James R. Gill

Early presentation of metastatic medullary carcinoma in multiple endocrine neoplasia, type IIA : Implications for therapy

A girl 5 years 11 months of age, belonging to an extensive kindred with multiple endocrine neoplasia, type IIA (MEN IIA), was found to have multifocal medullary thyroid carcinoma with metastasis in one paraglandular lymph node after positive findings on a calcium-pentagastrin stimulation test. Her sister, 3 years 8 months of age, also had an elevated calcitonin level, and thyroidectomy revealed C-cell hyperplasia and a focus of medullary thyroid carcinoma. These two cases underscore the need for prophylactic thyroidectomies in MEN IIA patients as young as 5 years of age and strict yearly provocative screening beginning at age 1 year.

Detection of thyroglobulin, thyroid peroxidase, and RET/PTC1 mRNA transcripts in the peripheral blood of patients with thyroid disease.

PURPOSE Detection of mRNA transcripts for thyroglobulin (TG), thyroid peroxidase (TPO) and RET/PTC1 in the peripheral blood of patients with thyroid disease. PATIENTS AND METHODS TG, TPO, and RET/PTC1 mRNA were analyzed in 52 peripheral-blood samples from 44 patients diagnosed with thyroid carcinoma (24 patients), adenoma (five patients), and nodular hyperplasia (15 patients) by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS TG and TPO were identified in 13 patients (54.2%) with thyroid carcinoma, which includes five of eight patients with no clinical evidence of disease at the time of blood collection. Four of 5 patients had cervical lymph node metastases and/or extrathyroid extension at the time of the initial surgery. RET/PTC1 mRNA was detected in the peripheral blood of only one patient with papillary thyroid carcinoma. This sample was also positive for TG and TPO. TG and TPO were detected in two patients (10%) with benign thyroid nodules. All positive samples from patients with benign thyroid lesions were collected before surgery, whereas all samples collected after surgery were negative. RET/PTC1 mRNA was not detected in any of the patients with benign thyroid nodules. RT-PCR positivity for TG and TPO mRNA was higher in patients with carcinoma than in patients with benign lesions (P = .002). CONCLUSION TG, TPO, and RET/PTC1 mRNA are detectable in the peripheral blood of patients with thyroid disease, which correlates with a diagnosis of carcinoma.

The syndrome of excited delirium.

The excited delirium syndrome (EDS) is a life-threatening condition caused by a variety of factors including drug intoxication and psychiatric illness. Fatal instances of excited delirium frequently come to the attention of the medical examiner/coroner due to the circumstances and potential causes. Excited delirium may include paranoid, aggressive, and incoherent behavior which may lead to an encounter with law enforcement. In some instances, the person may die while in the presence of law enforcement. This circumstance further broadens the potential causes of death particularly as EDS has no pathognomonic autopsy finding. Although the syndrome of excited delirium is sufficient to explain death, other intervening causes need to be considered. These include chest or neck compression during restraint, blunt trauma, and underlying natural disease. Since chest/neck compression, natural disease (e.g., atherosclerosis), blunt trauma, and excited delirium are not mutually exclusive, all may be present in one death. The forensic pathologist’s role is to determine what caused and/or contributed to the death. When attempting to determine the proximate cause of death in instances with multiple potential causes, determining the mechanism of death often is useful. As not all causes of death have pathologically-demonstrable mechanisms of death, examination of the circumstances of the death often are diagnostically important. The main goal of the autopsy of deaths suspected to be due to EDS is to identify (or exclude) intervening diseases or injuries sufficient to explain the death in the context of the investigated circumstances.

Inhalational anthrax: Gross autopsy findings

A Vietnamese woman with a history of hypertension had rapidly worsening dyspnea, chest pain, and a blood-tinged, productive cough for 2 days. She had immigrated to the United States more than 20 years ago, had not traveled recently, and was previously in her regular state of good health. She worked in a hospital stockroom, adjacent to the mail room. She did not have direct contact with patients nor did she handle the mail. On admission to the hospital, she was afebrile, with an oxygen saturation of 92% on room air. Physical examination results were notable for bilateral apical rales and edema of the lower extremities. A chest radiograph revealed pleural effusions and increased pulmonary vascular markings, and initially she was treated with diuretics for congestive heart failure and antibiotics for a possible pulmonary infection. Worsening respiratory failure required emergency intubation, and a chest computed tomographic (CT) scan showed mediastinal adenopathy. Bronchoscopy disclosed friability and hemorrhage of the tracheobronchial mucosae, and bronchi contained purulent secretions. A followup CT scan revealed marked mediastinal hemorrhage and worsening effusions. Bilateral chest tubes drained 2000 mL of serosanguinous fluid. She was treated for septic shock followed by disseminated intravascular coagulation and multiorgan system failure. Blood cultures grew Bacillus anthracis. Polymerase chain reaction studies for B anthracis on blood, pleural fluid, and bronchial specimens further confirmed the diagnosis. She died 3 days after admission. At autopsy, there were numerous foci of hemorrhage of the mediastinum. The hilar and peribronchial lymph nodes were enlarged, soft, and confluently hemorrhagic (Figure 1), and hemorrhage tracked along the peribronchial parenchyma (Figure 2). The trachea was encased in hemorrhagic soft tissue (Figure 3). Microscopically, the mediastinal lymph nodes showed acute hemorrhagic effacement with necrosis and karyorrhexis (Figure 4). Touch preparations of these lymph nodes revealed rare, scattered, gram-positive bacilli without definitive sporulation. Although the lungs were edematous, there was no bron-

9/11 and the New York City Office of Chief Medical Examiner

On September 11, 2001 two hijacked airplanes struck the Twin Towers at the World Trade Center in New York City. All of the remains (19,915) were examined by the Office of Chief Medical Examiner (OCME) of New York City. The major goals of the OCME were to accurately identify the decedents and to promptly issue death certificates. As of September 2005, there were 1594 identifications of a total of 2749 people reported missing. Of these, 976 were identified by a single means, which included DNA analysis in 852 of the victims. Use of legal statues can assist in the timely issuance of death certificates in mass fatalities, which benefit surviving family members. DNA analysis markedly improves the ability to identify remains and has become the standard method for identification in these types of disasters. Certain postmortem tissue samples are better suited for DNA analysis and yield better results than others.

Testing for Infectious Diseases in Sudden Unexpected Infant Death: A Survey of Medical Examiner and Coroner Offices in the United States

OBJECTIVES To determine interoffice variability in routinely performed sudden unexpected infant death (SUID) postmortem studies for infection and to assess availability and perceived utility of various tests of infectious diseases. STUDY DESIGN Online surveys were sent to all 154 offices of US medical examiners and coroners serving populations >300,000 people. Surveys included a set of potential laboratory tests for infectious disease. Respondents were asked to select which tests were available in their offices, and which tests were performed routinely in SUIDs vs which tests should be performed routinely. RESULTS Of the 45 complete responses, 4.4% did not routinely perform histology, 8.9% did not routinely perform viral studies (ie, culture or molecular diagnostics), 22.2% did not routinely perform blood cultures, 26.7% did not routinely perform lung bacterial cultures, and 44.4% did not routinely perform cerebrospinal fluid cultures. CONCLUSIONS Our findings suggest that there is considerable interoffice variability with testing for infectious diseases in SUIDs. This appeared to be largely the result of a perceived lack of testing utility rather than a lack of test availability. Evidence-based practice guidelines regarding the interpretation of microbial testing results, as well as common testing protocols/algorithms, may lead to more accurate and standardized data, thus improving SUID investigation and surveillance.

From Death to Death Certificate: What do the Dead say?

This is an overview of medicolegal death investigation and death certification. Postmortem toxicological analysis, particularly for ethanol and drugs of abuse, plays a large role in the forensic investigation of natural and unnatural deaths. Postmortem drug concentrations must be interpreted in light of the autopsy findings and circumstances. Interpretations of drug and ethanol concentrations are important for death certification, but they also may be important for other stakeholders such as police, attorneys, public health practitioners, and the next-of-kin.

Co-sleeping and suffocation.

As death is a functional event, forensic pathologists continue to be challenged by deaths with few or no anatomic findings. Toxicologists, and most-recently, molecular biologists have improved our diagnostic acumen, but certain sudden infant deaths continue to bewitch us. These deaths have occurred for millennia and even include the biblical judgment of Solomon: ‘‘this woman’s child died in the night; because she overlaid it’’ (Kings 3,19). For decades the pendulum of the explanation of these deaths has swung from asphyxia to various diseases or syndromes. A litany of diseases, and even normal anatomic findings (e.g., an ‘‘enlarged’’ thymus), have littered the certification landscape. Davis noted that the need for circumstantial details bears an inverse relationship to the extent of disease revealed by autopsy [1]. With a thorough investigation, many of these can be properly certified, but not all [2, 3]. After exclusion of disease and overt injury, the forensic pathologist is typically faced with three options for death certification: sudden infant death syndrome (SIDS), some form of asphyxia, and undetermined. As Nashelsky and Pinckard noted, there are ‘‘unequivocal accidental asphyxia deaths based on compelling scene information’’ as well as a ‘‘gray zone of possible asphyxia deaths based on environmental risk factors but without definite overlaying or entrapment’’ [4]. These ‘‘gray’’ instances and the deaths that occur in ‘‘safe’’ sleeping environments, both with a negative autopsy, can be the most challenging (and often frustrating) for the forensic pathologist. The key question with these ‘‘gray’’ deaths is whether an asphyxia-generating sleep environment by itself is a compelling enough circumstance to certify the death as asphyxial. There undoubtedly are unrecognized pathophysiologic defects that result in the sudden death of an infant in a safe sleeping environment. The causes of some of these deaths have been teased out as channelopathies or metabolic disorders but not all [5, 6]. Despite advances in scientific knowledge, we still must humbly recognize our scientific limitations and admit that there are physiologic/ response defects and diseases of which we are unaware. To that end, it is important to have nomenclature to track them. As it is unlikely that an unknown ‘‘physiologic defect’’ only has its lethal effect while the infant is in a safe sleeping environment, the assumption that all bed-sharing deaths are asphyxia-related should be resisted as sequence does not always imply consequence [7]. In addition, there are an untold but innumerable number of infants who intermittently or continuously bed share and survive the experience. There is a benefit to distinguish sudden infant deaths with negative autopsies that occur in benign sleep environments (SIDS/Natural) from those ‘‘gray’’ cases that occur in less safe environments. Until scientific advances help us to better understand and classify these deaths, a reasonable approach is to include circumstantial details on the death certificate in these equivocal ‘‘gray’’ deaths such as: sudden unexplained infant death (bed sharing with adult) with an undetermined manner of death. This says it like it is and provides public health researchers with potentially more useful information than ‘‘undetermined’’. Hopefully, our scientific advances and forensic investigations will continue to allow us to empty the dustbins. J. R. Gill (&) State of Connecticut Office of the Chief Medical Examiner, 11 Shuttle Rd, Farmington, CT 06032, USA e-mail: jgill@ocme.org

Epstein-Barr virus RNA detection and glandular differentiation in nasopharyngeal carcinoma: report of 2 cases.

Most tumors arising in the nasopharynx are either squamous cell carcinoma or so-called undifferentiated carcinoma of the nasopharyngeal type. Primary adenocarcinomas of the nasopharynx are rare, and glandular differentiation in undifferentiated carcinoma of the nasopharyngeal type has not been reported to date. We report 2 cases of undifferentiated carcinoma of the nasopharyngeal type that show distinct glandular differentiation by light microscopy, histochemistry, immunohistochemistry, and ultrastructure. Both tumors showed equal positivity for Epstein-Barr virus latent membrane protein and in situ hybridization for Epstein-Barr virus genome in the undifferentiated areas of the tumor and those featuring glandular differentiation.

Pediatric Nonalcoholic Fatty Liver Disease in New York City: An Autopsy Study

Objective To assess the prevalence and severity of nonalcoholic liver disease (NAFLD) in children in a diverse population sample in New York City. Study design Liver specimens were examined from children 2‐19 years old who died of unexpected causes within 48 hours of medical presentation and underwent autopsy in New York City from 2005 to 2010. Records were reviewed for age, sex, weight, height, and race. Two hepatopathologists evaluated each liver specimen to determine pathologic diagnosis. Results The final study cohort (n = 582) was 50% black, 33% Hispanic, 12% white, 3% Asian, and 2% other; 36% had a body mass index >85%. There were 26 cases of NAFLD (4.5%) of which 10 had nonalcoholic steatohepatitis (1.7%). There were no cases with severe fibrosis or cirrhosis. One percent (3/290) of black children had NAFLD and none had nonalcoholic steatohepatitis. White and Hispanic children had the highest percentages of NAFLD at 8.3% and 7.9%, respectively. In multiple logistic regression models, we observed that body mass index z‐score (P < .001) was associated with NAFLD, and that white (P = .003) and Hispanic (P = .005) children had higher odds of having NAFLD compared with black children. Conclusions This review of liver tissue demonstrates a lower prevalence and severity of NAFLD in black children compared with the general obese pediatric population. Hispanic children did not have a significantly increased rate of NAFLD compared with white children, most likely related to the large proportion of Caribbean Hispanic children in New York City.