Absence of BRAF mutations in UV-protected mucosal melanomas.

BACKGROUND: Mutations in BRAF have recently been identified in a significant percentage of primary and metastatic cutaneous malignant melanomas. As ultraviolet (UV) exposure may play a role in the development of cutaneous melanoma lesions with BRAF mutations, BRAF mutation frequency in melanomas arising in sites protected from sun exposure may be lower than those from sun-exposed areas. Thus, we determined the BRAF mutation frequency in a panel of 13 mucosal melanomas and compared those data with data from all currently published series of cutaneous melanomas. METHODS: BRAF exon 15 DNA from 13 archival primary mucosal melanomas (eight vulvar, four anorectal, and one laryngeal) was sequenced using intron-based primers. As archival DNA occasionally produces poor-quality template, results were confirmed with a TspRI restriction fragment length polymorphism (RFLP) that distinguishes wild-type BRAF from the common mutant form V599E. A binomial test was used to compare the mutation frequency in the mucosal melanomas with the published mutation frequency in cutaneous melanomas. RESULTS: None of the 13 mucosal melanomas in this series had an exon 15 BRAF mutation, as compared to 54/165 (33%) primary cutaneous melanomas with BRAF mutations in a compilation of all current published studies (p = 0.006). DISCUSSION: These data suggest that UV exposure, plays a role in the genesis of BRAF mutations in cutaneous melanoma, despite the absence of the characteristic C>T or CC>TT mutation signature associated with UV exposure, and suggests mechanisms other than pyrimidine dimer formation are important in UV-induced mutagenesis.

The lung in systemic lupus erythematosus. Analysis of the pathologic changes in 120 patients.

The nature and frequency of pulmonary involvement in systemic lupus erythematosus (SLE) is controversial. We reviewed the clinical and pathologic features of 120 patients with SLE described in autopsy records at The Johns Hopkins Hospital to determine the pulmonary parenchymal changes that could be attributed directly to SLE. Each case was reviewed to determine the extent of extrapulmonic SLE and possible alternative explanations for the observed lung pathology. Moderate or severe pulmonary parenchymal alterations that were attributed to SLE were found in 22 patients (18 percent). Five patients with interstitial fibrosis, two with pulmonary vasculitis, and one with pulmonary hematoxylin bodies were attributable only to SLE, as were 11 of 15 (73 percent) patients with interstitial pneumonitis. Alternative explanations for findings previously attributed to SLE included congestive heart failure, renal failure, infection, aspiration, oxygen toxicity and increased intracranial pressure. Alveolar hemorrhage, thought to be a feature of acute lupus pneumonitis, was unexplained in only two of 29 (7 percent) patients, alveolar wall necrosis was unexplained in one of seven (14 percent) and edema was unexplained in three of 70 (4 percent). Hyaline membranes, present in four patients, were always explained. Pleuritis and pleural effusions were attributed to SLE in 22 of 36 (61 percent) and three of 28 (11 percent) patients, respectively. The findings suggest that many nonspecific pulmonary lesions previously attributed to SLE, such as alveolar hemorrhage, alveolar wall necrosis, edema and hyaline membranes, are probably secondary to intercurrent infection, congestive heart failure, renal failure or oxygen toxicity.

Ara-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia.

Unexplained fatal pulmonary edema observed at autopsy in leukemic patients treated with cytosine arabinoside (Ara-C) suggested a possible role of the drug in causing increased alveolar capillary permeability. We reviewed clinical and pathologic features of the 181 patients with leukemia who were examined at autopsy at The Johns Hopkins Hospital in the past 12 years, 93 (51 percent) of whom had received intravenous Ara-C in doses of 7.5 to 30 mg/kg/day (average dose, 16 mg/kg/day). Fifty-one patients had received their last treatment within 30 days, and 42 patients between 31 and 894 days, prior to death. Among the 181 patients examined at autopsy 43 (24 percent) had massive edema, 59 (33 percent) had moderate edema, and 79 (44 percent) had either slight edema or no pulmonary edema. The 51 patients who had received Ara-C within 30 days of their death, compared to the other 130, had a highly significant increase in the frequency of pulmonary edema (p less than 0.001), which was massive in 24 and moderate in 18. In these 42 patients, causative or contributing factors that explained the edema were present in 14 (33 percent) of them, but in 28 (67 percent) there was no apparent explanation. In contrast, 60 of the 130 patients who had no or remote Ara-C therapy had massive (19 patients) or moderate (41 patients) pulmonary edema, which was explained in 55 (92 percent) and unexplained in only five (8 percent) (p less than 0.001). The unexplained pulmonary edema, a highly proteinaceous interstitial and intra-alveolar infiltrate, correlated with gastrointestinal lesions typical of Ara-C toxicity (p less than 0.001). Multivariate regression analysis showed that unexplained pulmonary edema was predicted by the recent administration of Ara-C, but by no other chemotherapeutic agent, including daunomycin, a potential cardiotoxin frequently given in conjunction with Ara-C. The study suggests that increased alveolar capillary permeability may result from the intravenous administration of cytosine arabinoside and that this complication should be considered when pulmonary edema develops in leukemic patients treated with Ara-C.

Gonadal morphology in patients receiving chemotherapy for leukemia. Evidence for reproductive potential and against a testicular tumor sanctuary.

To evaluate the possible reproductive potential in patients who receive chemotherapy for leukemia, we reviewed the gonadal histologic findings at autopsy in 183 treated leukemic patients and in 183 age- and sex-matched control subjects. The 103 male leukemic patients had significantly reduced spermatogenic activity and tubular fertility index and increased interstitial fibrosis as compared with control subjects (p less than 0.001). The 80 females had marked reduction of secondary follicles (p less than 0.001). These lesions showed no predilection for grouping by sexual maturity or by leukemia diagnosis. There was no correlation with the type of chemotherapy or time since last dose of any antileukemic agent. Despite these extensive pathologic changes, there was histologic evidence of residual reproductive potential--a tubular fertility index greater than zero in 65 percent of males and intact primary follicles in 81 percent of premenopausal females. Testicular leukemia was present in 25 percent of males; all of the patients with testicular leukemia had additional foci of leukemia in other organs. The study shows histologic evidence of possible reproductive potential in treated leukemic patients of both sexes and does not support the concept of the testis as a tumor sanctuary in leukemia.

Reexcision perineural invasion. Not a sign of malignancy.

Perineural invasion has been reported to occur in both benign and malignant neoplasms. We describe two cases in which perineural invasion by epithelial cells was present in reexcision skin specimens removed because of melanocytic lesions in the original biopsy material. Because of the absence of a primary epithelial neoplasm, this phenomenon was interpreted as a reactive or reparative process, most probably resulting from regenerating traumatized sweat gland ducts. On the basis of this study alone, it may not be possible to distinguish between reexcision perineural invasion and perineural invasion from a primary epithelial neoplasm. For such cases, the following histologic features serve as provisional guidelines favoring an interpretation of reexcision perineural invasion: absence of perineural spread beyond the immediate previous biopsy site, benign appearance of the perineural epithelial cells different from the appearance of the original tumor, and absence of residual epithelial tumor in the vicinity of the involved perineurium.

Pagetoid melanocytosis. Histologic features in benign and malignant lesions.

Pagetoid melanocytosis (PM), the upward discontinuous extension of melanocytes into the superficial epidermis, although generally considered a histologic feature of malignancy, may be seen in certain benign melanocytic lesions. To formulate the histologic criteria for distinction between benign and malignant PM, we examined 218 melanocytic tumors, including melanomas, Spitz nevi, nevi of palms and soles, pigmented spindle cell nevi, recurrent nevi, vulvar nevi, nevi of infancy and early childhood, and ordinary acquired nevi. We found PM to be present in 96% of melanomas, 38% of Spitz nevi, 61% of nevi of palms and soles, 20% of pigmented spindle cell nevi, 60% of recurrent nevi, 80% of vulvar nevi, and none of the ordinary acquired nevi. All the nevi of infancy and early childhood showed PM, but they had been selected for that feature. In melanomas, PM showed significant cellular atypia (81%), which was extensive and diffuse, and in 13% it extended laterally beyond the underlying junctional component. In the benign lesions, cellular atypia was generally absent, nor was lateral extension present, and PM was usually focal or multifocal rather than diffuse and not extensive. Although PM should be considered a tocsin for malignant melanoma, it may also occur in certain benign melanocytic lesions. Accurate interpretation depends on evaluation of all of the pertinent histologic and clinical findings.

Adenoid cystic carcinoma of the uterine cervix with malignant stroma. An unusual variant of carcinosarcoma?

An 80-year-old woman developed vaginal bleeding caused by a large tumor of the cervix. Histologically, the tumor proved to be composed predominantly of adenoid cystic carcinoma focally associated with squamous cell carcinoma. Of special interest was the stroma, which displayed pleomorphism, multinucleated tumor giant cells, and numerous mitoses, justifying the designation of carcinosarcoma. A single similar reported case also regarded as a carcinosarcoma described a primary cervical neoplasm in a postmenopausal woman containing an admixture of heterologous sarcoma and conventional cervical adenocarcinoma, which focally demonstrated areas of adenoid cystic carcinoma.

Breast carcinoma presenting with axillary lymph node metastases. An analysis of specific histopathologic features.

Forty-three patients with metastatic carcinoma in axillary lymph nodes from an unknown primary site were studied. Thirty-one women (72%) were subsequently identified as having primary carcinoma in the ipsilateral breast. Based on the histologic patterns of the metastasis, patients were divided into three groups. Type I axillary lymph node metastases were composed of sheets of large, apocrine-like pleomorphic cells with pale to granular pink cytoplasm, large nuclei, and prominent nucleoli. This type was found in two-thirds of the cases. Type II metastases were readily recognizable as characteristic of breast carcinoma and included glandular, cribriform, and papillary patterns and comedonecrosis. Type III metastases demonstrated a mixture of the two previous patterns. Patients proven to have breast carcinoma ranged in age from 33 to 83 (average 58). Among the 31 cases with proven breast carcinoma, mammography was abnormal in 11 (35%). In the 12 other cases (18%), no primary in the breast or other site was demonstrated. Patients not proven to have breast carcinoma had a similar age distribution, comparable proportions of histologic patterns of metastases, and similar survival results to those with a demonstrated breast carcinoma, and none of the 12 patients were later shown to have another primary. The findings described here indicate that when mammary carcinoma presents initially with axillary metastases, it often has a distinctive histological pattern. In most cases this consists of relatively large, apocrine-like cells growing diffusely without forming glands or papillary structures. A minority of metastases have patterns (comedonecrosis; trabecular, glandular, or trabecular growth) more characteristic of the usual spectrum of breast carcinoma. Awareness of this morphological diversity should assist the pathologist in suggesting the breast as a primary site when the initial manifestation is an axillary lymph node metastasis.

Basal cell carcinoma: clues to its presence in histologic sections when the initial slide is nondiagnostic.

Initial sections of skin biopsies may not be diagnostic of basal cell carcinoma (BCC). Are there histologic predictors of BCC that should prompt deeper sections? Ninety-four cases in which the clinical diagnosis was BCC or "rule-out BCC," and the initial histologic slides were nondiagnostic, were submitted for deeper sections on three additional slides. Of the 94 cases, 50 (53%) demonstrated BCC on deeper sections. This relatively high incidence suggests that deeper sections should be taken in all cases of clinically suspected BCCs unless alternate histologic findings adequately account for the clinical lesion. The results of this study suggest that additional sections are more likely to yield BCC when the initial nondiagnostic slide demonstrates focal epidermal atypia, equivocal adnexae, stromal fibrosis, empty dermal space, and microcalcifications, criteria which may be useful in determining the need to do deeper sections in cases in which BCC is not clinically suspected.

The heart and cardiac conduction system in polymyositis-dermatomyositis: a clinicopathologic study of 16 autopsied patients.

We reviewed the clinical records of 16 patients with polymyositis-dermatomyositis syndromes autopsied at The Johns Hopkins Hospital to determine the nature and extent of cardiac involvement and its correlation with the severity of disease as a whole. The adult patients ranged in age from 32 to 84 years (average 56); the 2 children were aged 2 and 10 years. The duration of disease ranged from 1 to 72 months (average 21). Seven patients had dermatomyositis, 5 had dermatomyositis with malignancy, 2 had childhood dermatomyositis, and 2 had an overlap syndrome. Seven patients had clinical evidence of congestive heart failure, 4 of whom had microscopic evidence of myocarditis. Two patients had bundle branch block; in 1 there was direct involvement of the conduction system by myositis and contraction band necrosis. Evidence of active myocarditis was present in 4 patients (25%); all had congestive failure. Focal myocardial fibrosis was present in 4 patients. Vascular alterations were present in the coronary arteries in 5 patients (31%). Three had active vasculitis, 1 had intimal proliferation, and 1 had medical sclerosis with calcification. All patients with active myocarditis had skeletal muscle involvement. Nine patients had myositis without myocarditis. There was no correlation of overall severity of the disease with the presence or absence of active myocarditis. The present study shows that cardiac involvement may be common in polymyositis; congestive failure or conduction abnormalities arising in this setting may be indicative of myocarditis.

Extension of donor criteria in cardiac transplantation: surgical risk versus supply-side economics.

To combat the continuing shortage of ideal donor hearts, we have used cardiac allografts from high-risk donors for critically ill recipients. We defined high-risk donor variables as age greater than 40 years, systemic (noncardiac) infection, cardiopulmonary resuscitation greater than 3 minutes, ischemic time longer than 5 hours, weight more than 20% less than that of the recipient, and requirements for high doses of inotropes. Of the 305 donors we have used, 73 (23.9%) have been high-risk, with 59/73 (80.8%) exhibiting one variable, 12/73 (16.4%) exhibiting two variables, and 2/73 (2.7%) exhibiting three variables. No correlation was found between the number of donor variables and a poor postoperative result. No infectious complications occurred in 17 patients receiving hearts from potentially infected donors. Hospital mortality rates (30 day) for recipients of high-risk donor versus non-high-risk donor hearts were 8.2% and 6.9%, respectively (not significant). The 1-, 6-, and 12-month actuarial survival rates were 91.7%, 81.2%, and 75.9% for the high-risk donor group and 93.5%, 80.3%, and 77.8% for the non-high-risk donor group (not significant). Among survivors with high-risk donor hearts, mean left ventricular ejection fractions were 0.54 +/- 0.08 at 3 months, 0.55 +/- 0.08 at 1 year, and 0.54 +/- 0.09 at 2 years after transplantation. These results suggest that accepting less than ideal donor hearts can be safe and might be considered when better options are not available.

Infarction of the spinal cord as a complication of pneumococcal meningitis. Case report.

Spinal cord infarction in association with pneumococcal meningitis has not been previously recognized. The case is reported of a 5 1/2-year-old boy who had Streptococcus pneumoniae meningitis complicated by the sudden onset of flaccid paraplegia and loss of all sensory modalities below the level of T-2. At operation, the spinal cord was pale and enveloped by dense adhesions, suggesting compromise of the arterial vasculature with concomitant infarction.

Asplenia and polysplenia malformation complexes explained by abnormal embryonic body curvature.

Asplenia and polysplenia malformation complexes characteristically have severe cardiovascular defects and visceral heterotaxy. We examined the hypothesis that the conditions may arise from an altered timing of development of embryonic body curvature: delayed in asplenia, accelerated in polysplenia. The morphologic features of the 25 patients with asplenia and 15 with polysplenia autopsied at The Johns Hopkins Hospital were determined. The time of appearance of various morphologic features and the evolution of body curvature was studied in 351 staged serially sectioned human embryos of The Carnegie Embryological Collection. All asplenia patients had severe atrioventricular canal malformations. Bilateral trilobed lungs were found in 12 patients. The polysplenia patients had severe interatrial septal defects in 10 patients; but ventricular septal defects in only six. Bilateral bilobed lungs were seen in five patients. Comparison of the time of appearance of anatomic structures in normal embryos with the observed malformations suggest that asplenia and polysplenia complexes originate in stages 13 to 15. The observations are consistent with the concept that the malformations in asplenia and polysplenia can be explained by minor alterations in the sequence of development of embryonic body curvature relative to organ maturation.

Argyrophilic nucleolar organizer regions and proliferating cell nuclear antigen/cyclin in Kaposi's sarcoma. Comparison with morphology and with immunoperoxidase staining for factor VIII-related antigen.

The proposal that Kaposi's sarcoma undergoes cellular transformation from early to late stages was studied with argyrophilic nucleolar organizer regions, proliferating cell nuclear antigen/cyclin, and immunoperoxidase staining for factor VIII-related antigen. Staining of argyrophilic nucleolar organizer regions was significantly increased in the plaque/nodular stage compared to the patch stage. The endothelial-selective marker factor VIII-related antigen stained more intensely in patch stage lesions. This was inversely correlated with staining of argyrophilic nucleolar organizer regions. Proliferating cell nuclear antigen/cyclin staining did not correlate with tumor stage or with factor VIII-related antigen. The changes in argyrophilic nucleolar organizer regions and factor VIII-related antigen staining are evidence for cellular transformation in Kaposi's sarcoma.

Pagetoid melanocytosis: tease or tocsin?

Pagetoid melanocytosis (PM) represents a more precise formulation of the histological phenomenon previously referred to as pagetoid scatter/spread. PM is defined as the upward discontinuous extension of melanocytes into the superficial epidermis. Three histological criteria are presented. PM is a frequent finding in malignant melanoma, occurring in approximately 76% of lesions. PM also occurs in a significant number of certain benign melanocytic lesions: Spitz nevi, nevi of palms and soles, pigmented spindle cell nevi, recurrent nevi, vulvar nevi, and nevi of infancy and childhood. Histological features of PM favoring malignant melanoma over benign melanocytic lesions are a diffuse and dense extension over a wide area, prominent melanocytic atypia, and PM without an underlying junctional melanocytic component (free-floating PM). PM should alert the pathologist to the possibility of melanoma but does not of necessity require a malignant interpretation. The final interpretation of a melanocytic lesion requires evaluation of all the pertinent histological and clinical findings.

Right ventricular infarction: role of the moderator band artery in determining infarct size.

We studied 19 patients with proximal right coronary artery occlusions associated with acute myocardial infarcts less than 30 days old. Right ventricular infarct size, determined as a percentage of right ventricular surface area, ranged from 0% to 29%. Correlation of 24 variables measuring infarct size, chamber size and coronary artery disease failed to demonstrate a significant correlation with the extent of right ventricular infarction. However, estimates of the degree of obstruction to potential collateral flow into the right coronary arterial system from the left anterior descending coronary artery, especially through the moderator band artery, showed a significant positive correlation with infarct size (p less than 0.02). Among the five patients with massive (greater than 25%) right ventricular infarction, four had significant (greater than 75%) obstruction of the left anterior descending system, resulting in potentially impaired collateral blood flow; the other patient had normal coronary arteries and embolic occlusion of the proximal right coronary artery with contraction band necrosis. The study suggests that collateral flow to the right ventricular myocardium, especially through the moderator band artery, protects against massive infarction in the presence of proximal right coronary artery occlusion.

Inflammatory melanoma.

Cutaneous inflammatory metastatic carcinoma is a well-documented entity most frequently associated with carcinoma of the breast. We present two patients with extensive inflammatory involvement of the skin overlying dermal lymphatic invasion by metastatic melanoma. The dermal lymphatic invasion and gross characteristics are similar to those previously described in inflammatory carcinoma, suggesting that melanoma should be added to the list of tumors which may result in this condition. As in other cases of inflammatory carcinoma, the recognition of this entity is important with regard to both prognosis and therapy.

Immunohistochemistry in the differential diagnosis of nodular hidradenoma and glomus tumor.

The histologic distinction between nodular hidradenoma and glomus tumor is an occasional difficult diagnostic problem. Both tumors may show circumscribed aggregates of uniform epithelioid cells, a myxoid stroma, and variable numbers of blood vessels. Especially troublesome are solid cellular hidradenomas without duct-like structures and glomus tumors without a vascular pattern. To develop an immunohistochemical profile useful in this differential diagnosis, 25 selected skin tumors and four normal glomus bodies were studied with antibodies against low molecular-weight cytokeratin (CAM 5.2), epithelial membrane antigen (EMA), carcino-embryonic antigen (CEA), S-100, and vimentin (VIM). The tumors included eight unequivocal hidradenomas, seven unequivocal glomus tumors, and 10 histologically equivocal cases, originally diagnosed as glomus tumors. In all unequivocal glomus tumors and glomus bodies, only VIM was positive. Of the eight unequivocal hidradenomas, three were positive for CAM 5.2, EMA, CEA, S-100, and VIM; two for CAM 5.2 only; one for CAM 5.2, EMA, and S-100; one for CAM 5.2, EMA, and CEA; and one for CEA only. In the histologically equivocal cases, eight were positive for VIM only, characteristic of glomus tumor; and two were positive for CAM 5.2, EMA, CEA, S-100, and VIM, and were reclassified as hidradenomas. The study suggests that morphologic criteria may not always accurately differentiate between hidradenoma and glomus tumor and that in equivocal cases immunohistochemistry may be useful in the differential diagnosis.