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.

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.

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.

Oncocytic nodular hidradenoma.

Oncocytic neoplasms are most commonly of salivary, thyroid, parathyroid, and renal origin. Ocular adnexal tumors with oncocytosis have been reported. We report an unusual example of a skin adnexal tumor from the back. A tumor of uncertain duration was excised from a 54-year-old man. Light microscopy of hematoxylin and eosin-stained sections showed a large, fairly well-defined cystic nodular hidradenoma with areas infiltrated by numerous closely arranged, large, uniform, oval and polygonal cells with abundant intensely eosinophilic cytoplasm and small central, dark, round nuclei. No significant cellular atypia or mitotic figures were observed. The cytoplasm of these cells showed markedly positive immunostaining with monoclonal antimitochondrial antibodies. Electron microscopy demonstrated cytoplasm packed with mitochondria. Pure oncocytic tumors usually follow a benign clinical course. The focal presence of oncocytes in an otherwise histologically recognizable tumor apparently does not affect the prognosis, which in this case is the favorable outcome expected for a nodular hidradenoma.

Basal cell carcinoma of the sole.

Basal cell carcinoma (BCC) of the plantar surface of the foot is rare, with only 22 previously reported cases. This clinicopathologic study is based on 20 cases of BCC of the plantar surface and plantar-like surfaces from adjacent lower lateral and medial aspects of the foot, submitted to a large podiatric laboratory from 1986 through June 1992 (total specimens for this period = 518,624; total BCC of lower extremities, below knee = 53). There were 15 women and 5 men. The average patient age was 73 years, with a range from 52 to 92 years. The duration of the lesion before diagnosis was 2 months to 12 years, with an average of 2 years. Three patients had a history of trauma. Podiatric clinical diagnoses included BCC (4), SCC (3), soft tissue tumor (2), nevus (1), granuloma (1), keratosis (2), verucca (1), and psoriasis (1). Follow-up information was available on 10 patients; all were free of disease up to 64 months, with an average follow-up of 15.7 months. Three of 20 BCC showed predominant histologic patterns characteristic of fibroepithelioma of Pinkus (FEP). An additional three BCC showed focal or suggestive patterns of FEP. Fourteen tumors showed ordinary BCC histologic patterns. No multicentric-superficial or morphea like BCC were observed. The relatively high incidence of FEP in BCC of the sole correlates with abundant sweat glands and lack of hair follicles on the plantar surface, in accordance with the recent proposal that FEP derives its histologic pattern from the spread of BCC down eccrine ducts, eventually replacing them with solid strands of tumor.

Proliferative activity in metastatic malignant melanoma: comparison of pre-treatment and post-treatment metastases.

In this study, the proliferative activity of malignant melanoma metastases was assessed before and after isolated limb perfusion chemotherapy by quantitating AgNORs, mitoses and PCNA activity. No significant difference in either AgNOR count, mitotic activity or PCNA index was observed. We conclude that AgNOR count, mitotic activity and PCNA index were not significantly effected by isolated limb perfusion chemotherapy.

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.

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.

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.

Fibroepithelioma of Pinkus. Eccrine duct spread of basal cell carcinoma.

The spread of basal cell carcinoma (BCC) directly into the dermis or down the sides of hair follicles is a common-place pathologic observation. BCC spread via eccrine ducts, which has received less recognition, is the subject of this investigation. We specifically address the question of whether eccrine duct spread accounts for the histologic pattern of the fibroepithelioma of Pinkus (feP) type of BCC. Twenty-five BCC, including 12 feP, five superficial BCC, six ordinary BCC, one BCC of the sole of the foot, and one BCC with prominent hair follicle spread were studied with H&E sections; 11 were immunostained for carcinoembryonic antigen. In ordinary BCC, occasional entrapped eccrine ducts were present. One superficial BCC surrounded the proximal portion of an eccrine duct. The BCC from the sole of the foot showed advanced spread down eccrine ducts; focal obliteration of duct epithelium and lumen was seen, as was transition to strands of solid BCC. Nine of the 12 feP showed one or several eccrine duct foci with tumor strands. These findings suggest that eccrine ducts serve as an initial template in feP and subsequently are replaced by the BCC. However, eccrine duct spread of BCC may occur without necessarily imparting an feP histologic pattern.

Malignant melanoma in xeroderma pigmentosum: search for a precursor lesion.

BACKGROUND: Malignant melanomas occur with increased frequency and at an early age in patients with xeroderma pigmentosum (XP). OBJECTIVE: The purpose of this study was to describe the histologic features of malignant melanomas in patients with XP and to search for a possible precursor lesion. METHODS: Clinical records and hematoxylin-eosin-stained sections of 19 malignant melanomas from seven patients with XP were examined. A search was conducted for malignant melanoma precursor lesions (melanocytic nevi and solar lentigines lateral to and contiguous with the malignant melanomas). Basal cell carcinomas removed from the same patients were used as controls. RESULTS: Malignant melanomas were characteristically found in biopsy specimens of small elevations and/or changed color foci arising in large, flat, darkly pigmented, gradually enlarging macules. Histologically, solar lentigo was lateral to and contiguous with malignant melanoma in 88% of the malignant melanomas. Transitional areas were present. A significantly lower number (22%) of contiguous solar lentigines, without transitional areas, were observed in the basal cell carcinoma controls. Most of the invasive malignant melanomas were spindle cell malignant melanomas. CONCLUSION: We propose that solar lentigo is the most common precursor lesion of malignant melanoma in patients with XP.

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.

Increased plasma viscosity and erythrocyte aggregation: indicators of an unfavourable clinical outcome in patients with unstable angina pectoris.

OBJECTIVE: To determine the prognostic significance of altered plasma viscosity and erythrocyte aggregation in unstable angina. DESIGN: A prospective study of 96 consecutive patients with unstable angina allocated to one of two groups according to predefined threshold values for plasma viscosity and erythrocyte aggregation at study entry. The patients received a standardised treatment and were followed up for six months or until angioplasty or bypass surgery. MAIN OUTCOME MEASURE: Frequency of myocardial infarction. RESULTS: Myocardial infarctions occurred in 7/26 patients with a plasma viscosity greater than or equal to 1.38 mPa s and in 8/35 with a rate constant of erythrocyte aggregate formation greater than or equal to 0.5 mPa (corrected for plasma viscosity) but in only 4/70 with a plasma viscosity less than 1.38 mPa s and in 3/61 with an erythrocyte aggregation less than 0.5 mPa (odds ratios: 6.1 (95% confidence interval 1.3 to 31), p = 0.008, and 5.7 (95% CI 1.2 to 35), p = 0.016). Plasma viscosity and erythrocyte aggregation were more predictive of myocardial infarction than age, male gender, fibrinogen concentration, ST segment abnormalities, or coronary score. Furthermore, Holter monitoring with ST segment analysis showed that ischaemic episodes were more common in patients in whom the rate constant of erythrocyte aggregate formation was greater than 0.5 mPa (15/27 v 17/50, p = 0.029). Cardiac troponin T release was increased in patients with a plasma viscosity of greater than 1.38 mPa s (10/26 v 9/70, p = 0.010). CONCLUSIONS: In patients with unstable angina a considerable increase in plasma viscosity and erythrocyte aggregation identified a subgroup of patients at a high risk of acute myocardial infarction in whom medical treatment was likely to be unsuccessful.

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.

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.

Haemorrheological abnormalities in unstable angina pectoris: a relation independent of risk factor profile and angiographic severity.

Plasma viscosity, photometric erythrocyte aggregation index, and erythrocyte filterability were measured in 194 patients with coronary artery disease. Patients with unstable angina (n = 64) had a higher plasma viscosity and photometric erythrocyte aggregation index than patients with stable angina (95% confidence intervals for the mean difference: 0.052-0.100 mPa.s for plasma viscosity, and 43%-72% for the photometric erythrocyte aggregation index). Multiple regression with fibrinogen, cholesterol, high density lipoprotein cholesterol, triglycerides, blood pressure, smoking habits, coronary artery score, and left ventricular ejection fraction as independent variables showed a significant partial correlation between fibrinogen and the photometric erythrocyte aggregation index (r2 = 0.20) and plasma viscosity (r2 = 0.09), between triglycerides and plasma viscosity (r2 = 0.05), and between aortic pressure and erythrocyte filterability (r2 = 0.03). Logistic regression for unstable/stable angina with the haemorrheological variables as independent variables correctly identified 72% of the patients with stable angina and 78% of those with unstable angina. Inclusion of all the variables investigated did not substantially improve the discriminative potential of the logistic regression model. Unstable angina is associated with an impairment of blood fluidity that is essentially independent of risk factor profile and angiographic data.

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.

Metastatic carcinoma involving the testis. Clinical and pathologic distinction from primary testicular neoplasms.

Metastatic carcinoma to the testis is unusual. There are only seven previously reported cases in which a testicular mass was the first clinical manifestation of an underlying malignancy. The authors review 127 cases in which the testis was involved by metastatic carcinoma, and describe an additional two patients in whom a malignant testicular mass was the presenting sign of an underlying nontesticular carcinoma. The tumors most commonly reported to metastasize to the testis are: prostate (45 cases), lung (25 cases), melanoma (12 cases), colon (11 cases), kidney (10 cases), stomach (6 cases), and pancreas (5 cases). Neuroblastoma, retinoblastoma, carcinoid tumor, and cancers of the bile duct, ureter, bladder, salivary gland, and thyroid have also involved the testis secondarily. Nineteen patients (15%) had bilateral testicular metastases. Patients with secondary testicular neoplasms were older in general than those with germ cell tumors (mean, 55 years; median, 57 years). Histologically, the presence of extensive lymphatic and vascular invasion and an interstitial pattern, in which the seminiferous tubules are spared, is suggestive of a metastasis. In four of the nine cases (44%) in which testicular enlargement was the first manifestation of an underlying carcinoma the correct pathologic diagnosis was initially missed. Serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) are occasionally elevated in patients with nontesticular primary tumors, but markedly elevated levels in young patients suggest a nonseminomatous germ cell tumor, as does positive immunoperoxidase staining for AFP and HCG.