bluuebunny/crossref_metadata_2025 huggingface dataset:
Interdigitating Dendritic Cell Sarcoma of the Duodenum With Rapidly Fatal Course: A Case Report and Review of the Literature
Authors: Kanaan Hassan , Al-Maghrabi Jaudah , Linjawi Ayman , Al-Abbassi Amira , Dandan Abdelghani , Haider Abdul Razzaq
Published: February 2021

Interdigitating dendritic cell sarcoma is an extremely rare malignancy derived from antigen-presenting cells. Dendritic cells constitute a heterogeneous group of cells, which includes Langerhans cells, dermal dendrocytes, follicular dendritic cells, and interdigitating dendritic cells present in lymphoid and nonlymphoid organs. We report the case of a 36-year-old woman who presented with epigastric pain, projectile vomiting, and significant weight loss. Upper gastrointestinal endoscopy showed a duodenal lesion; a biopsy of the lesion was taken and was diagnosed as sarcoma. She underwent a Whipple procedure. A final diagnosis of interdigitating dendritic cell sarcoma was made, with liver and peripancreatic lymph node involvement. The patient deteriorated rapidly and died 4 months later. Although interdigitating dendritic cell sarcoma of the duodenum is extremely rare, we think it should be included in the differential diagnosis of unusual spindle cell tumors with a rich lymphocytic infiltrate.
Diabetic Hepatosclerosis: Diabetic Microangiopathy of the Liver
Authors: Harrison Stephen A. , Brunt Elizabeth M. , Goodman Zachary D. , Di Bisceglie Adrian M.
Published: February 2021

Context.—Liver disease associated with diabetes mellitus is common and usually takes the form of simple steatosis or nonalcoholic steatohepatitis. After observing a noncirrhotic form of hepatic sinusoidal fibrosis in patients with long-standing diabetes mellitus who underwent liver biopsy, we set about to characterize this novel entity.

Design and Setting.—Cases with the hallmark histologic findings were gathered at Saint Louis University School of Medicine and the Armed Forces Institute of Pathology.

Patients.—The clinical records were examined in a systematic fashion. Results of light microscopy and prepared immunohistochemical stains were reviewed.

Main Outcome Measures.—Clinical findings of patients with the histologic, detailed light microscopic, and immunohistochemical findings on biopsies.

Results.—Twelve patients were identified from biopsy findings; all had a history of long-standing diabetes mellitus and a noncirrhotic form of hepatic sinusoidal fibrosis not associated with nonalcoholic steatohepatitis. Most of these patients had a body mass index less than 25 kg/m2 and had substantial evidence of microvascular complications, including retinopathy, nephropathy, and peripheral and autonomic neuropathy. Alkaline phosphatase elevation was common. Liver biopsy specimens showed extensive dense perisinusoidal fibrosis, and immunostaining revealed basement membrane components in a perisinusoidal distribution. Features of nonalcoholic steatohepatitis were not present in the biopsy specimens.

Conclusions.—We propose the term diabetic hepatosclerosis for this entity and suggest that it represents a form of diabetic microangiopathy affecting the liver. Further studies are needed to precisely characterize diabetic hepatosclerosis and to understand mechanisms of pathogenesis and the clinical significance.
Potential Predictive Patterns of Minimal Residual Disease Detected by Immunohistochemistry on Bone Marrow Biopsy Specimens During a Long-term Follow-up in Patients Treated With Cladribine for Hairy Cell Leukemia
Authors: Mhawech-Fauceglia Paulette , Oberholzer Martin , Aschenafi Senait , Baur Audrey , Kurrer Michael , Von Rohr Albert , Hsu-Schmitz Shu-Fang , Wagner Beatrice , Delacretaz Francoise , Hurwitz Nina
Published: February 2021

Context.—Minimal residual disease (MRD) in patients treated for hairy cell (HC) leukemia as assessed by immunohistochemistry has not been included routinely in evaluation of treatment results.

Objective.—To assess the presence of persistent HCs after treatment, as detected by immunohistochemistry, and to evaluate the correlation between the level of MRD and clinical outcome.

Design.—Percentages of DBA.44-positive HCs were assessed on 116 biopsy specimens from 17 patients. The patients had a median follow-up of 55.4 months.

Results.—Minimal residual disease was seen in 3 patterns. Group 1 (7 patients) had MRD levels ranging from “rare scattered suspicious HCs” to less than 1%. The MRD levels were stable throughout follow-up, and all patients remained in complete remission. Group 2 (6 patients) had MRD levels ranging from 1% to 5%, and 3 patients were in complete remission at 77.9, 63.8, and 108.0 months. Another patient showed evidence of disease activity (partial remission) at 47.6 months. Two other patients relapsed at 12.3 months and at 25.7 months, respectively, with greater than 1% HCs. Group 3 (4 patients) had MRD levels greater than 5%. Three patients relapsed at 11.3, 12.1, and 29.6 months, respectively, with greater than 5% HCs. The fourth patient had MRD levels of 5% at 14.6 months and 2% at 20.0 months but was subsequently lost to follow-up.

Conclusions.—Quantitative assessment of MRD may be of value in identifying patients at risk for relapse of hairy cell leukemia.
Normal and Neoplastic Cells of Brown Adipose Tissue Express the Adhesion Molecule CD31
Authors: Rosso Renato , Lucioni Marco
Published: February 2021

Context.—CD31 (platelet-endothelial cell adhesion molecule-1; PECAM-1), an adhesion molecule involved in the process of angiogenesis, is used as a marker of normal and neoplastic vascularization. During the assessment of angiogenesis and vascular invasion in a thymic carcinoid tumor, we observed unexpected immunostaining for CD31 in perithymic brown fat nests.

Objective.—To determine whether CD31 is expressed by normal and neoplastic cells of brown fat, a tissue whose thermogenetic activity depends heavily on high perfusion.

Design.—Formalin-fixed, paraffin-embedded archival tissues were immunostained by the labeled avidin-biotin method using antibodies against CD31 (clones JC70A and 1A10) after retrieval of heat-induced epitopes. Archival tissues included perithymic, periadrenal, axillary, and neck adipose tissue in which were embedded nests of brown fat (n = 15), hibernoma (n = 3), lipoma (n = 6), well-differentiated liposarcoma (n = 4), and myxoid liposarcoma (n = 4).

Results.—Invariably, multivacuolated and univacuolated adipocytes of normal brown fat and hibernomas were intensely positive for the CD31 antigen. The immunostaining “decorated” cell membranes and the membranes of intracytoplasmic vacuoles. No expression of CD31 was found in normal adipocytes of white fat, in neoplastic cells of lipomas, or in multivacuolated lipoblasts of well-differentiated and myxoid liposarcomas.

Conclusions.—The spectrum of cell types that express CD31 is expanded to include normal and neoplastic brown fat cells. We speculate that the expression of CD31 may play a role in the development and maintenance of the vascular network characterizing this specialized adipose tissue. Moreover, CD31 may inhibit the Bax-mediated apoptosis of brown fat cells. For practical purposes, CD31 may be used as an immunohistochemical marker for distinguishing between white and brown fat and for diagnosing hibernoma in paraffin sections.
Comprehensive Analysis of the Expression of the Metastasis-Associated Gene 1 in Human Neoplastic Tissue
Authors: Hofer Matthias D. , Tapia Coya , Browne Tara Jane , Mirlacher Martina , Sauter Guido , Rubin Mark A.
Published: February 2021

Context.—The metastasis-associated gene 1 (MTA1) is overexpressed in several human cancers. Recent reports suggest that MTA1 may play a role in cancer progression either through transcription repression and/or hormone receptor interactions.

Objective.—To analyze MTA1 expression levels in a wide variety of human tumors.

Design.—We used Oncomine, an Internet-based compendium of expression array data, to query more than 90 expression array studies, and we evaluated tissue microarrays composed of more than 3200 samples representing 138 different localized neoplasms.

Results.—Both analyses show that MTA1 is ubiquitously expressed in benign and malignant tumors. The highest levels of MTA1 expression were observed in diffuse B-cell lymphoma (mean staining intensity, 3.9/4), basal cell carcinomas (3.7/4), and consistently in tumors of neuroendocrine descent such as paraganglioma (3.7/4) and carcinoid tumor (3.1/4).

Conclusions.—This study characterizes MTA1 expression for the first time across a broad spectrum of primary tumors, demonstrating expression in both benign and malignant neoplasms in addition to showing an association with neuroendocrine differentiation. We also found evidence that MTA1 expression is associated with tissue invasion but may not be sufficient for the progression to metastatic stages.
The Criteria for Bone Marrow Recovery Post–Myelosuppressive Therapy for Acute Myelogenous Leukemia: A Quantitative Study
Authors: Khalil Farah , Cualing Hernani , Cogburn Julia , Miles Lili
Published: February 2021

Context.—Although the early post–myelosuppressive chemotherapy pathologic changes of the marrow have been described, the rate and the histologic definition of recovery are not defined.

Objective.—To study the rate of recovery of bone marrow in patients given myelosuppressive therapy for acute myelogenous leukemia, establish the histologic criteria of recovered marrow, and correlate the recovery pattern with those patients who received a bone marrow transplant by using histology, peripheral blood, immunophenotyping, and computerized morphometry and mathematical slope equation.

Design.—We studied the post–myelosuppression recovery of the bone marrow to determine patterns and rate of recovery in 135 serial bone marrow biopsies of 51 patients. These patients were divided into 2 groups: 1 group of 28 cases diagnosed with acute myeloid leukemia, the majority treated with cytarabine (Ara-C) infusion for 7 days and daunorubicin intravenously daily for 3 days (7+3 regimen), and the other control group of 23 cases treated with chemotherapy or allogeneic bone marrow transplantation for a variety of hematologic malignancies. All biopsies during the recovery period were obtained before consolidation regimen. We used morphometry to calculate the cellularity and myeloid to erythroid ratio and quantified megakaryocytes CD10 versus time from day 14 onward. The absolute neutrophil and platelet counts for 28 cases were related to histologic recovery.

Results.—From day 14, we noted a differential slope of recovery of these patients with no difference in male and female patients, P = .45, but a difference between younger and older patients (>58.5 years), P = .03. After regenerative hyperplasia, the cellularity plateaus, the myeloid to erythroid ratio, and the megakaryocytes even out with platelet normalization, and the early CD10+ B cells rise from day 40 onward, P = .01. The patterns of recovery after day 60 of postchemotherapy and posttransplantation patients are similar. Complete histologic and peripheral blood recovery is noted at day 38 and thereafter.

Conclusions.—By linear equation using at least 2 trephine biopsy specimens, the projected rate of cellular recovery may be determined, and 5 histologic features are associated with complete histologic recovery.
Immunophenotypic Characterization of Anal Gland Carcinoma: Loss of p63 and Cytokeratin 5/6
Authors: Lisovsky Mikhail , Patel Keyur , Cymes Karina , Chase Donald , Bhuiya Tawfiqul , Morgenstern Nora
Published: February 2021

Anal gland carcinoma (AGC) is a rare perianal invasive cancer composed of tubular glands lined by cuboidal epithelium. The clinical features and histogenesis of AGC are not well understood and its origin from anal glands is often difficult to prove. Little is known about immunophenotypic features of AGC that could be useful in establishing the diagnosis. This study evaluated the immunohistochemical profile of 2 cases of AGC in comparison to anal glands from 11 hemorrhoidectomy specimens. Sections from the specimens were routinely processed and immunostained using commercial antibodies to cytokeratin (CK) 7, CK20, CK5/ 6, p63, CDX2, smooth muscle actin, calponin, heavy chain smooth muscle myosin, p53, and p16. In case 1 of AGC, radiation and chemotherapy preceded an abdominoperineal resection. In biopsies from this case, the neoplastic anal glands had a tubular pattern, whereas most glands in the resection specimen exhibited mucinous features. The histologic pattern in case 2 was tubular. Normal anal glands showed immunoreactivity for myoepithelial and basal cell markers CK5/6 and p63 in basal and parabasal cell layers and for CK7 in superficial cell layers. In contrast, both cases of AGC were negative for CK5/6 and p63 and were diffusely positive for CK7. Normal glands and both cases of AGC were negative for the intestinal differentiation marker CDX2, CK20, smooth muscle actin, calponin, smooth muscle myosin heavy chain, p16, and p53. Our data suggest that loss of p63 and CK5/6 expression is a feature of AGC. Anal gland carcinoma shares negativity for CDX2 and CK7+/CK20− profile with normal anal glands. No evidence of myoepithelial cells was found in normal or malignant anal glands. These data may be useful in establishing the diagnosis of AGC.
Imatinib in the Management of Multiple Gastrointestinal Stromal Tumors Associated With a Germline KIT K642E Mutation
Authors: Graham Janet , Debiec-Rychter Maria , Corless Christopher L. , Reid Robin , Davidson Rosemarie , White Jeff D.
Published: February 2021

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gut and are distinguished by expression of CD117 (c-Kit). Oncogenic mutations in the KIT or PDGFRA gene are detected in approximately 85% of sporadic GISTs. In recent years, examples of familial GIST have been reported in which germline mutations of KIT or PDGFRA result in multiple GISTs, skin disorders, and other abnormalities. The most common germline mutations are in KIT exon 11, mutations in exons 8 and 17 have also been described, and there are 2 families with germline PDGFRA mutations. We present a case in which a germline KIT exon 13 mutation (K642E) was discovered in a patient with multiple GISTs of rectum, small intestine, and esophagus, as well as diffuse hyperplasia of the interstitial cells of Cajal. To our knowledge, this is only the second germline example of this particular mutation. The patient's esophageal tumors were stabilized with imatinib.
An Extranodal Nasal Natural Killer/T-Cell Lymphoma With Isochromosome 7q10 as the Sole Cytogenetic Aberration Was Initially Diagnosed Via Bone Marrow Biopsy
Authors: Wang Huan-You , Wilson Kathleen S. , McKenna Robert W. , Xu Yin , Karandikar Nitin
Published: February 2021

We report a 58-year-old man who presented with fever, pancytopenia, hepatosplenomegaly, and “sinusitis” of his right nostril. Flow cytometric analysis of his bone marrow aspirate revealed a population of cells that were CD56+ (bright), CD2+ (dim), and CD7+ (slight brightly) but negative for CD3, CD4, CD5, CD8, CD11b, CD16, CD57, and T-cell receptors, consistent with aberrant natural killer cells. Bone marrow biopsy showed an atypical lymphoid infiltrate expressing CD56 as well as Epstein-Barr virus– encoded RNA and histiocytic hyperplasia with hemophagocytosis. Subsequent biopsy of his right nasal vestibule demonstrated an atypical lymphoid infiltrate, which was cytoplasmic CD3+, CD56+, and Epstein-Barr virus–encoded RNA positive, consistent with an extranodal nasal natural killer cell lymphoma. Conventional cytogenetic studies of the bone marrow revealed isochromosome 7q10 [i(7)(q10)] as the sole chromosomal aberration. To our knowledge, this is the first report demonstrating i(7)(q10) as a primary cytogenetic abnormality in an extranodal nasal natural killer cell lymphoma.
Lymphoepithelioma-like Carcinoma of the Ovary: A Case Report and Review of the Literature
Authors: Lee Sun , Park Sang Yoon , Hong Eun Kyung , Ro Jae Yoon
Published: February 2021

Lymphoepithelioma-like carcinoma is an undifferentiated carcinoma morphologically characterized by sheets of pleomorphic epithelioid cells with an intense lymphoid infiltrate. A 51-year-old woman presenting with low abdominal pain was found to have a right ovarian mass and enlarged pelvic, left para-aortic, and left supraclavicular lymph nodes. Based on a clinical diagnosis of right ovarian carcinoma with lymph node metastases, she received 9 cycles of chemotherapy, resulting in a reduction of her ovarian tumor, disappearance of the enlarged pelvic and para-aortic lymph nodes, and normalization of serum CA 125 level. The residual mass was removed surgically. The histology of the multinodular tumor resembled that of lymphoepithelioma of the nasopharynx and was observed in the right ovary. However, there was no viable tumor in either supraclavicular or para-aortic lymph nodes. Seven months after surgery, the patient has no evidence of disease. Lymphoepithelioma-like carcinoma appears to be rare in the female genital tract.
Follicular Lymphoma in Staging Bone Marrow Specimens: Correlation of Histologic Findings With the Results of Flow Cytometry Immunophenotypic Analysis
Authors: Iancu Dan , Hao Suyang , Lin Pei , Anderson S. Keith , Jorgensen Jeffrey L. , McLaughlin Peter , Medeiros L. Jeffrey
Published: February 2021

Context.—Bone marrow (BM) examination is part of the staging workup of lymphoma patients. Few studies have compared BM histologic findings with results of flow cytometric immunophenotyping analysis in follicular lymphoma (FL) patients.

Objective.—To correlate histologic findings with immunophenotypic data in staging BM biopsy and aspiration specimens of FL patients.

Design.—Bone marrow biopsy specimens of untreated FL patients were reviewed. Histologic findings were correlated with 3-color flow cytometric immunophenotyping results on corresponding BM aspirates.

Results.—Bone marrow biopsy specimens (with or without aspirates) of 114 patients with histologic evidence of FL in BM were reviewed. There were 76 bilateral and 38 unilateral biopsies performed, resulting in 190 specimens: 187 involved by FL and 3 negative (in patients with a positive contralateral specimen). The extent of BM involvement was <5% in 32 (17.1%), ≥5% and ≤25% in 102 (54.6%), >25% and ≤50% in 27 (14.4%), and >50% in 26 (13.9%) specimens. The pattern of involvement was purely paratrabecular in 81 (43.3%), mixed in 80 (42.8%), and purely nonparatrabecular in 26 (13.9%). Immunophenotyping was only performed unilaterally, on BM aspirates of 92 patients, and was positive for a monoclonal B-cell population in 53 (57.6%) patients. Immunophenotyping was more often negative when biopsy specimens showed FL with a purely paratrabecular pattern. For comparison, we assessed 163 FL patients without histologic evidence of FL in BM also analyzed by flow cytometric immunophenotyping. A monoclonal B-cell population was identified in 5 patients (3%).

Conclusions.—Our data suggest that 3-color flow cytometric immunophenotyping adds little information to the evaluation of staging BM specimens of FL patients.
Diagnosis of Prostatic Carcinoma After Therapy
Authors: Bostwick David G. , Meiers Isabelle
Published: February 2021

Context.—Prostate cancer is the most common cancer of men in the United States and is third only to lung and colon cancer as a cause of cancer death. In 2006, 27 350 Americans will die of prostate cancer, and 234 460 new cases will be diagnosed. Treatment changes in the benign and cancerous prostate create diagnostic challenges in pathologic interpretation, particularly in needle biopsy specimens and in evaluation of extraprostatic metastases.

Objective.—To summarize therapy-related pathologic findings in the prostate with emphasis on recognition of treated adenocarcinoma.

Data Sources.—Extensive review of published literature and the authors' experience.

Conclusions.—Following therapy for prostate cancer, it is critical that the clinician provide the pertinent history of androgen deprivation or radiation therapy to assist the pathologist in rendering the correct diagnosis.
Parvovirus B19 Infection in the Immunocompromised Host
Authors: Florea Anca V. , Ionescu Diana N. , Melhem Mona F.
Published: February 2021

Human parvovirus B19 is a single-stranded DNA virus with a predilection for infecting rapidly dividing cell lines, such as bone marrow erythroid progenitor cells. People with defective cell-mediated immunity (eg, severe combined immunodeficiency syndrome; acquired immunodeficiency syndrome; and patients receiving immunosuppressive therapy, ie, post organ transplant) can develop pure red cell aplasia, in which suppression of erythroid precursors is permanent. Identification of parvovirus inclusions in marrow biopsies and subsequent confirmation of infection by in situ hybridization is important in the assessment of anemia in immunodeficient patients. Our objective is to provide a general overview of the parvovirus B19 infection and its characteristics in immunocompromised patients and to summarize updated information regarding the clinicopathologic features, pathobiology, and laboratory diagnosis of this subject. The pathologist should be aware of the wide spectrum of manifestations of parvovirus B19 infection depending on the patient's hematologic and immunologic status.
Methylation Profiles of Multiple CpG Island Loci in Extrahepatic Cholangiocarcinoma Versus Those of Intrahepatic Cholangiocarcinomas
Authors: Kim Baek-Hee , Cho Nam-Yun , Choi Minhee , Lee Sun , Jang Ja June , Kang Gyeong Hoon
Published: February 2021

Context.—CpG island hypermethylation is attracting attention because of its importance as a tumor marker and its potential mechanism for the development of human cancers. Extrahepatic cholangiocarcinoma has been poorly investigated with respect to CpG island hypermethylation, and the number of genes known to be methylated in extrahepatic cholangiocarcinomas is fewer than 20.

Objective.—To generate methylation profiles of 24 CpG island loci in extrahepatic cholangiocarcinomas, to correlate methylation findings with clinicopathologic findings, and to compare these findings with those of intrahepatic cholangiocarcinomas.

Design.—Sixty-three extrahepatic cholangiocarcinomas and 48 intrahepatic cholangiocarcinomas were investigated for hypermethylation in 24 CpG island loci by using methylation-specific polymerase chain reaction.

Results.—A total of 61 (96.8%) of 63 extrahepatic cholangiocarcinomas showed hypermethylation in at least one of the examined loci, and a high methylation frequency was seen in HOXA1 (95.2%), HPP1 (69.8%), and NEUROG1 (61.9%). The number of methylated CpG island loci was greater in extrahepatic cholangiocarcinomas with nodal metastasis than in those without nodal metastasis (P = .047), and hypermethylation of TIG1 was closely associated with nodal metastasis of extrahepatic cholangiocarcinomas (P = .007). CDH1 and NEUROG1 were more frequently methylated in extrahepatic cholangiocarcinoma than in intrahepatic cholangiocarcinoma, whereas CHFR, GSTP1, IGF2, MGMT, MINT31, p14, and RBP1 were more frequently methylated in intrahepatic cholangiocarcinoma: the differences was statistically significant (P < .05).

Conclusions.—A close relationship exists between CpG island hypermethylation and nodal metastasis of extrahepatic cholangiocarcinomas. Methylation profiles of extrahepatic cholangiocarcinomas are somewhat similar to but distinct from those of intrahepatic cholangiocarcinomas.
Promoter Hypermethylation for Molecular Nodal Staging in Non–Small Cell Lung Cancer
Authors: Safar A. Mazin , Spencer Horace , Su Xiaobo , Cooney Craig A. , Shwaiki Ali , Fan Chun-Yang
Published: February 2021

Context.— Even among cases of non–small cell lung cancer (NSCLC) in the most favorable stage (IA), the disease-specific mortality is 25% or greater. One plausible explanation implicates the simplistic standard pathologic procedures used to designate lymph node involvement. A more sensitive assessment of the nodal status may improve staging.

Objective.—To determine the prognostic impact of detecting an abnormal molecular event (promoter hypermethylation in a set of relevant genes) in histologically uninvolved lymph nodes in resected NSCLC.

Design.—In this retrospective analysis of archived material, we examined DNA extracted from lymph nodes of stage I NSCLC (n = 180). Patients underwent surgery between 1991 and 1995 in a single institution. Methylation-specific polymerase chain reaction was used to detect promoter hypermethylation in a panel of 8 genes. Survival data were extracted from the computerized database at the Tumor Registry.

Results.—Evidence of promoter hypermethylation in at least 1 gene was detected in 67% of these N0 nodes. The most commonly hypermethylated gene was E-cadherin (53%). The hypermethylation frequency for the remaining genes were as follows: APC, 5%; p16, 9%; MGMT, 11%; hMLH1, 15%; RASSF1A, 4%; DAP kinase, 9%; and ATM, 19%. The presence of promoter hypermethylation in 2 or more genes did not influence the overall, median, or 5-year survival rates.

Conclusions.—Identifying promoter hypermethylation (in our panel) in N0 lymph nodes in stage I NSCLC cannot be recommended for clinical decision making. Molecular abnormalities, including those found in cancer by qualitative methylation-specific polymerase chain reaction, are not synonymous with established, histologically detectable metastasis.
Mass Spectrometry–Based Proteomics: Principles, Perspectives, and Challenges
Authors: Wiśniewski Jacek R.
Published: February 2021

Mass spectrometry–based proteomics is a modern and rapidly developing methodology for qualitative and quantitative characterization of proteins and their posttranslational modification, subcellular localization, and interaction partners. It enables characterization of entire proteomes with unprecedented sensitivity and precision, providing platforms for identification of biomarkers and drug targets.
Suggested Guidelines for the Management of High-Profile Fatality Cases
Authors: Perper Joshua A. , Juste Gertrude M. , Schueler Harold E. , Motte Reinhard W. , Cina Stephen J.
Published: February 2021

Context.—The investigation of high-profile fatalities poses special challenges to medical examiners and coroners. Most high-profile cases can be readily recognized early in the course of the investigation. Commonly encountered examples include police-related fatalities or deaths in custody, deaths of celebrities, and mass fatalities or clustered deaths (eg, serial killers). Medical examiner and coroner offices should have policies and procedures in place for adequately handling such cases. A rational approach to these high-profile cases includes activating medical examiner or coroner investigative teams, preplanning before the autopsy, using special autopsy techniques and toxicology procedures, skillful questioning of key witnesses, preparing detailed and comprehensive reports, and planning effective communication with the media.

Objective.—The investigation of the sudden and unexpected death of Anna Nicole Smith, an entertainment personality, is presented as an example of how to address the challenging issues inherent in high-profile fatalities and how to adequately prepare for the forensic investigation of high-profile cases.

Design.—This article presents a methodical approach to the investigation of high-profile deaths.

Results.—A comprehensive, preplanned forensic investigation and autopsy (including use of adjunctive studies) following the death of Anna Nicole Smith resulted in the accurate determination of the cause and manner of her death while adequately convincing the public of the objectivity and reliability of the Medical Examiners Office with respect to its conclusions.

Conclusion.—The forensic investigation of death in high-profile cases can be much more tedious and demanding than the investigation of routine cases. It requires more stringent safekeeping of the body and its evidence, more extensive and sophisticated dissection techniques on occasion, and exhaustive toxicologic analysis to exclude low-probability allegations. Procedures for honest, unbiased, and judicious communication with outside agencies and the media must be followed. Failure to follow such procedures might have serious consequences for the medical examiner, the family of the deceased, and the community at large. Adherence to these suggested guidelines may resolve most of the intricate problems involved in the investigation of these types of cases.
Extranodal Follicular Dendritic Cell Sarcoma
Authors: Youens Kenneth E. , Waugh Michael S.
Published: February 2021

Extranodal follicular dendritic cell sarcoma is a rare tumor of follicular dendritic cells that can occur in a wide variety of sites. Although fairly well characterized histologically, with a distinct immunophenotype, it remains underrecognized, with as many as one third of cases initially misdiagnosed. This is often due to a failure to consider the entity. Patients with this tumor may have a worse prognosis than originally described. Prompted by a recent case at our institution, we briefly review the clinical features, etiology, histologic, and cytologic appearance of the tumor, as well as the ancillary studies useful in resolving diagnostic issues, primarily in an attempt to increase recognition of this rare neoplasm.
Production and Activation of Matrix Metalloproteinase 7 (Matrilysin 1) in the Lungs of Patients With Idiopathic Pulmonary Fibrosis
Authors: Fujishima Seitaro , Shiomi Takayuki , Yamashita Shuji , Yogo Yurika , Nakano Yasushi , Inoue Takashi , Nakamura Morio , Tasaka Sadatomo , Hasegawa Naoki , Aikawa Naoki , Ishizaka Akitoshi , Okada Yasunori
Published: February 2021

Context.—Idiopathic pulmonary fibrosis (IPF) is characterized by diffuse interstitial inflammation and fibroblast proliferation with accelerated remodeling of extracellular matrix, which result in irreversible destruction of the lung's architecture.

Objective.—To elucidate the production levels, tissue localization, and activation of matrix metalloproteinase 7 (MMP-7) in the lungs of patients with IPF.

Design.—Bronchoalveolar lavage analysis was performed in 17 IPF patients and 6 healthy volunteers. Levels of MMP-7 in blood were assayed in 23 IPF patients and 20 controls. Histologic and immunohistochemical analyses were performed on paraffin sections of the lung tissues from patients with IPF, interstitial pneumonia associated with rheumatoid arthritis, or nonspecific interstitial pneumonia.

Results.—The proMMP-7 levels in bronchoalveolar lavage fluids from IPF patients were significantly higher than those from healthy controls, although there was no difference in the serum levels between the 2 groups. By immunohistochemistry, proMMP-7 was localized mainly to the hyperplastic alveolar and metaplastic bronchiolar epithelial cells in the lung tissues from IPF patients. Active MMP-7 was immunolocalized on alveolar macrophages and hyperplastic epithelial cells, which were also immunostained with antibody against CD151, a molecule associated with activation of proMMP-7. Immunoblot analysis indicated the overproduction of proMMP-7 together with a small amount of active MMP-7 in bronchoalveolar lavage fluids from IPF patients. The MMP-7 activity was detected in a cross-linked carboxymethylated transferrin film assay.

Conclusions.—proMMP-7 is excessively produced by hyperplastic alveolar and metaplastic bronchiolar epithelial cells and activated locally in the lungs of IPF patients, suggesting that MMP-7 may contribute to the pathology of IPF.
The Prognostic Value of Ki-67, p53, Epidermal Growth Factor Receptor, 1p36, 9p21, 10q23, and 17p13 in Skull Base Chordomas
Authors: Horbinski Craig , Oakley Gerard J. , Cieply Kathleen , Mantha Geeta S. , Nikiforova Marina N. , Dacic Sanja , Seethala Raja R.
Published: February 2021

Context.—Skull base chordomas are rare, locally aggressive, notochord-derived neoplasms for which prognostically relevant biomarkers are not well established.

Objective.—To evaluate whether newly discovered molecular alterations in chordomas have prognostic significance similar to what has been described regarding Ki-67 proliferation index.

Design.—We conducted a retrospective study of 28 cases of primary clival chordomas.

Results.—Ki-67 proliferation index 5% or more, p53 accumulation, and epidermal growth factor receptor expression were seen in 32%, 44%, and 8% of chordomas, respectively. 1p loss of heterozygosity (LOH) and/or 1p36 hemizygous deletion was seen in 30% of tumors, while 9p LOH and/or 9p21 homozygous deletion was seen in 21% of cases. Loss of heterozygosity at 10q23 and 17p13 were identified in 57% and 52% of cases, respectively. Ki-67 proliferation index 5% or more and 9p LOH were significantly associated with a shorter overall survival, while homozygous deletion at 9p21 via fluorescence in situ hybridization approached significance. No correlation with survival was found for p53 or epidermal growth factor receptor expression, 1p36 hemizygous deletion, or LOH at 1p, 10q23, or 17p13.

Conclusions.—Chordomas with elevated Ki-67 proliferation index or deletion at 9p21 may be at risk for a more aggressive clinical course and shorter survival. These biomarkers may thus be used to improve therapeutic stratification.
Deep Penetrating Nevus: A Review
Authors: Luzar Boštjan , Calonje Eduardo
Published: February 2021

Context.—Deep penetrating nevus is a distinctive melanocytic lesion that may simulate melanoma both clinically and histologically.

Objective.—To review clinical and histologic features of deep penetrating nevi and discuss their differential diagnosis, especially regarding melanoma.

Data Sources.—The literature on deep penetrating nevi is reviewed and supplemented by our experiences with deep penetrating nevi.

Conclusions.—One or more disturbing histologic features may frequently be found in deep penetrating nevi, including asymmetry, plump but fairly regular nests of melanocytes in the dermis, cytologic atypia with some nuclear pleomorphism, a small to medium-sized eosinophilic nucleolus, absence of maturation, occasional presence of normal dermal mitoses, and a patchy mononuclear inflammatory cell infiltrate. Although unusual, such histologic features should not be regarded as a sign of malignancy in deep penetrating nevi.
Detection of C4d Deposition in Cardiac Allografts: A Comparative Study of Immunofluorescence and Immunoperoxidase Methods
Authors: Miller Dylan V. , Roden Anja C. , Gamez Jeffrey D. , Tazelaar Henry D.
Published: February 2021

Context.—Complement activation, evidenced by deposition of C4d, is important in the diagnosis of antibody-mediated rejection of cardiac allografts. C4d deposition can be assessed by either immunofluorescence (IF)– or immunoperoxidase (IP)–based methods. The use of methods varies considerably among institutions, but there are few data addressing their diagnostic equivalence.

Objective.—To compare IF and IP C4d staining on paired endomyocardial biopsy samples from a large number of heart transplant patients.

Design.—Retrospectively selected paired frozen and paraffin-embedded samples from the same biopsy were stained for C4d by IF and IP methods. Capillary staining was scored by using a 0, 1+, 2+, 3+ scale.

Results.—A total of 296 biopsy pairs from 70 patients were studied. There were two hundred forty-three cases that were scored 0, twenty-four scored 1+, sixteen scored 2+, and thirteen scored 3+ by IF. Two hundred thirty-one cases scored 0, forty scored 1+, ten scored 2+, and fifteen scored 3+ by IP. Complete agreement was seen in 81% of cases. Among discrepant cases, 89% (n  =  51) were minor (±1) and 11% (n  =  6) were major (±2). Five of the 6 major discrepancy biopsies came from 2 patients, both of whom had concordant (IF and IP) 3+ results on prior biopsies. The weighted κ value for the entire sample set was 0.78 and for the first biopsy only set (to correct for bias introduced by multiple biopsies from the same patient) the weighted κ value was 0.88.

Conclusions.—Immunofluorescence and IP C4d staining methods are highly comparable and are both viable options for antibody-mediated rejection surveillance in transplant heart biopsies.
Lentiginous Melanoma
Authors: King Roy
Published: February 2021

Context.—Atypical lentiginous melanocytic lesions, particularly in older individuals, continue to pose a diagnostic challenge. Such lesions often show features intermediate between lentiginous nevus and melanoma in situ. We have recently defined within this group of lesions a histologic pattern of lentiginous melanoma, a slowly progressing variant of melanoma typically found on the trunk and proximal extremities of middle-aged and older individuals.

Objective.—To review the clinical and histologic features of lentiginous melanoma and its histologic differential diagnosis.

Data Sources.—Review of pertinent published literature and work in our laboratory.

Conclusions.—Lentiginous melanoma defines a subset of slowly progressing melanoma occurring in middle-aged and older patients. It is histologically characterized by a broad atypical lentiginous growth pattern of moderately atypical melanocytes showing focal nesting and pagetoid spread without significant dermal fibroplasia or alteration of the rete ridges. Lentiginous melanoma shows significant overlap in clinical and histologic features with atypical lentiginous nevus (of the elderly). Relationship between these entities requires further investigations. Given the risk of progression to invasive melanoma, all lesions showing features of lentiginous melanoma should be treated with adequately wide excision.
Neoplasia of Gallbladder and Biliary Epithelium
Authors: Katabi Nora
Published: February 2021

Context.—Diagnosis of biliary neoplasia can be challenging but is essential for the appropriate clinical management of patients. Therefore, it is important to recognize the morphologic features of the biliary neoplasms to report a correct diagnosis.

Objectives.—(1) To discuss the differential diagnosis of dysplasia in the gallbladder and differentiate dysplasia from reactive atypia and invasive carcinoma, (2) review the histologic features of adenoma and polypoid biliary lesions, (3) highlight the differential diagnosis of adenocarcinoma in liver biopsy, and (4) discuss the differential diagnosis of atypical biliary glandular lesions.

Data Sources.—Current English literature related to gallbladder and biliary neoplasia.

Conclusions.—Biliary glandular neoplasms show a wide spectrum of morphology and have many mimics. Careful examination of the histologic features of these lesions and familiarity with their morphology can help to achieve the correct diagnosis.
Collagenous Sprue: A Rare, Severe Small-Bowel Malabsorptive Disorder
Authors: Zhao Xiangrong , Johnson Rebecca L.
Published: February 2021

Collagenous sprue is a severe malabsorptive disorder, histologically characterized by small intestinal villous and crypt atrophy, and a subepithelial collagen deposit, thicker than 12 µm, that entraps lamina propria cellular elements. Collagenous sprue is a rare disease entity, with only about 60 sporadic cases reported worldwide since it was first described in 1947. Its exact etiology is still under investigation, and its relationship with classic celiac disease and other refractory, spruelike intestinal disorders remains controversial. Two larger-scale studies, in 2009, brought new insights into this elusive, yet emerging, topic. Here, we present a review of the literature on the possible etiology of collagenous sprue, its proposed links to classic celiac disease and to refractory sprue, and its clinical, biochemical, histologic, and molecular features. To our knowledge, all case reports on collagenous sprue in the medical literature to date are summarized.
The Significance of “Indefinite for Dysplasia” Grading in Barrett Metaplasia
Authors: Younes Mamoun , Lauwers Gregory Y , Ertan Atilla , Ergun Gulchin , Verm Ray , Bridges Margaret , Woods Karen , Meriano Frank , Schmulen Carl , Johnson Craig , Barroso Alberto , Schwartz Jim , McKechnie John , Lechago Juan
Published: February 2021

Context.—For a confident diagnosis of dysplasia in Barrett metaplasia, the epithelial atypia should also involve the surface epithelium. However, pathologists are often faced with biopsies where the crypts show dysplasia, but the surface epithelium is either uninvolved or unevaluable. We previously grouped these cases with indefinite for dysplasia (IND).

Objective.—To determine the clinical significance of IND grading in Barrett metaplasia.

Design.—All biopsies from 276 prospectively followed patients with Barrett metaplasia, who did not have high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) on initial biopsy, were graded as negative for dysplasia, IND, low-grade dysplasia (LGD), HGD, and EAC. Biopsies with multifocal IND or LGD were graded as INDM or LGDM, respectively.

Results.—Only 3 of 193 patients (2%) with an initial diagnosis of negative for dysplasia and only 1 of 48 patients (2%) diagnosed with IND progressed to HGD or EAC. By contrast, 1 of 7 patients (14%) with INDM, 2 of 21 (10%) with LGD, and 1 of 7 (14%) with LGDM progressed to HGD or EAC. There was no significant difference in progression rate between patients with an initial diagnosis of negative for dysplasia and those diagnosed IND nor were there significant differences among patients with initial diagnoses of INDM, LGD, or LGDM. Kaplan-Meier analysis showed that patients with INDM, LGD, or LGDM on initial biopsy (group 1) were more likely to progress to HGD or EAC than were those patients who were diagnosed negative for dysplasia or IND (group 2; log-rank test, P < .001).

Conclusions.—Multifocal IND in an esophageal biopsy from a patient with Barrett metaplasia has the same clinical implication as LGD.
A Case of Black Esophagus With Histopathologic Description and Characterization
Authors: Altenburger Dana L. , Wagner Aaron S. , Li Shuan , Garavaglia Jan
Published: February 2021

Black esophagus, or acute necrotizing esophagitis, is a blackening of the esophagus that is usually distal with a sharp demarcation at the gastroesophageal border. Black esophagus is known to the gastroenterology community; however, to our knowledge it is virtually unknown in the pathology literature with only a single instance described in 1967. It is thought to occur as a poorly elucidated ischemic phenomenon. We report a case of black esophagus in a 45-year-old woman with a history of cocaine and alcohol abuse who was found unresponsive after a vague 2-day illness. On autopsy examination, the esophagus was black with ischemic necrosis of the mucosa, submucosa, and muscularis propria including a diffuse acute inflammatory infiltrate and brown pigmentation limited to the mucosa. Positive periodic acid–Schiff and negative iron stains suggest that the pigment is lipofuscin, likely secondary to ischemia.
Osteoblastoma
Authors: Lucas David R.
Published: February 2021

Osteoblastoma is a rare benign bone tumor. Although the histologic features in most cases are distinctive, there are various permutations that make the diagnosis challenging. It can mimic a variety of other benign bone tumors, but more importantly, distinguishing it from osteoblastoma-like osteosarcoma can be difficult. In this case report, I describe the clinicopathologic findings for a 13-year-old adolescent boy with T7 spinal osteoblastoma and review salient clinical, radiographic, and pathologic features of osteoblastoma, as well as the differential diagnoses.
Diagnosing Emerging and Reemerging Infectious Diseases: The Pivotal Role of the Pathologist
Authors: Olano Juan P. , Walker David H.
Published: February 2021

Context—Molecular diagnostics continues to evolve very rapidly, and its impact in the diagnosis of infectious diseases is undeniable. Molecular tools have played a pivotal role in discovering and characterizing several emerging infectious agents and have now become the gold standard for the diagnosis of infectious diseases caused by fastidious or uncultivable agents. Multiple challenges still remain for the widespread use of cost-effective, validated, and commercially available molecular tools. Automated instruments capable of sample processing and multiplex nucleic acid amplification and postamplification analysis have already been approved by the US Food and Drug Administration (FDA) for use in the clinical setting. Nanobiotechnology is beginning to impact laboratory diagnostics in the clinical setting.

Objective—To address current nucleic acid techniques used in the clinical laboratory for diagnosis of infectious diseases. FDA-approved tests are listed, as well as molecular techniques (amplification and postamplification analysis). A comprehensive list of emerging pathogens during the last 4 decades is also presented. Biosurveillance systems are discussed in the context of molecular tools. The rapidly evolving field of nanobiotechnology is briefly addressed.

Data Sources—Original publications, major reviews, and book chapters were used to present a comprehensive, yet short, review of molecular diagnostics in infectious diseases.

Conclusions—We will continue to witness an exponential growth of molecular techniques used for the initial diagnosis of infectious diseases. Molecular tools will also continue to have an impact on disease prognosis and response to therapeutic interventions. Automation, multiplexing, and miniaturization will continue to be driving forces in the development of new instruments.
Development of an Evidence-Based Approach to External Quality Assurance for Breast Cancer Hormone Receptor Immunohistochemistry: Comparison of Reference Values
Authors: Makretsov Nikita , Gilks C. Blake , Alaghehbandan Reza , Garratt John , Quenneville Louise , Mercer Joel , Palavdzic Dragana , Torlakovic Emina E. ,   on behalf of the Canadian Immunohistochemistry Quality Control Program, Canadian Association of Pathologists
Published: February 2021

Context.—External quality assurance and proficiency testing programs for breast cancer predictive biomarkers are based largely on traditional ad hoc design; at present there is no universal consensus on definition of a standard reference value for samples used in external quality assurance programs.

Objective.—To explore reference values for estrogen receptor and progesterone receptor immunohistochemistry in order to develop an evidence-based analytic platform for external quality assurance.

Design.—There were 31 participating laboratories, 4 of which were previously designated as “expert” laboratories. Each participant tested a tissue microarray slide with 44 breast carcinomas for estrogen receptor and progesterone receptor and submitted it to the Canadian Immunohistochemistry Quality Control Program for analysis. Nuclear staining in 1% or more of the tumor cells was a positive score. Five methods for determining reference values were compared.

Results.—All reference values showed 100% agreement for estrogen receptor and progesterone receptor scores, when indeterminate results were excluded. Individual laboratory performance (agreement rates, test sensitivity, test specificity, positive predictive value, negative predictive value, and κ value) was very similar for all reference values. Identification of suboptimal performance by all methods was identical for 30 of 31 laboratories. Estrogen receptor assessment of 1 laboratory was discordant: agreement was less than 90% for 3 of 5 reference values and greater than 90% with the use of 2 other reference values.

Conclusions.—Various reference values provide equivalent laboratory rating. In addition to descriptive feedback, our approach allows calculation of technical test sensitivity and specificity, positive and negative predictive values, agreement rates, and κ values to guide corrective actions.