Current perspective new insights into the molecular basis of familial dilated cardiomyopathy.

Genetic disease transmission has been identified in a significant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, as well as recent molecular genetic data, indicate the existence of several genes causing the disease. Several distinct subtypes of familial DCM have been identified. Autosomal dominant DCM is the most frequent form (56% of our cases), and several candidate disease loci have been identified by linkage analysis. Three disease genes are presently known: the cardiac actin gene, the desmin gene, and the lamin A/C gene. This latter gene has recently been found to be responsible for both the autosomal dominant form of DCM with subclinical skeletal muscle disease (7.7% of cases) and the familial form with conduction defects (2.6% of cases) or the autosomal dominant variant of Emery-Dreifuss muscular dystrophy. The autosomal recessive form of DCM accounts for 16% of cases and is characterized by a worse prognosis. An X-linked form of DCM (10% of cases) manifests in the adult population and is due to mutations in the dystrophin gene. In the rare infantile form of DCM, mutations in the G4.5 gene have been identified. Finally, some of the rare unclassifiable forms (7.7% of cases) may be due to mitochondrial DNA mutations. Clinical and experimental evidence based on animal models suggest that, in a large number of cases, DCMs are diseases of the cytoskeleton. However, other causes, such as alterations in regulatory elements and in signaling molecules, are possible. Moreover, other genes called modifier genes can influence the severity, penetrance, and expression of the disease, and they will be a main objective of future investigations. Familial DCM is frequent, cannot be predicted on a clinical or morphological basis and requires family screening for identification. The advances in the genetics of familial DCM can allow improved diagnosis, prevention and genetic counseling, and represent the basis for the development of new therapies.

Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement.

BACKGROUND: Dilated cardiomyopathy is a form of heart muscle disease characterized by impaired systolic function and ventricular dilation. Familial transmission of the disease is frequently observed, and genetic heterogeneity is indicated by clinical and morphological variability in the disease phenotype. In the family MDDC1 reported here, the disease phenotype is severe and characterized by an autosomal dominant pattern of transmission. In addition, the majority of affected family members show signs of mild skeletal muscle involvement. METHODS AND RESULTS: On the basis of the clinical observation of both cardiac and skeletal muscle abnormalities in the MDDC1 family, the lamin A/C gene was examined in this kindred. Coding regions were polymerase chain reaction-amplified from genomic DNA and sequenced. A single nucleotide deletion was identified within exon 6, and all affected individuals were found to be heterozygous for this deletion. CONCLUSIONS: Heterozygosity for a single nucleotide deletion in exon 6 of lamin A/C segregates with both the cardiac and skeletal abnormalities observed in the MDDC1 family.

Bias in the assessment of family history of melanoma and its association with dysplastic nevi in a case-control study.

Family history of melanoma is an important risk factor for both melanoma and, it is thought, dysplastic nevi. However, assessment of family history of melanoma in epidemiologic investigations has typically been limited to interview of the proband. As part of a case-control study of dysplastic nevi, we attempted to confirm family histories. We disproved about half of the reported family histories of melanoma among first-degree relatives, and confirmed them by medical records in only 17%. Few family histories pertaining to other relatives could be confirmed. We documented the association of melanoma family history with dysplastic nevus risk, and we further documented a substantially greater odds ratio for this association when history was based on confirmation by medical records, compared to confirmation by proband interview only. The bias thus documented must be considered in evaluating the many published epidemiologic studies of melanoma and related disorders. Future research should attempt to confirm family histories of melanoma whenever possible, despite the practical difficulties.

Reliability of the histopathologic diagnosis of melanocytic dysplasia. The Dysplastic Nevus Panel.

OBJECTIVE: To determine the reliability of the histopathologic diagnosis of melanocytic dysplasia among diverse dermatopathologists who had no joint training, agreed to abide by predetermined criteria, and who were provided reference photomicrographs illustrative of the criteria. DESIGN, SETTING, AND PARTICIPANTS: A stratified random sample of 112 melanocytic tumors were chosen from the files of the pathology department of a large staff-model health maintenance organization. The original diagnoses included typical and dysplastic melanocytic nevi and melanoma. A single representative slide for each case was interpreted independently by each of the 5 panel dermatopathologists and 2 melanoma specialists. They had no prior knowledge of the original diagnosis or the diagnoses of the other panel members. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Interrater reliability was measured by intraclass and Pearson correlation coefficients. Each case was graded on a 5-point scale from no dysplasia to melanoma. RESULTS: The intraclass correlation among the panel members was 0.67 (95% confidence interval, 0.59-0.73). The Pearson correlations of each of the 5 panel dermatopathologists with the mean of the 2 melanoma specialists ranged from 0.67 to 0.84, and the correlations of the mean of the panel with the 2 melanoma specialists were 0.79 and 0.82; the mean reading of the melanoma specialists correlated 0.89 with the mean panel reading. Apparent protocol violations occurred in 6.5% of the readings. CONCLUSIONS: Agreement was substantial to excellent for the histopathologic diagnosis of 112 melanocytic tumors by dermatopathologists. Using predetermined criteria, melanocytic dysplasia can be reproducibly graded among diverse general dermatopathologists.

Multifocal adenocarcinoma in situ with underlying carcinoid tumor of the gallbladder.

We describe a case of combined multifocal carcinoma in situ and carcinoid tumor of the gallbladder. Morphologic and immunohistochemical studies revealed two distinct neoplastic patterns without clear evidence of transition between the two processes.

Pathology of bladder carcinoma.

Pathologists play an important role in the evaluation of bladder carcinomas. They are responsible for the diagnosis of the tumor and its categorization, grading, and staging, all of which guides urologists and oncologists in subsequent management. There are considerable differences of opinion as to the categorization and grading of papillary neoplasms, which represent the largest subset of bladder biopsy pathologic specimens.

Pathology of testicular germ cell tumors.

The pathology report on a testicular germ cell tumor should include the following information: Tumor type: The histologic type of tumor present. If the tumor is of mixed type, the components should be listed, in order of relative abundance. The pathologist may endeavor to give a numeric estimate of the percentages of each element. Staging information: The size of the tumor should be listed. Local spread--into rete testis, tunica albuginea, epididymis, and spermatic cord--should be listed. If the cord is involved, possible involvement of its surgical resection margin should be assessed. Vascular/lymphatic invasion should be assessed for its presence or absence. Status of the remainder of the testis: Evidence of cryptorchidism or other dysgenetic features should be mentioned. Such features may imply a greater risk for the development of a contralateral tumor. Also, the presence of normal spermatogenesis elsewhere in the uninvolved testis should be reported. This finding may suggest a relatively decreased risk for contralateral tumor development and is a likely indicator of fertility should the patient consider sperm banking prior to retroperitoneal surgery and chemotherapy. The finding of mature sperm in the epididymis is an easy way to confirm spermatogenesis in the testis. Incidental findings: Lipomas or hydroceles of the cord, adrenal rests, and adnexal cysts may be found. The pathologist plays a crucial role in the diagnosis of germ cell tumors. In addition to elucidating tumor type, the pathologist is relied upon for precise local staging and for the classification of metastases, all of which have important implications in determining optimal therapy. As the clinical management of germ cell tumors evolves, the pathologist will continue to play a role in defining those features that have a bearing on patient outcome.

Stage I nonseminomatous germ cell testicular tumor: prediction of metastatic potential by primary histopathology.

A study of 60 patients with clinical stage I nonseminomatous germ cell testicular tumor (NSGCT) was conducted to identify prognostic factors that may predict the likelihood of metastasis. Clinical features and histopathologic features of the primary testicular tumor were examined and analyzed for correlations with the presence of retroperitoneal nodal metastasis documented by surgery (N+) and with development of relapse (R+). Pathologic tumor stage greater than or equal to 2, with tumor extension into the tunica albuginea, rete testis, epididymis, or spermatic cord, was correlated with an increased rate of N+ compared with pathologic tumor stage I (P = .001). Vascular invasion was correlated with a higher rate of N+ (P = .05) and had a similar association with R+ (P = .08). Tumors containing less than 50% teratoma were found to have a higher rate of N+ than tumors with greater than or equal to 50% teratoma (P = .02). Based on the identified prognostic factors, a model for predicting the probability of retroperitoneal nodal metastasis in clinical stage I patients is proposed. The risk factors for nodal metastasis are: pathologic tumor stage greater than or equal to 2, vascular invasion, and less than 50% teratoma. Patients with none of the risk factors are considered at low risk and may be offered orchiectomy alone with surveillance for initial treatment. Patients with all three risk factors are at high risk and should be treated with a retroperitoneal lymph node dissection (RPLND) or possibly chemotherapy. Patients with one or two risk factors are at intermediate risk; it is recommended that they undergo RPLND. This risk model facilitates a rational approach to the management of clinical stage I NSGCT.

Metal ion blockage of tritium incorporation into gamma-carboxyglutamic acid of prothrombin. Stoichiometry of gamma-carboxyglutamic acid to Gd3+ for the high affinity sites.

Prothrombin possesses two high affinity and four low affinity gamma-carboxyglutamic acid (Gla)-dependent gadolinium binding sites. Earlier work (Price, P. A., Williamson, M. K., and Epstein, D. J. (1981) J. Biol. Chem. 256, 1172-1176) has shown that tritium can be specifically incorporated at the gamma-carbon of Gla in proteins at pH 5. In the present work we show that inclusion of saturating concentrations of Ca2+ in nondenaturing buffer systems ranging from pH 5.5 to 8.5 prevents the exchange of tritium into all 10 Gla residues of prothrombin. Similarly, saturating concentrations of Gd3+ prevent tritium incorporation into Gla at pH 5.5. Positive cooperativity was observed for the binding of Gd3+ to human prothrombin (at pH 5.5) for the two high affinity sites (Kd congruent to 35 nM). The four low affinity sites bind Gd3+ with a Kd congruent to 5 microM. Incubation of prothrombin ranging in concentrations from 10 to 40 microM with 2 eq of Gd3+ at pH 5.5 prevents 5.7 (average of seven determinations) Gla residues from tritium incorporation. Sedimentation velocity experiments conducted at pH 5.5 indicate that prothrombin in the presence of saturating concentrations of Gd3+ polymerizes, most likely, to a trimer. Further, in the presence of 2 eq of Gd3+, calculated percent weight average concentration of monomer prothrombin is congruent to 100% at 10 microM, approximately equal to 95% at 20 microM, and congruento to 80% at 40 microM protein concentration. Thus, it appears that under conditions in which prothrombin primarily exists as a monomer, occupancy of the initial two metal binding sites by Gd3+ involves six Gla residues.

Management of patients with clinical stage I or II nonseminomatous germ cell tumors of the testis. Evolving therapeutic options.

Eighty patients with clinical stage I or II nonseminomatous germ cell tumors of the testis were managed with modified protocols, including modified nerve-sparing retroperitoneal lymph node dissection for patients with stage I cancer, retroperitoneal lymph node dissection for patients with low-volume stage II cancer, and initial chemotherapy with or without subsequent retroperitoneal lymphadenectomy for patients with high-volume stage II cancer. Patients with low-stage disease (clinical stage I) were treated successfully with modified retroperitoneal lymph node dissection (relapse rate, three of 40 patients). Clinical understaging was evidenced in 14 of 48 patients with clinical stage I disease who were found to have pathologic involvement of the retroperitoneal lymph nodes, including six patients with extensive retroperitoneal nodal involvement (pathologic stage B2). Of nine patients with retroperitoneal tumors less than 3 cm in diameter, four patients were satisfactorily treated with retroperitoneal lymph node dissection alone while five patients required chemotherapy after retroperitoneal lymph node dissection. Of 26 patients with retroperitoneal tumors 3 to 5 cm in diameter, 17 patients were treated with chemotherapy alone. All patients remain free of disease after the completion of definitive therapy. We conclude that therapeutic options should be modified based on histologic factors in the primary tumor, extent of retroperitoneal disease as indicated on a computed tomographic scan, and presence or absence of elevated tumor markers. By consideration these factors, optimum therapy can be selected to achieve the highest long-term survival rate with the least morbidity.

Studies of nontraumatic osteonecrosis. The role of core decompression in the treatment of nontraumatic osteonecrosis of the femoral head.

This study reports a five-year experience with core decompression for treatment of nontraumatic osteonecrosis of the femoral head. There were 25 patients (39 hips) with predominantly steroid-associated osteonecrosis followed postoperatively for a minimum of two years. All patients were evaluated functionally, roentgenographically, histologically, and hemodynamically. At latest follow-up examination, two of 12 hips (17%) with Stage I disease, seven of 12 hips (58%) with Stage IIA disease, four of four hips with Stage IIB disease, and nine of 11 hips (82%) with Stage III disease have progressed roentgenographically and/or clinically. A lack of correlation between pressure manometrics, venography, and clinical outcome in this study suggests that mechanisms other than progressive ischemia may be involved. Current indications for core decompression are Ficat Stage 0, I, and IIA (sclerotic predominant) disease.

Studies of nontraumatic osteonecrosis. Manometric and histologic studies of the femoral head after chronic steroid treatment: an experimental study in rabbits.

High-dose methylprednisolone was administered to adult rabbits over a five- to nine-week period, according to previously described experimental models of nontraumatic osteonecrosis (NON). Manometric studies were performed using a sensitive computer-directed microvolume flow system. Osteocyte viability within the femoral head was assessed by counting empty osteocyte lacunae in five random high-power fields of hematoxylin- and eosin-stained sections. There was no significant elevation of intramedullary pressure or venous outflow resistance in femoral heads of animals receiving steroids, and a significant random loss of osteocytes was observed in these femoral heads. The clinical relevance of these studies is as follows. NON associated with steroids may not simply be the result of progressive ischemia. Ischemia and elevated intramedullary pressure may be epiphenomena, and a direct cytotoxic effect of steroids on osteocytes may be the earliest event in the development of nontraumatic osteonecrosis. The stress test, as it is currently being used in the clinical setting, may be unreliable.

Adenolymphoma with massive necrosis and squamous metaplasia.

A 61-year-old female presented with a longstanding parotid mass with recent change in size. Histologically, the mass was composed of extensively necrotic tissue with a peripheral rim of ribbons of epithelium. In one focus, a double layer of oxyphilic epithelium overlying a lymphoid stroma in a papillary configuration was present, establishing the diagnosis of adenolymphoma (AL). The possibility of infarction and/or infection complicating AL is discussed. In any parotid gland lesion clinically presenting as a longstanding tumor with recent change clinically suggestive of infarction and/or infection, the diagnosis of AL should be considered. In the pathologic specimen with extensive necrosis, areas of preserved epithelium and stroma should be searched for carefully to confirm the diagnosis.

Internal derangements of the temporomandibular joint: diagnosis by direct sagittal computed tomography.

The authors performed direct sagittal computed tomography (CT) on 4 cadaver temporomandibular joints (TMJ) and examined 51 TMJs in 47 patients clinically. The results were correlated with cadaver anatomical sections and clinical arthrographic findings. A fat plane between the bellies of the lateral pterygoid muscles, termed the "lateral pterygoid fat pad," served as the anatomical basis for detection of internal derangements by CT. CT was 94% accurate in detecting meniscal derangements and 96% accurate in detecting degenerative arthritis. The authors suggest that CT rather than arthrography be employed as the primary TMJ imaging modality when internal derangement or arthritis is suspected.

An immunohistochemical study of a carcinoma of the parotid gland exhibiting both ductal and acinic cell differentiation.

A 76-year-old man underwent a subtotal parotidectomy for removal of a 3 cm. multicystic mass. The tumor was a salivary gland carcinoma, with both infiltrating and intraductal/intra-acinar components, exhibiting three histologic patterns: cribriform, papillary, and comedo-like. Immunohistochemical stain for keratin by the immunoperoxidase technique was strongly reactive in the vast majority of the tumor cells, indicating ductal differentiation of the tumor. Ultrastructural studies indicated primarily ductal differentiation of the tumor cells, with additional areas of acinous and myoepithelial differentiation.