bluuebunny/crossref_metadata_2025 huggingface dataset:
Nuclear Localization of E-Cadherin Expression in Merkel Cell Carcinoma
Authors: Han Aaron C. , Soler Alejandro Peralta , Tang Chik-Kwun , Knudsen Karen A. , Salazar Hernando
Published: January 2021

Context.—Cadherins are cell-cell adhesion proteins that act as tumor suppressor genes and have a critical role in cell sorting and tissue formation during organogenesis. The pattern of cadherin expression constitutes a useful diagnostic and prognostic tool in the evaluation of tumors and for determining the histogenesis of tumor cells. We have previously characterized the cell types of several tumors based on the expression of individual cadherins.

Objective.—To investigate the expression of cadherins in Merkel cell carcinomas.

Design.—Paraffin immunohistochemical analysis of the 3 best-studied cadherins was performed on 35 cases of Merkel cell carcinoma.

Results.—E-cadherin was expressed in 34 (97%) of 35 Merkel cell carcinomas examined, N-cadherin was expressed in 22 (63%) of 35 cases, and P-cadherin was expressed in 15 (43%) of 35 cases. This frequency of cadherin expression was similar to a group of small cell and neuroendocrine tumors from other primary sites. Interestingly, the localization of E-cadherin expression was unique in Merkel cell carcinomas compared with other primary neuroendocrine tumors. Merkel cell carcinomas showed marked preference for nuclear versus membrane localization, whereas small cell tumors from other sites showed fewer cases of nuclear E-cadherin expression. The nuclear localization of E-cadherin did not correlate with cadherin-associated protein β-catenin nuclear expression.

Conclusions.—Our findings show that E-cadherin is the most frequently expressed cadherin in Merkel cell carcinoma, followed in frequency by N-cadherin then P-cadherin. The pattern of nuclear E-cadherin expression is more frequent for Merkel cell carcinoma than small cell tumors of other primary sites. These observations suggest that E-cadherin expression and function are altered in Merkel cell carcinoma, and this finding has potential use in the differential diagnosis of these tumors.
The Cost-Effectiveness of Immunohistochemistry
Authors: Raab Stephen S.
Published: January 2021

Objective.—To evaluate the cost-effectiveness of immunohistochemistry.

Design.—Using a theoretical decision analytic model, the cost-effectiveness of immunohistochemistry was evaluated in different scenarios depicting the beneficial use of immunohistochemistry. Data regarding the effectiveness of immunohistochemistry were obtained from the medical literature and costs were obtained from Allegheny General Hospital.

Settings.—The scenarios depicted both private practice and university patients from which anatomic pathology specimens were obtained. Immunohistochemistry was subsequently performed on these specimens.

Main Outcome Measures.—Cost, life expectancy, diagnostic certainty, ability to predict prognosis, and cost-effectiveness were evaluated.

Results.—In all scenarios, immunohistochemistry was cost-effective at very low efficacies. Assuming a per-antibody cost of $50 and use of a 5-antibody panel, immunohistochemistry was cost-effective if it resulted in a 1-year gain of population life expectancy in 1 or more of every 200 cases in which it was applied. Alternatively, if the gain in diagnostic certainty by using immunohistochemistry was 10% and the value placed on a percentage gain in diagnostic certainty was $1000, immunohistochemistry was cost-effective if it produced this increase in certainty in 1 of every 40 tests. If a life-year was valued at $50 000, immunohistochemistry was cost-effective if it resulted in a change in patient prognosis of 0.5 years in 1 of every 100 tests.

Conclusions.—Using theoretical modeling, immunohistochemistry is extremely cost-effective. These data have implications in an era of managed care when providers attempt to trim laboratory services. Additional studies are needed to evaluate the actual practice efficacy of immunohistochemistry.
Warthin-like Papillary Carcinoma of the Thyroid
Authors: Baloch Zubair W. , LiVolsi Virginia A.
Published: January 2021

Background.—Warthin-like papillary carcinoma of thyroid is characterized by distinct papillary formations lined by tumor cells with oncocytic cytoplasm, nuclear features of papillary carcinoma, and brisk lymphoplasmacytic infiltrates in the papillary stalks. This tumor derives its name from its close resemblance to Warthin tumor of major salivary glands.

Design.—The clinicopathologic features of 17 patients with Warthin-like papillary carcinoma were studied.

Results.—Fifteen tumors occurred in women and 2 arose in men (age range, 23–63 years). The lesions ranged in size from 3 mm to 2.5 cm. Fine-needle aspiration biopsies were performed in 7 cases; 4 were diagnosed as papillary carcinoma, 2 as consistent with lymphocytic thyroiditis, and 1 as atypical cells. All 17 tumors were confined to the thyroid; 6 showed prominent cyst formation and the remaining tumors were solid. In each case, the tumor arose in a background of lymphocytic thyroiditis. Nodal metastases were identified in 3 cases; however, none showed distant metastases. In 7 cases, foci of papillary microcarcinoma and follicular variant of papillary carcinoma were found in other areas of the thyroid.

Conclusions.—Warthin-like tumors can be mistaken for benign lymphoepithelial lesions of the thyroid, Hürthle cell carcinoma, and tall cell variant of papillary carcinoma in both fine-needle aspiration and histology specimens. Follow-up information on the previously reported cases has suggested that these tumors behave similarly to usual papillary carcinoma. The extensive lymphocytic infiltration in these tumors and their association with chronic lymphocytic thyroiditis may suggest a role for immunological mechanisms in the pathogenesis of thyroid tumors.
Nuchal Fibrocartilaginous Pseudotumor in a 10-Year-Old Girl
Authors: Luévano-Flores Eduardo , Aguirre-Madrid Arturo
Published: January 2021

We report a case of a 10-year-old girl who, 4 years after a trauma to the neck, developed a soft tissue mass in the midline at the C5-6 level. The lesion was not attached to the bone and was composed of fibrocartilaginous tissue, similar to the nuchal fibrocartilaginous pseudotumor, a rare, recently reported condition that has been described in the medical literature in only 4 cases, all of them adults.
Intravascular Papillary Endothelial Hyperplasia in a Vascular Lesion of the Paranasal Sinus
Authors: Moon Woo Sung , Chung Gyung Ho , Hong Ki Hwan
Published: January 2021

Intravascular papillary endothelial hyperplasia (IPEH) is usually a cutaneous lesion thought to represent a peculiar manifestation of an organizing thrombus. The principal significance of IPEH is its microscopic resemblance to angiosarcoma and possible misinterpretation as such. The occurrence of IPEH in the paranasal sinus is exceedingly rare. In this article, we report the first case to our knowledge of IPEH in a vascular lesion that originated from the ethmoid sinus and extended into the sphenoid sinus and sella. Despite the benign nature of this lesion, it could have been mistaken for a malignant tumor because of its clinical course and radiologic findings.
Generalized Tuberculosis in the Acquired Immune Deficiency Syndrome
Authors: Smith Michael B. , Boyars Michael C. , Veasey Sparks , Woods Gail L.
Published: January 2021

Objective.—Generalized, or hematogenously disseminated, tuberculosis (TB) in patients with the acquired immune deficiency syndrome (AIDS) has been associated with a high incidence of cases remaining undiagnosed until postmortem. To better characterize generalized TB in the setting of AIDS, this report describes the clinical, laboratory, radiologic, and pathologic features of 20 fatal cases.

Design.—The medical records, autopsy protocols, and histologic material from patients with AIDS and concomitant TB were reviewed. All patients were autopsied at a tertiary care medical center during the years 1985–1997.

Results.—In 50% of our 20 cases, diagnosis was not made until postmortem. Signs and symptoms were few, including the absence of fever (temperature ≥38°C) in 55% of patients. Consistent laboratory abnormalities of a nonspecific nature were limited to hyponatremia (sodium <135 mmol/L) in 60%. Both peripheral and deep (thoracic and abdominal) lymphadenopathy, unusual in adults with TB, occurred in 45% and 95% of cases, respectively. In contrast to previous reports, all of the 6 cases of tuberculous meningitis presented as acute meningitis with a predominance of neutrophils in cerebrospinal fluid. Necrotizing encephalitis with extension of the acute inflammation into the superficial cortex was seen in all cases and tuberculous brain abscesses occurred in 50% of cases, a higher frequency than previously reported. Despite lung involvement in 90% of the cases, 33% of chest radiographs were interpreted as normal and disseminated mycobacterial disease was not suggested in the radiograph report in any of the other cases. Soft tissue abscesses in uncharacteristic locations such as the neck, mediastinum, and perirectal area occurred in these patients. Histologically, 95% of organs sampled showed inflammatory foci characterized by extensive necrosis with numerous neutrophils and/or karyorrhectic debris, numerous acid-fast bacilli, few or no epithelioid histiocytes, and no Langhans giant cells.

Conclusion.—Clinically and pathologically, generalized TB in the setting of AIDS is characterized by either unusual features or a lack of the typical features described for generalized TB in patients who do not have AIDS. This absence of classic features contributes to the high incidence of cases that remain undiagnosed until postmortem examination.
Congenital Macroglossal Angiodysplasia (“Lymphangioendotheliomatosis”)
Authors: Bakaeen Ghazi , Winkler Sheldon , Bakaeen Lara , Rehani Lina A. , Katsetos Christos D.
Published: January 2021

A case of congenital lingual angiodysplasia with macroglossia in a 5-year-old girl is presented. A diffusely enlarged tongue was present at birth and continued to grow as the child aged. It was accompanied by impaired speech, difficulty in eating and breathing, and sleep apnea, necessitating surgical intervention. The fundamental lesion represents a complex vascular malformation of the lymphangioma-hemangioma type, involving extensively the deep musculature of the tongue. Multifocal and multicentric cavernous lymphangioma-like and hemangioma-like areas merge with benign angioendotheliomatous-like foci in a background of variable muscle degeneration and marked fibrosis. Neither a borderline nor an overtly malignant vasoformative neoplasm was present. Because of its distinctively widespread, multicentric intramuscular distribution, this lesion may be construed as a diffuse variant of lingual lymphangioma-hemangioma malformation, closely resembling a previously described case of macroglossal lymphangioendotheliomatosis.
Recurrent Umbilical Cord Torsion Leading to Fetal Death in 3 Subsequent Pregnancies
Authors: Bakotic Bradley W. , Boyd Theonia , Poppiti Robert , Pflueger Solveig
Published: January 2021

During a span of 3.5 years, a 30-year-old, gravida 9, para 3 woman experienced 3 pregnancies complicated by umbilical cord torsion and constriction. In each case, the complication resulted in acute vascular compromise and intrauterine fetal demise. Gross examination disclosed cord constriction and torsion at the fetal end of the cord in each instance. Histologic sections from the cord torsion sites demonstrated fibrosis and deficiencies in Wharton's jelly in each case. Cytogenetic studies prepared using fetal villous tissue demonstrated normal karyotypes in fetal cells from the first 2 pregnancies (46,XX and 46,XY, respectively). The karyotype from the third pregnancy showed a 46,XX,del(X)(q24) mutation in 3 of 15 cultured cells, while 12 of 15 cells possessed a normal 46,XX karyotype. This cytogenetic abnormality was not believed to represent the cause of fetal demise in this case. To our knowledge, this is the first report of umbilical cord torsion in 3 pregnancies within one family. The familial clustering observed in this report suggests that a genetic predisposition for umbilical cord torsion may exist in some cases.
An Unusual Variant of Composite Lymphoma
Authors: Thirumala Seshadri , Esposito Michael , Fuchs Alexander
Published: January 2021

We recently encountered an unusual case of composite lymphoma arising in a 73-year-old man with a history of follicular small cleaved cell lymphoma. The neoplasm was composed of follicular small cleaved cell lymphoma and nodular sclerosing Hodgkin disease within a single groin lymph node. In addition to morphologic evidence, the immunologic studies performed in this case demonstrated the simultaneous occurrence of 2 separate lymphocytic proliferations. To the best of our knowledge, only one such histologic type has been reported in the literature.1 Hodgkin lymphoma can develop in patients with non-Hodgkin disease and vice versa, especially after treatment. The simultaneous occurrence of Hodgkin disease and non-Hodgkin lymphoma in a single lymph node is extremely rare. In this article, the relationship between Hodgkin disease and non-Hodgkin lymphoma is explored, possible explanations for the occurrence of composite lymphoma are discussed, and the literature is reviewed.
Cellular Origin of Gastrointestinal Stromal Tumors
Authors: Wang Lina , Vargas Hernan , French Samuel W.
Published: January 2021

Context.—Interstitial cells of Cajal (ICCs), also known as pacemaker cells, are cells in the gastrointestinal tract that play a role in the control of gut motility. The ICCs express the c-kit proto-oncogene encoding a type III tyrosine kinase (KIT) receptor, a ligand that is known as stem cell factor (SCF). The maturation of ICCs is dependent on SCF-KIT interaction. The cellular origin, differentiation, nomenclature, and prognosis of gastrointestinal stromal tumors (GISTs) are controversial.

Objective.—To test the hypothesis that GISTs originate from CD34-positive stem cells and differentiate toward an ICC phenotype.

Materials and Methods.—We studied 27 cases of smooth muscle differentiated GISTs collected for 14 years (1985–1999), including 8 benign (leiomyoma), 15 malignant primary (leiomyosarcoma), and 4 metastatic to the liver. Immunohistochemical studies of selected lineage-directed monoclonal antibodies of c-kit (CD117), CD34, vimentin, desmin, α-actin, S100, and MIB-1 were performed on both normal and tumor tissues.

Results.—Immunoperoxidase stains of normal gastrointestinal tract showed both c-kit and CD34-positive cells surrounding the Auerbach ganglia plexus in the gastrointestinal tract. Twenty-seven of 27 tumors strongly expressed c-kit. Fourteen of 27 tumors were positive for CD34. Of the malignant GISTs, 14 of 19 were positive for CD34; of the benign tumors, 0 of 8 were positive for CD34. Thus, CD34 was the best indicator of malignant phenotype.

Conclusion.—This is the first description of benign smooth muscle GISTs negative for CD34. The results of this study suggest that GISTs originate from CD34-positive stem cells and differentiate toward pacemaker cell phenotype. The lack of expression of CD34 in the benign GIST may indicate that benign GISTs are composed of more mature ICCs, whereas malignant GISTs are composed of dedifferentiated ICCs that express CD34-positive stem cells.
Effect of a New International Reference Preparation for Proteins in Human Serum (Certified Reference Material 470) on Results of the College of American Pathologists Surveys for Plasma Proteins
Authors: Johnson A. Myron , Whicher John T. , Ledue Thomas B. , Carlström Anders , Itoh Yoshihisa , Petersen Per Hyltoff
Published: January 2021

Objective.—To examine the impact of a new international reference preparation for serum proteins on the among-manufacturer variance in the College of American Pathologists Surveys.

Data Source.—The results of the Surveys for the years 1993–1998, supplied by the College of American Pathologists.

Data Extraction and Synthesis.—Mean values for manufacturers' assays were compared for each protein in the quality control samples. Results were separated by the reported reference material from which values for calibrators had been transferred. Standard statistical parameters (means, standard deviations, and coefficients of variation) were calculated from the reported means.

Conclusions.—Among-manufacturer coefficients of variation have dropped significantly for most serum proteins since the introduction of the new reference material. Possible reasons for continued differences are discussed.
Kaposiform Hemangioendothelioma of the Thymus
Authors: Wilken Jennifer J. , Meier Frederick A. , Kornstein Michael J.
Published: January 2021

Kaposiform hemangioendothelioma is a rare pediatric neoplasm that presents most commonly in the soft tissues. We report the case of a 1-month-old infant who presented with stridor and was found to have a diffusely infiltrating tumor in the thymus that extended into the pericardium and up the carotid sheaths. Histologic examination revealed a vascular tumor infiltrating among the lobules of the lymphocyte-depleted thymus. The lesion had features of both a capillary hemangioma and Kaposi sarcoma. Immunoperoxidase studies on formalin-fixed, paraffin-embedded tissue demonstrated the neoplastic endothelial cells to be positive for vascular markers CD31 and CD34. Antibody to factor VIII-related antigen labeled feeding vessels, but failed to stain the lobules of tumor. Although these tumors have been treated in a fashion similar to capillary hemangiomas in the past, it may be important to differentiate Kaposiform hemangioendotheliomas because of their association with Kasabach-Merritt syndrome and recent success with more aggressive chemotherapy regimens.
Mixed Mucus-Secreting and Oncocytic Carcinoma of the Thyroid
Authors: Uccella Silvia , La Rosa Stefano , Finzi Giovanna , Erba Silvia , Sessa Fausto
Published: January 2021

We report a carcinoma that is, to the best of our knowledge, the first case of a mixed mucus-secreting and oncocytic carcinoma of the thyroid. We also describe the histochemical, immunohistochemical, and ultrastructural features of this tumor. A 59-year-old man complaining of severe bone pain and weight loss underwent clinical and radiologic investigations. The studies revealed a nodule in the left thyroid lobe that was “cold” by 131I scintiscan and multiple lytic lesions of the skeleton that showed increased uptake by 99mTc-Sestamibi scintiscan. Left hemithyroidectomy was performed and the surgical specimen contained a well-circumscribed nodule of 3 cm in the greatest diameter. Light microscopy showed an oncocytic carcinoma with an area of glandular and papillary proliferation of mucin-producing cells. A double histochemical approach (Alcian blue–periodic acid–Schiff and Alcian blue–high-iron diamine) combined with ultrastructural investigation confirmed the presence of true mucus, ruling out the presence of breakdown products of thyroglobulin. Ultrastructural and immunohistochemical studies, together with clinical findings, excluded a possible metastatic origin of the mucin-producing component.
Hyperplasia of Type II Pneumocytes in Pulmonary Lymphangioleiomyomatosis
Authors: Matsui Kazuhiro , Riemenschneider William K. , Hilbert Stephen L. , Yu Zu-Xi , Takeda Kazuyo , Travis William D. , Moss Joel , Ferrans Victor J.
Published: January 2021

Background.—Little is known of the morphology of the pneumocytes lining the parenchymal cysts in lymphangioleiomyomatosis (LAM).

Objective.—To evaluate the structural characteristics of the alveolar epithelial cells in LAM.

Methods.—Immunohistochemical and electron microscopic studies were performed on lung tissue from 22 women with pulmonary LAM.

Results.—Epithelial cells that reacted with PE-10 (a mouse monoclonal antibody that recognizes the surfactant apoprotein A in type II pneumocytes) and TTF-1 (an antibody that identifies nuclear transcription factor found in type II pneumocytes) were the predominant cell type lining the surfaces of lesions of LAM and normal areas of lung. Scanning and transmission electron microscopic studies confirmed that these cells were type II pneumocytes as demonstrated by (1) apical microvilli, (2) electron-dense lamellar bodies, and (3) cytoplasmic projections that extended from the basal surfaces into the underlying connective tissue, where they made extensive contact with interstitial connective tissue cells. A few cells had morphologic characteristics of type I pneumocytes, including large flat surfaces lacking microvilli. Cells that appeared intermediate between type I and type II pneumocytes were observed occasionally.

Conclusions.—These observations and the reactivity of these cells with antibody to proliferating cell nuclear antigen demonstrate that extensive hyperplasia of type II pneumocytes is a major characteristic of LAM.
Pathophysiology of Heparin-Induced Thrombocytopenia
Authors: Fabris Fabrizio , Ahmad Sarfraz , Cella Giuseppe , Jeske Walter P. , Walenga Jeanine M. , Fareed Jawed
Published: January 2021

Objective.—This review of heparin-induced thrombocytopenia (HIT), the most frequent and dangerous side effect of heparin exposure, covers the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of this disease syndrome.

Data Sources and Study Selection.—Current consensus of opinion is given based on literature reports, as well as new information where available. A comprehensive analysis of the reasons for discrepancies in incidence numbers is given. The currently known mechanism is that HIT is mediated by an antibody to the complex of heparin–platelet factor 4, which binds to the Fc receptor on platelets. New evidence suggests a functional heterogeneity in the anti-heparin-platelet factor 4 antibodies generated to heparin, and a “superactive” heparin-platelet factor 4 antibody that does not require the presence of heparin to promote platelet activation or aggregation has been identified. Up-regulation of cell adhesion molecules and inflammatory markers, as well as preactivation of platelets/endothelial cells/leukocytes, are also considered to be related to the pathophysiology of HIT. Issues related to the specificity of currently available and new laboratory assays that support a clinical diagnosis are addressed in relation to the serotonin-release assay. Past experience with various anticoagulant treatments is reviewed with a focus on the recent successes of thrombin inhibitors and platelet GPIIb/IIIa inhibitors to combat the platelet activation and severe thrombotic episodes associated with HIT.

Conclusions.—The pathophysiology of HIT is multifactorial. However, the primary factor in the mediation of the cellular activation is due to the generation of an antibody to the heparin-platelet factor 4 complex. This review is written as a reference for HIT research.
Smooth Muscle Tumor of the Pleura
Authors: Proca Daniela M. , Ross Patrick , Pratt Jerry , Frankel Wendy L.
Published: January 2021

Smooth muscle tumors of the serosal membranes are extremely rare and have received little attention in the literature. To the best of our knowledge, only 1 published series of 5 pleural smooth muscle neoplasms has been published to date. We describe a primary pleural neoplasm with smooth muscle differentiation documented by light microscopy, immunohistochemistry, and electron microscopy. This tumor originated in the parietal pleura in a 32-year-old white man and was diagnosed incidentally by chest radiography; the diagnosis was confirmed by magnetic resonance imaging and biopsy. Four years later, the tumor was noted to have increased in size and disseminated into the chest wall as a separate circumscribed mass located in the pectoral muscle. Both masses were resected and diagnosed as smooth muscle tumors. We conclude that smooth muscle tumor of the pleura is a well-defined entity with a low, but definite malignant potential; therefore, we recommend complete resection and long-term follow-up for all patients.
Malakoplakia of the Appendix
Authors: Jain Mona , Arora Vinod K. , Singh Navjeevan , Bhatia Arati
Published: January 2021

Malakoplakia of the appendix is an unusual condition that has been reported to occur in association with tumors, infections, and immunocompromised states. We describe a case of appendicular malakoplakia associated with eggs of Taenia species. The diagnosis was made on histopathologic examination of surgically resected tissue from an appendicular mass. To the best of our knowledge, this is the first time that helminths have been documented to be associated with malakoplakia. We also discuss the implications of helminthic infestation in the pathogenesis of the lesion.
Fat Replacement of the Glycogen in the Liver as a Cause of Death: Seventy-five Years Later
Authors: Chejfec Gregorio
Published: January 2021

Seventy-five years ago, E. R. LeCount and H. A. Singer published a report in the first issue of the Archives of Pathology & Laboratory Medicine entitled “Fat Replacement of the Glycogen in the Liver as a Cause of Death.” The report described 11 patients with chronic alcoholism who died suddenly. Markedly enlarged fatty livers were the only abnormality noted at postmortem examination in each of the subjects. Groups in this country and abroad subsequently repeated the authors' observation. The mechanism of sudden death in patients with fatty livers due to chronic alcoholism is currently understood to be an abnormality in the conduction system of the heart, manifested as a prolonged QT interval. The triggering event leading to the conduction defect has been suggested to be hypoglycemia complicated by hypopotassemia and hypomagnesemia. In this review we will summarize the changes that have taken place in this field since the initial publication by LeCount and Singer.
Hereditary Cancer Syndromes
Authors: Frank Thomas S.
Published: January 2021

Objective.—To summarize the biological basis, clinical implications, identification, and medical management of syndromes associated with increased risk of common adult cancers.

Data Sources.—Recent studies and data available from molecular and clinical analysis of genes responsible for autosomal-dominant inheritance of cancer risk.

Data Synthesis.—Several hereditary cancer syndromes have been identified for which there are increasingly effective diagnostic and management options. Specific hereditary susceptibility syndromes have been characterized that increase the risk of malignancies of the breast, ovary, colon, endometrium, and endocrine organs. Following a summary of the biological basis of hereditary cancer risk in adults, the identification of such syndromes by clinical and laboratory means is reviewed. Finally, management options for individuals with these syndromes are summarized.

Conclusions.—Advances in gene discovery have allowed the diagnosis of recently characterized hereditary cancer syndromes to enhance medical management for individuals with inherited susceptibility to common cancers.
Expression of c-Kit (CD117) in Benign and Malignant Human Endometrial Epithelium
Authors: Elmore Lynne W. , Domson Kelly , Moore Jonathan R. , Kornstein Michael , Burks R. Tucker
Published: January 2021

Background.—The proto-oncogene c-kit encodes a tyrosine kinase receptor (CD117) with a molecular weight of 145 kd. Previous studies, predominantly utilizing immunohistochemistry, have led to contradictory findings regarding the expression of CD117 in the endometrium. To help resolve this issue, we analyzed a series of benign and malignant endometrial tissues using both immunohistochemistry and Western blot analysis.

Objective.—To examine the expression of CD117 in benign and malignant human endometrial tissues.

Methods.—The expression of CD117 in 35 benign endometrial tissues (7 hyperplastic, 14 proliferative, 14 secretory) and 10 endometrioid carcinomas was investigated by immunohistochemistry (clone K45 monoclonal antibody). Immunoprecipitation (clone K69 monoclonal antibody) followed by Western blotting (clone K45 monoclonal antibody and clone 1.D9.3D6 monoclonal antibody) was performed to confirm CD117 expression.

Results.—Fifty-seven percent of the hyperplasias, 93% of proliferative endometria, and 79% of secretory endometria immunostained positively for CD117. In benign endometria, epithelial staining tended to be more intense in the hyperplastic and proliferative endometria as compared to the secretory endometria, whereas endometrial stromal cells were not immunoreactive. Of the 10 frozen endometrial tissues analyzed by immunohistochemistry, 4 of 9 endometrioid carcinomas and a single case of an endometrioid polyp developing in association with a carcinoma expressed CD117. Immunoprecipitation followed by Western blot analysis confirmed expression of full-length CD117 in an endometrial polyp and carcinoma, and revealed a correlation between levels of immunoprecipitated CD117 and immunohistochemical staining intensity.

Conclusions.—Benign and malignant endometrial tissues express CD117. Our data suggest (a) a possible relationship between estrogen and CD117 expression in benign endometrium and (b) potential involvement of this growth factor receptor in endometrial carcinogenesis.
Sources of Variability
Authors: Steele Bernard W. , Wang Edward , Palomaki Glenn , Klee George G. , Elin Ronald J. , Witte David L.
Published: January 2021

Objective.—To determine the magnitudes and sources of analytic variation in testing for therapeutic drugs. Specifically, among laboratories using the same analytic method, to compare the within-laboratory variation (including both short- and long-term variation) with the between-laboratory variation.

Design.—Four identical challenges were prepared from a lyophilized pool of spiked sera and were sent in pairs 4 months apart to laboratories participating in a nationwide proficiency-testing program. For each of 25 drugs, the variability in reported results from laboratories using the same method was investigated using nested analysis of variance.

Setting.—The first 2 mailings of the College of American Pathologists Therapeutic Drug Monitoring Survey, 1996, sets Z and ZM.

Main Outcome Measures.—For each drug, total variance was partitioned into within- and between-laboratory components for common methods. The within-laboratory component was further partitioned into short- and long-term components.

Participants.—The approximately 5000 laboratories enrolled in the survey.

Results.—For the 25 drugs, the average percentages of the total variance due to short-term, within-laboratory variance; long-term, within-laboratory variance; between-laboratory variance; and total laboratory variance were 25.0% (range, 8.8–50.6%), 57.8% (35.3–73.7%), 17.3% (5.0–35.4%), and 82.7% (64.6–95.0%), respectively.

Conclusion.—For all drugs tested, the within-laboratory component of variance was greater than the between-laboratory component of variance. Within laboratories, the magnitude of the long-term component was generally greater than the magnitude of the short-term component. This information will be helpful in determining the clinical utility of various drug assays and in evaluating the appropriateness of regulations involving therapeutic drug testing.
Detection of T-Cell Receptor-γ Gene Rearrangement in Lymphoproliferative Disorders by Temperature Gradient Gel Electrophoresis
Authors: Alkan Serhan , Cosar Ediz , Ergin Melek , Hsi Eric
Published: January 2021

Objective.—Polymerase chain reaction amplification of DNA for T-cell receptor (TCR) gene rearrangement analysis is helpful in the evaluation of T-cell lymphoproliferative disorders. Detection of polymerase chain reaction products is limited by the poor resolution of bands analyzed by agarose or polyacrylamide gel electrophoresis. To improve the detection of a clonal T-cell population, we used temperature gradient gel electrophoresis (TGGE) as an alternative method for analysis of TCR gene rearrangement.

Design.—One hundred eighteen archival DNA samples were randomly selected based on previous Southern blot analysis results. Samples included 58 T-cell neoplasms with positivity for TCRβ gene rearrangement, 22 cases of reactive hyperplasia with germline pattern for both TCRβ and JH, and 38 patients with B-cell lymphoma. MOLT-16, a T-cell lymphoblastic cell line, was used for the sensitivity assay. Polymerase chain reaction was performed using GC;chclamped multiplex primers to amplify the TCRγ locus and was analyzed by TGGE. The range of temperature gradients was empirically determined for optimal resolution of bands.

Results.—The sensitivity of TGGE was 0.1% when DNA from the MOLT-16 cell line was serially diluted with DNA from reactive lymphoid tissue. Fifty-four (93%) of 58 T-cell neoplasms with TCRβ gene rearrangements showed rearrangement patterns by TCRγ TGGE, and only 1 of 60 samples (reactive or B-cell lymphomas) showed evidence of gene rearrangement by TGGE. Patients with T-cell neoplasm and involvement of multiple sites showed an identical migration pattern by TGGE analysis.

Conclusion.—We demonstrate that TGGE is an effective method for analysis of TCR gene rearrangement in the evaluation of nodal and extranodal lymphoid lesions.
Primitive Neuroectodermal Tumor of Cerebrum With Adipose Tissue
Authors: Krishnamurthy Satish , Powers Stephen Kent , Towfighi Javad
Published: January 2021

Primitive neuroectodermal tumors (PNETs) of the central nervous system are uncommon embryonal neoplasms, rarely occurring in adults. Differentiation into specific mesenchymal tissues, such as cartilage, bone, skeletal muscle, smooth muscle, or adipose tissue, is rare. We report a case of a 51-year-old woman with a PNET of cerebrum that showed extensive mature adipose tissue differentiation. This is the second case, to our knowledge, of PNET of cerebrum with adipose tissue elements that has been described.
Surgical Pathology–Based Outcomes Assessment of Breast Cancer Early Diagnosis
Authors: Nakhleh Raouf E. , Zarbo Richard J.
Published: January 2021

Objective.—To develop breast cancer outcomes data relating pathologic tumor variables at diagnosis with clinical method of detection.

Design.—Anatomic pathologists assessed 30 consecutive breast cancers at each institution, resulting in an aggregate database of 4232 breast cancers.

Setting.—Hospital-based laboratories from the United States (98%), Canada, Australia, and Belgium.

Participants.—One hundred ninety-nine laboratories in the 1999 College of American Pathologists Q-Probes voluntary quality improvement program.

Main Outcome Measures.—Pathologic variables indicative of favorable outcomes included percentage of carcinomas detected at the in situ stage, tumors ≤1 cm in diameter, and invasive cancers with lymph nodes negative for metastases.

Results.—All outcomes measures, including percent in situ carcinomas (26.9% vs 13.8%), tumor size ≤1 cm (57.8% vs 36.5%), and lymph node–negative status (77.8% vs 64%), were more favorable when tumors were detected by screening mammography (P < .001) compared to all other detection methods.

Conclusions.—This study demonstrates an opportunity for pathologists to develop outcomes information of interest to health care organizations, providers, patients, and payers by integrating routine oncologic surgical pathology and clinical breast cancer detection data. Such readily obtained interim outcomes data trended and benchmarked over time can demonstrate the relative clinical efficacy of preventive breast care provided by health care systems long before mortality data are available.
Detection of Human Papillomavirus on Papanicolaou-Stained Cervical Smears Using Indirect In Situ Polymerase Chain Reaction Hybridization
Authors: Manavi Mahmood , Bauer Margit , Pischinger Kerstin , Czerwenka Klaus
Published: January 2021

Objective.—Polymerase chain reaction (PCR) and indirect in situ hybridization were combined to detect human papillomavirus (HPV) DNA on Papanicolaou (PAP)-stained cervical smears. To our knowledge, this is the first report of an experiment using indirect in situ PCR (IS-PCR) on PAP-stained cervical smears.

Design.—We collected native cell specimens from cervicovaginal lavage of 162 patients with squamous intraepithelial lesions. Solution-phase PCR (SP-PCR) was performed as the reference method in the detection of HPV DNA. Indirect IS-PCR was carried out for the same patients to detect the HPV DNA types 6/11 and 16/18 after the PAP-stained smears had been decolorized. Low-risk and high-risk HPV DNA types were also detected by both SP-PCR and indirect IS-PCR.

Results.—In the evaluation by indirect IS-PCR, 48 of 81 PAP-stained cell smears of low-grade squamous intraepithelial lesions were positive for HPV DNA, as compared to 40 positive cell smears determined by indirect SP-PCR (sensitivity of indirect IS-PCR compared to SP-PCR, 98.1%). Forty-two of 42 high-grade squamous intraepithelial lesion samples were positive for HPV DNA, as determined by both methods (sensitivity of IS-PCR, 100%). Cell lines investigated in this study as positive or negative controls for HPV DNA were confirmed by indirect IS-PCR and SP-PCR.

Conclusions.—Our data show that in comparison to SP-PCR, indirect IS-PCR is a highly sensitive method to detect HPV DNA in cell smears from the uterine cervix. The advantages of indirect IS-PCR are (a) low numbers of cells needed, (b) the possibility of using PAP-stained specimens, and (c) cytologic details of smears can be preserved.
Two-Color, Cytokeratin-Labeled DNA Flow Cytometric Analysis of 332 Breast Cancers
Authors: Prasad Anil R. , Divine George , Zarbo Richard J.
Published: January 2021

Context.—DNA flow cytometry of breast cancer is a proposed tumor marker of prognostic significance that is of controversial clinical utility because of lack of standardization and confirmatory studies.

Objective.—To evaluate the prognostic significance of the more informative technique of multiparametric 2-color DNA flow cytometry as recommended by the 1992 DNA Cytometry Consensus Conference.

Design.—Three hundred thirty-two breast carcinomas with 7 to 12 years of follow-up were prospectively analyzed as fresh tumors that were mechanically dissociated into whole cell suspensions. These suspensions were dual fluorescence–labeled with propidium iodide (DNA) and antibodies to cytokeratin (epithelium) and leukocyte common antigen (internal leukocyte control) for gated analysis of subpopulations. Multicycle software with histogram-dependent algorithms employing background, aggregate, and debris correction were used in DNA and cell-cycle quantitation. Data were analyzed according to the DNA Flow Cytometry Consensus Conference recommendations.

Results.—DNA ploidy and proliferation stratified into 3 categories were not predictive of overall or disease-free survival. Sixty-five percent of tumors were nondiploid, and 35.4% were diploid. Two hundred six tumors were able to be evaluated for synthesis-phase fraction (SPF) analysis, with 74 of 206 cases in the low range (<13.4%), 36.4% in the intermediate range (>13.5 to <25.4%), and 27.6% in the high SPF (>25.5%) category. Aneuploid tumors tended to have a higher SPF. Univariate survival analysis showed prognostic significance of the following: tumor size, stage, TNM components, vascular invasion, nuclear grade, and histologic grade. Only T classification, presence of positive axillary lymph nodes, and distant metastases were significant independent predictors of survival in multivariate Cox regression models. Age and hormone receptor status showed no prognostic significance. Synthesis-phase fraction was significantly correlated with tumor size, stage, T classification, nuclear and histologic grade, presence of estrogen or progesterone receptors, and axillary lymph node status. None of the histologic parameters showed any significant association with DNA aneuploidy, except for high nuclear and histologic grade and the absence of estrogen receptors.

Conclusions.—Despite the use of state-of-the-art processing and flow cytometry analytic techniques, DNA ploidy and proliferation measurements were not predictive of survival in any stage of breast cancer. However, select histopathologic parameters and TNM stage were significant predictors of survival in univariate and multivariate analyses. We conclude that DNA ploidy and proliferation measurements do not provide significant prognostic information for clinicians to integrate into therapeutic decision making for patients with breast cancer.
Splenic Inflammatory Myofibroblastic Tumor (Inflammatory Pseudotumor)
Authors: Neuhauser Thomas S. , Derringer Gregory A. , Thompson Lester D. R. , Fanburg-Smith Julie C. , Aguilera Nadine S. I. , Andriko Jo Ann , Chu Wei-Sing , Abbondanzo Susan L.
Published: January 2021

Context.—Inflammatory pseudotumor is an uncommon and enigmatic lesion. The spindle cells found in this tumor have features of myofibroblasts. Because of the indefinite relationship of these lesions with inflammatory fibrosarcoma and their indefinite biologic behavior, inflammatory pseudotumor is currently classified as inflammatory myofibroblastic tumor (IMT). To date, only case reports or small series have been published on these tumors, which are primary in the spleen.

Design.—In this study, we describe the clinical, morphologic, and immunophenotypic findings of 12 cases of splenic IMT and examine their relationship to Epstein-Barr virus (EBV).

Results.—The patients included 8 women and 3 men, ranging from 19 to 77 years of age (mean, 53 years; median, 60 years). Demographic data were unavailable for 1 patient. Patients generally presented with abdominal pain (n = 5) and fever (n = 4). Associated lesions included renal cell carcinoma (n = 2), colonic adenocarcinoma (n = 1), and cholecystitis (n = 1). All tumors were composed of a bland spindle cell proliferation in association with a variable mixed inflammatory component. There were 2 growth patterns, namely, a cellular spindle cell pattern and a hypocellular fibrous pattern. An immunohistochemical panel confirmed the myofibroblastic nature of the spindle cells. The spindle cells of 2 cases were immunoreactive for EBV latent membrane protein 1, whereas 6 of 10 cases were positive for EBV-encoded RNA using in situ hybridization. Follow-up was available for 8 patients; 6 were alive with no evidence of recurrence and 2 were dead of other causes.

Conclusion.—Splenic IMTs are uncommon lesions that can be distinguished from other conditions using a combination of clinical, histologic, and immunophenotypic findings. Epstein-Barr virus may play a role in the pathogenesis of splenic IMT, and there may be an association of splenic IMT with concomitant disease or malignancy. Most splenic IMTs have an excellent long-term prognosis.
Primitive Neuroectodermal Tumor of the Lung
Authors: Kahn Andrea G. , Avagnina Alejandra , Nazar Jorge , Elsner Boris
Published: January 2021

Primitive neuroectodermal tumors occur most frequently in bone and soft tissue but have been reported in other locations. Primary lung primitive neuroectodermal tumors without pleural or chest wall involvement are extremely rare. We present a case with immunohistochemical and ultrastructural studies and follow-up of the patient. An 18-year-old man presented with hemoptysis. Chest radiographs revealed a right middle lobe mass, and bronchoscopy showed an endobronchial tumor. The lesion was resected by middle lobectomy. After 2 years, a local recurrence was treated by pneumonectomy. The patient died after surgery. Histologically, the tumor was composed of uniform cells with round nuclei and scanty cytoplasm arranged in cohesive lobules with occasional rosette formation. Immunohistochemically, the tumor was positive for vimentin, CD99, neuron-specific enolase, and neurofilaments. Ultrastructural study revealed neurosecretory granules and cytoplasmic processes. Our case shows the value of immunohistochemistry and electron microscopy in the diagnosis of primitive neuroectodermal tumors in unusual locations.
Natural Killer Cell Precursor Acute Lymphoma/Leukemia Presenting in an Infant
Authors: Natkunam Yasodha , Cherry Athena M. , Cornbleet P. Joanne
Published: January 2021

Lymphoma/leukemia derived from immature natural killer (NK) cells occur most commonly in adults and are characterized by blastic cytologic features and an aggressive outcome. Predilection for extranodal sites and absence of the Epstein-Barr virus associated with mature NK cell malignancies further distinguish this entity. We present a NK precursor acute lymphoma presenting with multiple masses in an infant without circulating blasts or marrow replacement by disease. The diagnostic difficulty arose from several factors, including young age, presentation with multiple masses, blastic cytologic features mistaken for a small, round, blue cell tumor, and the absence of lineage-specific markers. The CD56+, CD34+, CD33+, MPO−, cytoplasmic CD3+, CD45−, CD7−, HLA-DR−, and TdT− immunophenotype of this neoplasm overlaps with previously reported cases of myeloid/NK precursor acute leukemia and blastic NK cell lymphoma/leukemia. This case emphasizes the need for a strong index of suspicion to recognize this rare entity and to distinguish it from solid tumors and other hematolymphoid neoplasms that occur in infancy.
Primary Paratesticular Lymphoma
Authors: Vega Francisco , Medeiros L. Jeffrey , Abruzzo Lynne V.
Published: January 2021

Non-Hodgkin lymphoma arising in the paratesticular organs without testicular involvement is rare. In most previously reported cases, the classification systems that were used are now outdated and/or immunologic studies were not done. We report the clinical and pathologic features of 2 cases of non-Hodgkin lymphoma arising in the epididymis and the spermatic cord. Patient 1 was a 35-year-old man who presented with a painless scrotal mass. Patient 2 was a 61-year-old man who presented with a right inguinal mass. Orchiectomy performed in both patients revealed a mass confined to the epididymis in patient 1 and to the spermatic cord in patient 2. Histologic examination in both cases revealed diffuse large cell lymphoma, and immunohistochemical studies supported B-cell lineage. Subsequent staging studies showed no other site of disease in patient 1 and an isolated mass anterior to the right psoas muscle in patient 2. Malignant lymphoma involving testicular adnexal structures without involvement of the testis is extremely uncommon. To our knowledge, only 6 cases confined to the epididymis and 12 cases confined to the spermatic cord have been reported previously.