Unusual patterns of Histoplasma capsulatum meningitis and progressive multifocal leukoencephalopathy in a patient with the acquired immunodeficiency virus.

Disseminated histoplasmosis (DH) and progressive multifocal leukoencephalopathy occur in acquired immunodeficiency syndrome (AIDS). At autopsy, DH patients with central nervous system involvement almost always show extensive involvement of the lungs and reticuloendothelial system in addition to the brain, and progressive multifocal leukoencephalopathy is manifest as multiple demyelinating lesions in several locations in the brain. We describe an AIDS patient with a long history of aggressively treated DH who died with DH in the brain only; fungus was not found elsewhere at autopsy. In addition, there was a papovavirus infection restricted to the cerebellum with predominant involvement of the internal granular cell layer; again, demyelinating lesions were not found elsewhere in the brain. Each of these patterns of brain involvement is rare. As the incidence of AIDS increases and patients are treated aggressively, the frequency of unusual neuropathologic patterns of opportunistic infections may be expected to increase.     

Giant cell myocarditis after mitral valve replacement: case report and studies of the nature of giant cells

A 22-year-old man with Marfan's syndrome and a history of antinuclear antibody-positive hepatitis died 25 days after undergoing cardiac valve replacement surgery for mitral valve prolapse. Giant cell myocarditis was found at autopsy. The multinucleated giant cells were shown by immunoperoxidase techniques to contain lysozyme, but not myosin or creatine phosphokinase, suggesting that they were derived from macrophage, rather than myocyte, precursors.     

Lack of allelic loss at the multiple endocrine neoplasia type 1(MEN-1) gene locus in a pancreatic ductal (non-endocrine) adenocarcinoma of a patient with the MEN-1 syndrome

The gene responsible for multiple endocrine neoplasia type I (MEN-1) syndrome has been mapped to chromosome 11q13. It appears to function as a tumour-suppressor gene analogous to that for retinoblastoma and allelic losses involving the wild-type of the MEN-1 allele have been found in parathyroid and pancreatic endocrine tumours of MEN-1 patients. No genetic information has been provided so far on non-endocrine malignancies that may occur in MEN-1 patients. A case of exocrine pancreatic adenocarcinoma presenting as the terminal event in a woman with a long standing history of MEN-1 syndrome and multiple endocrine tumours of the pancreas was investigated for possible allelic losses at the MEN-1 gene locus using restriction fragment length polymorphisms (RFLPs) closely linked to the MEN-1 gene and polymerase chain reaction (PCR) for D11S533 locus. No allelic losses were found in tumour tissue with two informative RFLPs (D11S97, D11S146) or with PCR analysis. These findings suggest that the MEN-1 gene does not confer a predisposition to develop tumours other than those that typify the syndrome.     

Von Recklinghausen's Disease Associated with Somatostatin-rich Duodenal Carcinoid (Somatostatinoma), Medullary Thyroid Carcinoma and Diffuse Adrenal Medullary Hyperplasia

This report describes the concomitant occurrence of a somatostatin-rich duodenal carcinoid, a medullary thyroid carcinoma and a diffuse adrenal medullary hyperplasia in a patient with von Recklinghausen's disease. A 50-year-old Japanese man died from lung metastasis of a malignant schwannoma. In addition to extensive viscero-cutaneous neurofibromatosis, two different types of neuroendocrine tumors were found in the duodenum and thyroid gland at autopsy. The duodenal tumor, which was located in the second portion, showed the histologic appearance of a carcinoid tumor with glandular differentiation and psammoma-bodies. Immunohistochemically the tumor cells were intensely positive for somatostatin. The thyroid tumor was composed of nests of tumor cells arranged in an endocrine pattern, and showed immunoreactivity for calcitonin. A review of the literature revealed no previously reported case of concomitant occurrence of duodenal somatostatinoma and medullary thyroid carcinoma in a single patient with von Recklinghausen's disease. Morphometric analysis of adrenal glands disclosed the presence of diffuse medullary hyperplasia. Thus, the present case exhibited a similarity in some respects with multiple endocrine neoplasia (MEN) syndrome, Type Ila or IIb.     

von Recklinghausen's disease associated with somatostatin-rich duodenal carcinoid (somatostatinoma), medullary thyroid carcinoma and diffuse adrenal medullary hyperplasia.

This report describes the concomitant occurrence of a somatostatin-rich duodenal carcinoid, a medullary thyroid carcinoma and a diffuse adrenal medullary hyperplasia in a patient with von Recklinghausen's disease. A 50-year-old Japanese man died from lung metastasis of a malignant schwannoma. In addition to extensive viscero-cutaneous neurofibromatosis, two different types of neuroendocrine tumors were found in the duodenum and thyroid gland at autopsy. The duodenal tumor, which was located in the second portion, showed the histologic appearance of a carcinoid tumor with glandular differentiation and psammoma-bodies. Immunohistochemically the tumor cells were intensely positive for somatostatin. The thyroid tumor was composed of nests of tumor cells arranged in an endocrine pattern, and showed immunoreactivity for calcitonin. A review of the literature revealed no previously reported case of concomitant occurrence of duodenal somatostatinoma and medullary thyroid carcinoma in a single patient with von Recklinghausen's disease. Morphometric analysis of adrenal glands disclosed the presence of diffuse medullary hyperplasia. Thus, the present case exhibited a similarity in some respects with multiple endocrine neoplasia (MEN) syndrome, Type IIa or IIb.     

Surgery to cure the Zollinger-Ellison syndrome.

BACKGROUND AND METHODS: The role of surgery in patients with the Zollinger-Ellison syndrome is controversial. To determine the efficacy of surgery in patients with this syndrome, we followed 151 consecutive patients who underwent laparotomy between 1981 and 1998. Of these patients, 123 had sporadic gastrinomas and 28 had multiple endocrine neoplasia type 1 with an imaged tumor of at least 3 cm in diameter. Tumor-localization studies and functional localization studies were performed routinely. All patients underwent surgery according to a similar operative protocol, and all patients who had surgery after 1986 underwent duodenotomy. RESULTS: The 151 patients underwent 180 exploratory operations. The mean (+/-SD) follow-up after the first operation was 8+/-4 years. Gastrinomas were found in 141 of the patients (93 percent), including all of the last 81 patients to undergo surgery. The tumors were located in the duodenum in 74 patients (49 percent) and in the pancreas in 36 patients (24 percent); however, primary tumors were found in lymph nodes in 17 patients (11 percent) and in another location in 13 patients (9 percent). The primary location was unknown in 24 patients (16 percent). Among the patients with sporadic gastrinomas, 34 percent were free of disease at 10 years, as compared with none of the patients with multiple endocrine neoplasia type 1. The overall 10-year survival rate was 94 percent. CONCLUSIONS: All patients with the Zollinger-Ellison syndrome who do not have multiple endocrine neoplasia type 1 or metastatic disease should be offered surgical exploration for possible cure.     

Early diagnosis of multiple endocrine neoplasia type IIa

Summary We report on incidental findings during family screening of two kindreds with multiple endocrine neoplasia type IIa. Pheochromocytoma and medullary thyroid carcinoma of considerable size were detected. The results underline the importance of early diagnosis of the syndrome, since the afflicted may be almost or wholly asymptomatic. High resolution chromosome banding studies were carried out in both families, but no abnormality was found. Linkage analysis using DNA markers closely related to the chromosomal locus at chromosome 10 was carried out and was positive in two asymptomatic offspring of one family, whereas the markers were not informative in a second family. We recommend early linkage analysis for establishing the genetic status in offspring of multiple endocrine neoplasia type IIa families to identify for further screening those who are predicted to be gene carrier.Abbreviations MEN Multiple endocrine neoplasia - Q-Banding=QFQ-Banding Q-bands labeled by quinacrine florescence using quinacrine staining - R-Banding=RBA-Banding R-bands labeled by BrdU incorporation and acridine-orange staining - BrdU Bromodeoxyuridine - RFLP Restriction fragment length polymorphism - MIBG Metaiodobenzylguanidine     

Chromosome 22q11 deletion complicated by dissecting pulmonary arterial aneurysm and jejunal atresia in an infant

We present an autopsy case of a 46-day-old male infant with chromosome 22q11 deletion, which is considered the primary cause of several diseases, including DiGeorge syndrome and velocardiofacial syndrome. The patient had 2 notable congenital abnormalities: multiple dissecting pulmonary arterial aneurysms distributed in both lungs and multiple jejunal atresia with apple-peel deformity. The former, a very rare pathologic condition especially in infancy, was found incidentally at autopsy and was the primary cause of death. To our knowledge, neither of these lesions has been reported previously in a patient with chromosome 22q11 deletion.     

Aicardi syndrome,metastatic angiosarcoma of the leg,and scalp lipoma

An infant girl with Aicardi syndrome, scalp lipomas, and angiosarcoma of a limb is reported. The cavernous hemangioma of the leg was benign when biopsied at age 5 months but became malignant at 11 months. Angiosarcoma caused multiple distant metastases which were evident at autopsy at age 19 months. This is the first case of Aicardi syndrome associated with lipoma and metastatic angiosarcoma. © 1993 Wiley-Liss, Inc.     

Churg-Strauss syndrome and sudden cardiac death.

Churg-Strauss syndrome is a rare disorder characterized by necrotizing vasculitis, granulomas with eosinophilic necrosis, and tissue infiltration by eosinophils. Sudden cardiac death is rarely described in Churg-Strauss syndrome. In this article, we describe a case of Churg-Strauss syndrome with multiorgan involvement manifested as sudden cardiac death. To the best of our knowledge, this form of presentation has not been reported. A 49-year-old woman was found dead in her room. No premonitory complaints had been noted during the days preceding her death. Past medical history did not reveal any relevant illness. At autopsy, multiorganic Churg-Strauss syndrome with prominent cardiac involvement was found. Therefore, this syndrome in the active vasculitic phase may be asymptomatic and may involve predominantly the heart. This variant of the syndrome may be fulminant and present as sudden cardiac death. This form can only be elucidated by autopsy study.     

Pulmonary tumor thrombotic microangiopathy associated with extramammary Paget's disease: An autopsy case report

Pulmonary tumor thrombotic microangiopathy (PTTM) is histologically characterized by micro tumor cell embolism and intimal fibrocellular proliferation of pulmonary arteries or arterioles. We report a secondary case of PTTM associated with extramammary Paget's disease (EMPD). The patient was a 72‐year‐old man with exertional dyspnea. Clinical examinations found he had pulmonary hypertension and multiple osteolytic lesions of vertebra. Cytological analysis of pulmonary wedge artery sample detected malignant cells and he was dead before treatment was started. Multiple tumor embolisms (>17) were identified in pulmonary arteries or arterioles at autopsy, consistent with PTTM. Metastatic nodules were found in liver and lymph node. Furthermore, disseminated carcinomatosis of the bone marrow (DCBM) was seen. Immunostaining results pointed out that tumor cells possessed mammary gland phenotype. He had 4‐years history of EMPD in the left axilla without recurrence, and immunohistochemistry results were the same as the autopsy specimen. Thus, we diagnosed the primary site of PTTM to be EMPD. Our case highlights the usefulness of the recent proposed classification of PTTM, potential association between PTTM and DCBM, and the necessity for long‐term follow‐up in EMPD. EMPD can rarely cause PTTM to manifest as a paraneoplastic syndrome.     

Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension

Pulmonary hypertension (pHTN) is a severe, life‐threatening disease, which can be idiopathic or associated with an underlying syndrome or genetic diagnosis. Here we discuss a patient who presented with severe pHTN and was later found to be compound heterozygous for pathogenic variants in the NFU1 gene causing multiple mitochondrial dysfunctions syndrome 1 (MMDS1). Review of autopsy slides from an older sibling revealed the same diagnosis along with pulmonary findings consistent with a developmental lung disorder. In particular, these postmortem, autopsy findings have not been described previously in humans with this mitochondrial syndrome and suggest a possible developmental basis for the severe pHTN seen in this disease. Given the rarity of patients reported with MMDS1, we review the current state of knowledge of this disease and our novel management strategies for pHTN and MMDS1‐associated complications in this population.     

Ovarian strumal carcinoid in association with multiple endocrine neoplasia, type IIA.

Strumal carcinoid is an unusual form of monodermal ovarian teratoma with thyroid-like follicles admixed with typical carcinoid tumor patterns. We encountered a case of this neoplasm in a patient with multiple endocrine neoplasia, type IIA (Sipple's syndrome), including a medullary thyroid carcinoma diagnosed 24 years previously. During evaluation of bilateral adrenal pheochromocytomas, a unilateral left ovarian strumal carcinoid was discovered. Subsequently, the patient had a parathyroid adenoma excised. The ovarian tumor was immunohistochemically reactive for neuron-specific enolase, chromogranin, synaptophysin, and serotonin, but did not stain for calcitonin. The follicular structures stained for thyroglobulin. This unusual case shows that ovarian strumal carcinoid, like carcinoid tumors at other sites, may arise in association with multiple endocrine neoplasia.     

Primary hyperparathyroidism in multiple endocrine neoplasia type 1: when to perform surgery?

Primary hyperparathyroidism is a common endocrinological disorder. In rare circumstances, it is associated with familial syndromes, such as multiple endocrine neoplasia type 1. This syndrome is caused by a germline mutation in the multiple endocrine neoplasia type 1 gene encoding the tumor-suppressor protein menin. Usually, primary hyperparathyroidism is the initial clinical expression in carriers of multiple endocrine neoplasia type 1 mutations, occurring in more than 90% of patients and appearing at a young age (20-25 years). Multiple endocrine neoplasia type 1/primary hyperparathyroidism is generally accompanied by multiglandular disease, clinically manifesting with hypercalcemia, although it can remain asymptomatic for a long time and consequently not always be recognized early. Surgery is the recommended treatment. The goal of this short review is to discuss the timing of surgery in patients when primary hyperparathyroidism is associated with multiple endocrine neoplasia type 1.     

Multiple endocrine neoplasia type 1-associated thyrotropin-producing pituitary carcinoma: report of a probable de novo example

Pituitary carcinomas are exceedingly rare. At present, the sole diagnostic criterion is metastatic spread, either craniospinal or systemic. There is no agreement on a histologic, immunohistochemical, and/or ultrastructural definition. We report a clinically and morphologically well-documented example of pituitary thyrotropin cell carcinoma in a man with multiple endocrine neoplasia type 1 syndrome. The tumor produced thyrotropin, alpha-subunit, and prolactin and, through electron microscopy, was found to consist solely of Thyrotroph cells. Over a protracted course, craniospinal and systemic metastases were noted. The primary and metastatic deposits of this aggressive tumor were studied. To our knowledge, this tumor is the first reported case of thyrotropin cell carcinoma occurring in association with the multiple endocrine neoplasia type 1 syndrome. The literature regarding thyrotropin carcinomas is reviewed. Based on the study of several biopsies during disease progression, we believe that the carcinoma originated de novo without an intermediary adenoma phase.     

Metastatic Medullary Carcinoma of Thyroid Presenting as a Dural-Based Mass: Case Report and Review of Literature

Dural metastasis from medullary thyroid carcinoma (MTC) is not well established in English literature. We present the case report of MTC with unusual clinical presentation as a dural-based mass in a 39-year-old male with no family history of multiple endocrine neoplasia syndrome. Magnetic resonance imaging showed an extra-axial dural-based mass in right frontal lobe with calvarium and soft tissue extension to the right superior orbit. Histopathology showed MTC with variegated morphology and various patterns. Thyroid mass and widespread metastases from medullary thyroid carcinoma were subsequently identified.     

Familial pheochromocytomas and paragangliomas: Stories from the sign-out room

In this overview we present five patients with apparently sporadic pheochromocytomas or paragangliomas which turned out to be associated with an inheritable familial disease. For each patient a family history together with clinical, morphological, as well as molecular data are reported. The identified syndromes include multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), and familial pheochromocytoma/paraganglioma syndrome (SDHx). A brief summary of phenotypes, the genes involved, and typical mutations in these syndromes is provided.     

Agenesis of the corpus callosum in Schinzel-Giedion syndrome associated with 47, XXY karyotype

The Schinzel-Giedion syndrome is a rare autosomal recessive condition with typical facial features, skeletal manifestations and congenital hydronephrosis and/or hydroureter. We report a male infant with Schinzel-Giedion syndrome, also showing the karyotypic abnormality 47, XXY. Agenesis of the corpus callosum and laryngeal stenosis were determined at autopsy. Besides typical Schinzel-Giedion syndrome, our propositus was found to be affected by Klinefelter syndrome. This represents a fortuitous anomaly, which is probably of no importance in the phenotype of the patient.     

Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1

Surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. Presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. Of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. Non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. The vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. The usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. Surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. Some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. Furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. Hepatic trans-arterial chemo-embolization is usually associated with surgical resection. Liver transplantation may be needed for select cases. Finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and localization of multiple endocrine neoplasia type 1 related tumors are crucial for determining the best surgical strategies in each individual case with pancreatic endocrine tumors.     

Autopsy findings in umbilical cord blood transplant recipients.

Human umbilical cord blood stem cells have been used to reconstitute hematopoiesis in patients with malignant and nonmalignant diseases. The immunologic immaturity of cord blood cells confers peculiar characteristics to these hematopoietic precursors. Autopsy reports from January 1, 1988, through June 30, 1998, were searched for patients who had received an umbilical cord blood transplant (UCBT). Thirty-two patients (19 male, 13 female) were identified with a mean age at autopsy of 13.0 years with a range from 1 to 52 years. Most patients (24) underwent UCBT for treatment of a malignant neoplasm, while the remainder were treated for immunodeficiencies (4), Lesch-Nyhan syndrome (2), Hurler syndrome (1), and Diamond-Blackfan syndrome (1). Sixteen patients had at least 1 infectious complication, and 8 patients had multiple infections. Organisms included mycoses (7 patients), viruses (8 patients), bacteria (3 patients), and Toxoplasma (2 patients). Hemorrhagic complications, such as intra-alveolar hemorrhage and gastrointestinal tract hemorrhage, were found in 24 patients. Other frequent findings at autopsy included diffuse alveolar damage (15 patients), hepatic veno-occlusive disease (11 patients), and acute or chronic graft-vs-host disease (9 patients). Patients who have received UCBT represent a unique population of immunosuppressed patients. Infectious and hemorrhagic complications frequently are encountered at autopsy, and pathologists performing autopsies on these patients should be alert to unusual pathogens.