not participated in the development of the algorithm (3 faculty and 3 fellows) but who were trained in its use by referring to a website designed for the purpose. They then reviewed a set of microscopic slides, which contained 41 mucosal lesions of the fallopian tube. Overall consensus (≥4 of 6 pathologists) for the 4 categories of STIC, serous tubal intraepithelial lesion (our atypical intermediate category), p53 signature, and normal/reactive was achieved in 76% of the lesions, with no consensus in 24%. Combining diagnoses into 2 categories (STIC versus non-STIC) resulted in an overall consensus of 93% and no consensus in 7%. The κ value for STIC versus non-STIC among all 6 observers was also high at 0.67 and did not significantly differ, whether for faculty (κ=0.66) or fellows (κ=0.60). These findings confirm the reproducibility of this algorithm by a group of gynecologic pathologists who were trained on a website for that purpose. Accordingly, we recommend its use in research studies. Before applying it to routine clinical practice, the algorithm should be evaluated by general surgical pathologists in a community setting.

Distinction of hydatidiform moles (HMs) from nonmolar specimens (NMs) and subclassification of HMs as complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs) are important for clinical practice and investigational studies; yet, diagnosis based solely on morphology is affected by interobserver variability. Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively. Eighty genotyped cases (27 CHMs, 27 PHMs, and 26 NMs) were selected from a series of 200 potentially molar specimens previously diagnosed using p57 immunostaining and genotyping. Cases were classified by 3 gynecologic pathologists on the basis of H&E slides (masked to p57 immunostaining and genotyping results) into 1 of 3 categories (CHM, PHM, or NM) during 2 diagnostic rounds; a third round incorporating p57 immunostaining results was also conducted. Consensus diagnoses (those rendered by 2 of 3 pathologists) were determined. Genotyping results were used as the gold standard for assessing diagnostic performance. Sensitivity of a diagnosis of CHM ranged from 59% to 100% for individual pathologists and from 70% to 81% by consensus; specificity ranged from 91% to 96% for individuals and from 94% to 98% by consensus. Sensitivity of a diagnosis of PHM ranged from 56% to 93% for individual pathologists and from 70% to 78% by consensus; specificity ranged from 58% to 92% for individuals and from 74% to 85% by consensus. The percentage of correct classification of all cases by morphology ranged from 55% to 75% for individual pathologists and from 70% to 75% by consensus. The kappa values for interobserver agreement ranged from 0.59 to 0.73 (moderate to good) for a diagnosis of CHM, from 0.15 to 0.43 (poor to moderate) for PHM, and from 0.13 to 0.42 (poor to moderate) for NM. The kappa values for intraobserver agreement ranged from 0.44 to 0.67 (moderate to good). Addition of the p57 immunostain improved sensitivity of a diagnosis of CHM to a range of 93% to 96% for individual pathologists and 96% by consensus; specificity was improved from a range of 96% to 98% for individual pathologists and 96% by consensus; there was no substantial impact on diagnosis of PHMs and NMs. Interobserver agreement for interpretation of the p57 immunostain was 0.96 (almost perfect). Even with morphologic assessment by gynecologic pathologists and p57 immunohistochemistry, 20% to 30% of cases will be misclassified, and, in particular, distinction of PHMs and NMs will remain problematic.

Neuroendocrine secretory protein-55 (NESP-55) is a recently described member of the chromogranin family and appears to be a marker of the constitutive secretory pathway in certain neural, neuroendocrine, and endocrine cell types. It has been shown to be selectively expressed in tumors differentiating towards the adrenal chromaffin and pancreatic islet cell phenotypes. The highest levels of NESP-55 expression, at least in animals, appear to be in the adrenal medulla and the pituitary gland. However, very little is known about the status of NESP-55 expression in pituitary adenomas. We therefore studied the immunohistochemical profile of NESP-55 expression in a series of 30 well-characterized pituitary adenomas (five each of FSH/LH and ACTH, four GH, three TSH, seven prolactin, and six null cells). All tumors were positive for one or more generic marker(s) (chromogranin A, synaptophysin, neuron-specific enolase) of neuroendocrine differentiation. All pituitary adenomas selected for study were stained for NESP-55 with appropriate positive and negative controls. NESP-55 immunoreactivity, seen as brown finely granular cytoplasmic staining of the tumor cells with prominent perinuclear accentuation, was graded as focal (<10% tumor cells staining), moderate (10-50% tumor cells staining), and diffuse (>50% tumor cell staining). Four of seven prolactinomas were positive for NESP-55 (one focal, two moderate, and one diffuse). Two of four GH adenomas were also positive (one focal and one diffuse) while only 1/5 FSH tumors showed a moderately intense immunoreactivity. All other pituitary adenomas were completely negative for NESP-55. Our results indicate that, in human pituitary adenomas, NESP-55 has a more restricted pattern of expression than that of chromogranins A and B. Since immunohistochemical expression of NESP-55 is largely confined to prolactinomas and GH adenomas, it raises the possibility that NESP-55 may somehow be involved in the secretory pathways of these specific cell types.

PURPOSE/OBJECTIVE:The serum free light chain (FLC) assay quantitates free kappa (κ) and free lambda (λ) immunoglobulin light chains. This assay has prognostic value in plasma cell proliferative disorders. There are limited data on serum FLC in B-cell malignancies. PATIENTS AND METHODS/METHODS:The association of pretreatment FLC with event-free survival (EFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) was evaluated in 76 patients from the North Central Cancer Treatment Group trial N0489 (NCT00301821) and 219 patients from the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER). Published reference ranges were used to define an elevated FLC or an abnormal κ:λ FLC ratio. RESULTS:Elevated FLC or abnormal κ:λ FLC ratio was present in 32% and 14% of patients, respectively. Patients with elevated FLC had an inferior OS and EFS in both cohorts compared with patients with normal FLC (N0489: EFS hazard ratio [HR], 3.06; OS HR, 3.16; both P < .02; MER: EFS HR, 2.42; OS HR, 3.40; both P < .001; combined EFS HR, 2.57; OS HR, 3.74; both P < .001). All associations remained significant for EFS and OS after adjusting for the International Prognostic Index (IPI). Abnormal κ:λ FLC ratio was modestly associated with outcome in the combined group (EFS HR, 1.61; OS HR, 1.67; both P = .07), but not in patients without corresponding elevated κ or λ. Elevated FLC was the strongest predictor of outcome in multivariable models with the IPI components. CONCLUSION/CONCLUSIONS:Increased serum FLC is an independent, adverse prognostic factor for EFS and OS in DLBCL and warrants further evaluation as a biomarker in DLBCL.

Uterine tumors resembling ovarian sex cord tumors (UTROSCT) are tumors of unclear histogenesis. The authors analyzed the ultrastructural features of 13 UTROSCT and correlated the findings with their immunohistochemical profile. Features included cells with frequent organoid, nested or cord-like arrangement (8), lumen formation (2; one of which showed surface microvilli), nuclei with irregular indentations (8), intermediate filaments (13), prominent paranuclear aggregates (5), cell junctions (9), desmosome-like junctions (2), tonofilaments (2), basal lamina (1), and cytoplasmic lipid droplets (7; prominent in 3). No dense bodies, subplasmalemmal densities or pinocytotic vesicles were seen. Ultrastructural epithelial differentiation was present in 2 tumors (positive for keratin or epithelial membrane antigen). Prominent lipid droplets correlated with sex cord markers positivity in 2 tumors. Ultrastructural features of smooth muscle differentiation were lacking and abundant paranuclear filaments did not correlate with myoid markers. UTROSCT are polyphenotypic neoplasms ultrastructurally with focal epithelial and variable sex cord-like differentiation. These findings suggest that UTROSCT may result from divergent differentiation in endometrial stromal tumors or represent a distinct group of uterine tumors with sex cord-like differentiation that are closer in histogenesis to ovarian sex cord stromal tumors.

While dematiaceous (dark-walled) fungi are ubiquitous in the environment, their involvement in invasive human infections has rarely been reported. However, these organisms have been identified as potential emerging pathogens, particularly among immunocompromised hosts. We describe a diabetic patient with Lecythophora mutabilis prosthetic valve endocarditis who was treated surgically, as well as with amphotericin B lipid complex and voriconazole, which were subsequently followed by prolonged voriconazole suppressive therapy. To the best of our knowledge, our patient is the first reported survivor of L. mutabilis prosthetic valve endocarditis.

Isolated bilateral renal malakoplakia in the absence of concomitant involvement of the urinary tract is a rare occurrence. We report imaging, cytologic, and histologic findings of such a case diagnosed initially by fine-needle aspiration (FNA) cytology. A 26-yr-old female presented with pain in the left flank, fever, anorexia, and weight loss for the past 2 mo. A left lumbar lump was palpable on physical examination. Imaging studies showed an enlarged nonfunctioning left kidney and a small lesion in the right kidney with preserved function. FNA from both kidneys yielded purulent material positive for E. coli on culture. The smears were inflammatory, with a predominance of neutrophilic polymorphs and numerous histiocytes along with some intracellular and extracellular Michaelis-Guttman bodies, which were highlighted with the use of a PAS stain. Histology of the nephrectomy specimen showed ill-defined nodules, composed of foamy histiocytes intermingled with neutrophils, plasma cells, and many variably sized concentric laminated bodies. The right-side lesion resolved with the use of broad-spectrum antibiotics in conjunction with ascorbic acid and bethanecol. When imaging studies are suggestive of a chronic inflammatory process, renal malakoplakia must always be considered in the differential diagnosis even if aspirated material shows a predominance of polymorphonuclear leukocytes. The use of special stains like PAS, Von Kossa, and Perl's helps in reaching the correct diagnosis.

BACKGROUND:Giant cell tumor of tendon sheath (GCTTS), also known as localized nodular tenosynovitis, is a benign neoplasm that occurs principally on the digits. The cytomorphologic features of this lesion on fine needle aspiration (FNA) have not been fully characterized. CASES/METHODS:In case 1, a 23-year-old female presented with a circumscribed soft tissue swelling in the left second toe. In case 2, a 16-year-old female presented with a tender swelling at the base of the right great toe. FNA smears in both instances were highly cellular, with mononuclear cells predominating and interspersed binucleated and multinucleated osteoclastlike giant cells along with hemosiderin-laden macrophages. CONCLUSION/CONCLUSIONS:When interpreted along with clinical data, the diagnosis of GCTTS can usually be made with certainty using FNA cytology.