Aromatase activities of endometrial carcinomas and both basic and clinical analyses of endometrial hyperplasia as a premalignant disease

Paraffin-embedded materials obtained from 117 cases of endometrial hyperplasia and 84 cases of carcinoma were used for measurement of both ki-ras and p53 gene mutation and aromatase (ARO) and TGF-alpha immunostaining. The overall incidence of ki-ras mutations in the hyperplasia specimens (16%) was similar to the incidence detected in carcinomas (18%). None of 117 endometrial hyperplasias were found to have mutations in the p53 gene, whereas mutations were seen in 3 (13.3%) endometrial carcinomas. The intensity of both ARO and TGF-alpha immunostaining was increased in glands of both hyperplasia and carcinoma, and also in the interstitium of carcinoma. The positive sites of both ARO and TGF-alpha were almost the same, with an incidence below 40% in both hyperplasias and carcinomas. The cultured cells of endometrial carcinoma showed aromatase activity below MCF-7 cells, because testosterone was converted to estradiol (E2). TGF-alpha induced cell growth with at an optimal concentration. In HEC-59 cells, TGF-alpha increased both ARO-activity and mRNA. Some promoters on ARO-exon 1 in HEC-59 cells were different from those in BeWo cells. Progesterone inhibited the E2-induced excretion of pre TGF-alpha in endometrial carcinoma cells. These findings suggest that endometrial hyperplasia can be a premalignant condition of carcinoma, and can be initiated by both ki-ras codon 12 mutation and abnormal activity of ARO induced by TGF-alpha. In addition, HEC-59 cells may possess autocrine/paracrine properties involving ARO, E2 and TGF-alpha.     

Malignant melanoma in the CNS, subtyping and immunocytochemistry

Paraffin-embedded specimens from 21 patients (mean age 49 years) with malignant melanocytic tumors of the central nervous system were studied. Extraneuronal primary tumors were situated at the trunk (38%), the lower (14%) or upper extremity (10%), and the head/neck region (5%). In 33% no extraneural primary tumor could be detected. The tumor location was frontal (19%), occipital (19%), parietal, spinal, multifocally (14%, respectively), or temporal (5%). Four subtypes were distinguished according to the predominant histological cell type: pleomorphic, epithelioid, spindle- and mixed-cell tumors. 29% contained no melanin, most of them belonging to the epithelioid subtype. The morphology and immunohistochemical reactivity for different antibodies (KL-1, EMA, VIM, HMB-45, NKI-C3, S-100, and MIB-1/Ki-67) were assessed. Positive staining was demonstrated for HMB-45 (in 86% of cases), NKI-C3 (100%), S-100 (95%), vimentin (75%), and KL-1 (33%). No expression of the cytokeratin EMA could be detected. The mean proliferation index measured by MIB-1 immunoreactivity was 21%. The 4 histological subtypes were found to express different antigen patterns. In the analysis of CNS tumors of unknown origin, the panel of antibodies used for diagnosis should include HMB-45 as the most specific marker for malignant melanoma.     

Dynamics of cell-associated viremia and antibody response during the early phase of lentivirus infection in sheep

OBJECTIVE: To investigate the characteristic epiluminescent microscopic features of early lesions of malignant melanoma affecting glabrous skin, which is the most prevalent site of the neoplasm in nonwhite populations. DESIGN: The epiluminescent microscopic features of various kinds of melanocytic lesions affecting glabrous skin were investigated using a videomicroscope. All the diagnoses were determined clinically and histopathologically using the standard criteria. SETTING: A dermatology clinic at a university hospital. PATIENTS: The following 130 melanocytic lesions consecutively diagnosed at our department were examined: 16 lesions of acral lentiginous melanoma, 6 lesions of malignant melanoma in situ, and 108 lesions of benign melanocytic nevus (acquired or congenital). MAIN OUTCOME MEASURE: The incidence of each characteristic epiluminescent feature was compared among disease categories. RESULTS: On epiluminescent microscopy, malignant melanoma in situ and the macular portions of invasive malignant melanoma showed accentuated pigmentation on the ridges of the skin markings, which are arranged in parallel patterns on glabrous skin. This "parallel ridge pattern" was found in 5 (83%) of 6 lesions of malignant melanoma in situ and in 15 (94%) of 16 lesions of malignant melanoma. The parallel ridge pattern was rarely found in the lesions of benign melanocytic nevus. Most benign melanocytic nevi showed 1 of the following 3 typical epiluminescent patterns: (1) a parallel furrow pattern exhibiting pigmentation on the parallel sulci of [he skin markings (54%), (2) a latticelike pattern (21%), and (3) a fibrillar pattern showing filamentous or meshlike pigmentation (15%). The remaining 11 benign nevi (10%) showed a nontypical pattern. CONCLUSION: Because epiluminescent microscopic features of early malignant melanoma on glabrous skin are characteristic, we can effectively detect early lesions using this noninvasive method.     

Persistent and recurrent sporadic primary hyperparathyroidism: histopathology, complications, and results of reoperation

BACKGROUND: Our purpose was to analyze the causes of persistent and recurrent sporadic primary hyperparathyroidism (PD and RD). METHODS: The histopathology, complications, and results of reoperation were studied. Five hundred sixty-eight patients with primary hyperparathyroidism were operated on initially by one surgeon and underwent follow-up examination for 3.7 +/- 3.8 years. During the operation, all parathyroids were sought and confirmed by biopsy. Enlarged glands were resected, and subtotal parathyroidectomy was done for multiglandular disease (hyperplasia). RESULTS: The cure rate after the initial surgical procedure was 96.4%, PD = 2.8% (16 of 568). At reoperation (10 of 16), nine of 10 were cured (90%) (two adenomas, six hyperplasias, one lung carcinoma). RD was documented (at years 4, 4, 10, 15, 16) in five (0.9%) patients, one with parathyroid carcinoma and four with hyperplasia. Thirty-five patients with PD and two patients with RD were referred for reoperation: 17 with adenomas (eight mediastinal) and 18 with hyperplasias (one mediastinal gland). Preoperative calcium level was higher for PD (12.57 mg/dl) and RD (13.89 mg/dl) versus all cases (12.19 mg/dl) (p < 0.03 and p < 0.0005, respectively). After reoperation, normocalcemia was achieved in 47 (92.%) of 51 patients with PD or RD. Transient hypocalcemia occurred in 22% of patients (permanent, 2.0%) and transient hoarseness in 2.0% of patients (no permanent nerve damage). Permanent hypocalcemia and nerve damage after 568 initial operations were 0% and 0%, respectively. Two perioperative deaths occurred. CONCLUSIONS: We conclude that inadequate neck exploration or resection of hyperplastic tissue accounts for most cases of PD and RD. Optimal results necessitate intraoperative identification of all parathyroids whenever possible, with minimal morbidity.     

The piloting of a group for the fathers of children with Down syndrome

Inflammatory lesions and cysts are by far the most common causes of swelling or enlargement of Bartholin's glands, and carcinomas, though rare, are the most frequent solid lesions that arise at this site. There have been very few reports of benign solid lesions of Bartholin's gland, and, among these lesions, the distinction between adenoma (AD) and hyperplasia has not been well defined. All cases diagnosed as either Bartholin's gland adenoma or hyperplasia in the Armed Forces Institute of Pathology files were reviewed. Using specific criteria, 17 qualified as nodular hyperplasia (NH), 1 as AD, and 1 as adenomyoma (AM). Five NHs, the AD, and the AM were studied with immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), MIB-1, and p53. The average age of the patients with NH was 35 years (range, 19 to 56). These lesions were solid or solid and cystic, had a mean maximal dimension of 2.3 cm, and were frequently thought to be Bartholin's cysts on clinical examination. Microscopically, the NHs had an irregular or lobulated contour and were composed of a proliferation of cytologically bland mucinous acini with maintenance of the normal duct-to-acinar relationship. Varying degrees of inflammation and squamous metaplasia of the ducts were common in NH. The patient with the AD was 45 years old and the patient with AM was 65. Both were well-circumscribed, solid lesions, 2.2 and 2.5 cm in maximal dimension, respectively, and composed of a haphazard proliferation of acini and tubules. A small adenoid cystic carcinoma (ACC) arose from the periphery of the AD. p53 positivity was evident in up to 40% of the ACC cells; the cells in the adjacent AD were negative for p53. Only occasional cells were MIB-1 positive (< 5%) in some cases, and ER and PR were absent in the epithelial elements in all 7 cases tested but were focally present in the stromal cells of 3 of the 5 NHs and the fibromuscular stroma of the AM. The patient with the AM and the one with the AD are alive without evidence of recurrent or metastatic disease after 4 months and 19.8 years, respectively. NH, AD, and AM of the Bartholin's gland, as defined in this study, are extremely rare lesions. NH occurs in younger patients and is often associated with inflammation or obstruction of Bartholin's duct.     

Ultrasonic-pathologic comparison of postangioplasty myointimal hyperplasia and primary atheroma of the superficial femoral artery

The purpose of this study was to characterize postangioplasty myointimal hyperplasia as compared to primary atheroma of superficial femoral arteries using color-coded duplex sonography (CCD), and to correlate sonographic findings with the histopathology of samples obtained from these lesions by catheter atherectomy (Redha-cut device). Preinterventionally, homogeneity, echogeneity, and the surface of plaques were described using CCD in nine cases with secondary stenoses after percutaneous transluminal angioplasty and in seven cases with primary atheroma. Myointimal hyperplasia of femoral restenoses showed a homogeneous (7 of 9 vs. 1 of 7) and hypoechogenic (7 of 9 vs. 0 of 7) wall thickening compared to primary atheromas (p < 0.05). Primary atherosclerotic plaques showed a rather heterogeneous, hypo- and hyperechogenic ultrasonic appearance with or without echo shadowing in six of seven cases. The surface of restenoses was more often regular than that of primary atherosclerotic lesions, but this finding did not reach statistical significance (6 of 9 vs. 2 of 7, p = 0.14). Thrombotic material appeared homogeneous and hypoechogenic in three of five cases and could not be discriminated from intimal hyperplasia. In summary, postangioplasty intimal hyperplasia is characterised by a hypoechogenic, homogeneous, rather regularly confined vessel wall thickening and can be differentiated from primary atheroma at CCD.     

Treatment of American cutaneous leishmaniasis: a comparison between low dosage (5 mg/kg/day) and high dosage (20 mg/kg/day) antimony regimens

There is debate about the margin of normal tissue that should be included with excisions of melanocytic lesions of the skin, and about which lesions should be referred for specialist care. We describe the determinants of the margins of excised melanocytic skin lesions and of referral patterns from primary care. Copies of the pathology reports of melanocytic skin lesions excised from two cities in tropical Queensland were obtained; questionnaires about each lesion were administered to the excising doctor. Data about 3275 lesions (2914 naevi, 130 lentigos, 151 melanomas, 51 dysplastic naevi, 21 Hutchinson's melanotic freckles and eight other melanocytic lesions) were analysed. Twenty-one per cent of the treatment sessions involved the excision of more than one lesion; 5% involved three lesions or more. Most lesions were managed by one doctor. The overall mean margin of excision was 2.8 mm. It was greater for longer qualified doctors, surgeons and college-affiliated general practitioners, for lesions excised to address malignancy (3.0 mm) rather than cosmetic appearance (2.4 mm), for Hutchinson's melanotic freckles (5.9 mm) and melanomas (5.1 mm) compared with benign lesions (2.7 mm) (P < 0.001) and for older patients (2.6 mm for those < or = 15, 3.5 mm for those > 40 years) (P = 0.001). Wider excisions of skin melanocytic lesions are performed by older and more experienced doctors, on older patients, and for lesions in which malignancy is being addressed.     

Kaposi's sarcoma of the head and neck in patients with acquired immunodeficiency syndrome

Kaposi's sarcoma is the most common neoplastic process in patients infected with the human immunodeficiency virus. Moreover, the occurrence of Kaposi's sarcoma in human immunodeficiency virus-infected patients advances their classification to having the acquired immunodeficiency syndrome. We reviewed the medical records of 48 patients with human immunodeficiency virus infection who had Kaposi's sarcoma documented on their initial visit to the hospital. The onset of Kaposi's sarcoma occurred independent of the Centers for Disease Control and Prevention classification of human immunodeficiency virus infection (modified to exclude Kaposi's sarcoma). This neoplasm developed more frequently in patients who acquired human immunodeficiency virus infection by sexual contact (75% of cases), but manifestations were not significantly different in any of the risk populations for human immunodeficiency virus infection. Kaposi's sarcoma lesions were unpredictable and either showed progression, remained static, or occasionally, regressed spontaneously. Moreover, the lesions were usually multifocal at presentation, with the head and neck (62.5% of cases) as the primary site of involvement. In this region cutaneous lesions predominated (66.7%), followed by mucosal (56.7%) and deep structure (13.3%) involvement. The majority of patients with acquired immunodeficiency syndrome Kaposi's sarcoma involving head and neck structures were asymptomatic (80% of cases). Mucosal lesions were associated with symptoms in 29.3% of cases, whereas cutaneous lesions had symptoms in 5% of cases.     

Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis

The p16(INK4a) (p16) tumor suppressor gene can be inactivated by promoter region hypermethylation in many tumor types including lung cancer, the leading cause of cancer-related deaths in the U.S. We have determined the timing of this event in an animal model of lung carcinogenesis and in human squamous cell carcinomas (SCCs). In the rat, 94% of adenocarcinomas induced by the tobacco specific carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone were hypermethylated at the p16 gene promoter; most important, this methylation change was frequently detected in precursor lesions to the tumors: adenomas, and hyperplastic lesions. The timing for p16 methylation was recapitulated in human SCCs where the p16 gene was coordinately methylated in 75% of carcinoma in situ lesions adjacent to SCCs harboring this change. Moreover, the frequency of this event increased during disease progression from basal cell hyperplasia (17%) to squamous metaplasia (24%) to carcinoma in situ (50%) lesions. Methylation of p16 was associated with loss of expression in both tumors and precursor lesions indicating that both alleles were functionally inactivated. The potential of using assays for aberrant p16 methylation to identify disease and/or risk was validated by detection of this change in sputum from three of seven patients with cancer and 5 of 26 cancer-free individuals at high risk. These studies show for the first time that an epigenetic alteration, aberrant methylation of the p16 gene, can be an early event in lung cancer and may constitute a new biomarker for early detection and monitoring of prevention trials.     

Pigmented lesions in newborn infants

1058 newborn infants were examined. Forty-one (3-9%) had clinically discernible pigmented lesions compatible with melanocytic naevi. Biopsy was performed on thirty-four of the forty-one and of these; eleven, representing 1-01% of the infants, proved to be melanocytic naevi. No giant (garment) naevi were seen in this series. Two of the eleven naevi pathologically examined showed histological changes similar to those that have been reported in some giant naevi, but the remaining nine were not only different from criteria usually assigned to giant naevi, but they also differed from the usual adult naevi, in that most were predominantly junctional. None of the melanocytic naevi in this series showed any suggestion of malignant change. In newborn infants it is often impossible clinically to distinguish naevi from other types of pigmented lesions, as only eleven out of the thirty-four pigmented lesions were melanocytic naevi. Seven of the eleven melanocytic naevi were under 1-5 cm in diameter. No pigmented lesions were found on the palms, soles or genitalia.     

Excising the reexcision: stereotactic core-needle biopsy decreases need for reexcision of breast cancer

There is debate regarding use of the stereotactic core-needle biopsy (SCNB) for highly suspicious mammographic lesions. This study compares a serial group of mammography-detected breast cancer patients treated before and after the use of SCNB. We studied 113 consecutive nonpalpable breast cancers between 1994 and 1996. Altogether 47 patients were diagnosed by wire-localized breast biopsy (wire group) and the next 66 consecutive breast cancer patients by SCNB (stereo group). Negative margins were found more often in the stereo group than in the wire group (77% vs. 38%, p < 0.001). Reexcision was required more frequently in the wire group than in the stereo group (68% vs. 21%, p < 0.001), and one-staged surgical procedures were done more often in the stereo group than the wire group (79% vs. 21%, p < 0.001). The volume of the initial wide excision was much larger in the stereo group than in the wire group (p = 0.002). Those in the wire group required 50% more operations per patient (1.8 vs. 1.2) than the stereo group. A significant cost savings can be estimated in the stereo group compared with the wire group. The use of SCNB was associated with breast excisions of larger volume, negative margins, and decreased need for reexcision. Simultaneous adjunct procedures resulted in one-stage operations, improving cost savings. The use of SCNB for nonpalpable breast cancer benefits the patient, the surgeon, and the payor. It should be undertaken prior to the first surgical procedure.     

Atypical melanosis of the foot

We present a case of a seemingly malignant pigmented lesion on the foot, arising in a Japanese female. Clinically, the lesion was characterized by irregular borders and variegated pigmentation closely mimicking those of acral lentiginous melanoma in situ. However, the histologic findings revealed only focal, slight, melanocytic hyperplasia with minimal cytologic atypia along the basal layer. Despite the malignant clinical features, thorough histologic examination failed to disclose any area with significant melanocytic atypia or evidence of malignancy. To the best of our knowledge, no similar lesions with the clinical appearance of melanoma in situ and completely lacking histologic evidence of malignancy have been reported. We, therefore, prefer to designate this lesion as atypical melanosis of the foot, to highlight the clinically atypical findings and to distinguish this from malignant melanoma in situ of the foot (1).     

Does the placement of surgical clips within the excision cavity influence local control for patients treated with breast-conserving surgery and irradiation

PURPOSE: A number of authors have demonstrated the importance of using surgical clips to define the tumor bed in the treatment planning of early-stage breast cancer. The clips have been useful in delineating the borders of the tangential fields, especially for very medial and very lateral lesions as the boost volume. If surgical clips better define the tumor bed, then a reduction in true or marginal recurrences should be appreciated. We sought to compare the incidence of breast recurrence in women with and without surgical clips, controlling for other recognized prognostic factors. METHODS AND MATERIALS: Between 1980 and 1992, 1364 women with clinical Stage I or II invasive breast cancer underwent excisional biopsy, axillary dissection, and definitive irradiation. Median follow-up was 60 months. Median age was 55 years. Seventy-one percent of patients were path NO, 22% had one to three nodes, and 7% had > than four nodes. Sixty-one percent were ER positive and 44% PR positive. Margin status was negative in 62%, positive in 10%, close in 9%, and unknown in 19%. Fifty-seven percent of women underwent a reexcision. Adjuvant chemotherapy + tamoxifen was administered in 29%, and tamoxifen alone in 17%. Surgical clips were placed in the excision cavity in 556 patients, while the other 808 did not have clips placed. All patients had a boost of the tumor bed. Patients had their boost planned with CT scanning or stereo shift radiographs. No significant differences between the two groups were noted for median age, T stage, nodal status, race, ER/PR receptor status, region irradiated, or tumor location. Patients without clips had negative margins less often, a higher rate of unknown or positive margins and more often received no adjuvant therapy compared to patients with surgical clips. RESULTS: Twenty-five and 27 patients with and without surgical clips, respectively, developed a true or marginal recurrence in the treated breast. The actuarial probability of a breast recurrence was 2% at 5 years and 5% at 10 years for patients without clips compared to 5 and 11%, respectively, for patients with clips (p=0.01). Comparing the breast recurrence rates for patients with and without clips there was no significant difference for the following factors: chemotherapy, tamoxifen, negative, positive or close margins, reexcision, N1, and central or inner primary. Increased rates of breast recurrence were noted for patients with clips for the following variables: no adjuvant treatment (p < 0.001), unknown margins (p < 0.001), a single excision (p = 0.003), path NO (p = 0.001), and outer location (p= 0.02). A forward stepwise multivariate analysis for all 1364 patients was performed using the aforementioned variables as well as the presence or absence of surgical clips and the primary surgeon. The surgeon (p = 0.03) and no adjuvant treatment (p = 0.01) significantly influenced breast recurrence. For patients with surgical clips the 10 year isolated breast recurrence rate was 21% for a single surgeon vs. 6% in the remainder of the group (p = 0.01). For patients with clips, this surgeon had unknown margins in 48% of cases compared to 10% overall (p = 0.001). Excluding this surgeon from analysis the isolated breast recurrence for patients with clips was 6 vs. 5% for patients without clips (p = 0.18). CONCLUSIONS: Overall, there was a significant difference in the 10-year breast recurrence rate favoring women without clips despite more adverse prognostic factors. There was no difference in the breast recurrence rate for patients with or without surgical clips if careful attention to margin status was addressed. Failure to ink the surgical specimen resulting in unknown margins cannot be compensated for with the placement of .     

Interval training at VO2max: effects on aerobic performance and overtraining markers

BACKGROUND: Nuchal-type fibroma (NTF) usually arises in the posterior aspect of the neck. Previously published reports describe only 11 cases and provide limited clinicopathologic information. METHODS: Fifty-two examples of NTF from 50 patients were analyzed from the files of the Soft Tissue Registries of the Armed Forces Institute of Pathology in Washington, DC, and the Faculty Hospital in Pilsen, Czech Republic. RESULTS: The age of the patients ranged from 3 to 74 years (mean, 40 years). There were 41 males and 9 females. Thirty-six NTFs were located in the posterior neck region and 16 were from extranuchal sites. Two patients had had lesions excised from both a nuchal and an extranuchal location. The mean greatest tumor dimension was 3.2 cm. Microscopically, all examples had a superficial (subcutaneous and sometimes dermal) component and consisted of paucicellular, thick bundles of lobulated collagen fibers with inconspicuous fibroblasts. Entrapped adipose tissue and traumatic neuromalike nerve proliferations were typically present. Skeletal muscle infiltration was also seen in a minority of cases. Eleven of 25 patients (44%) for whom clinical information was available reportedly had diabetes. Gardner's syndrome was documented in one patient and was possibly present in two additional individuals. During follow-up, five patients had local recurrences, but none of the recurrences were destructive and all were ultimately controlled by local reexcision. CONCLUSIONS: NTF is a rare, tumorlike accumulation of collagen that often affects the posterior neck region but can also occur in a number of other sites. The process has a strong association with diabetes and also appears to be linked to Gardner's syndrome. Local recurrence probably reflects the persistence of local or systemic factors related to its pathogenesis.     

Diagnosing and treating congenital melanocytic nevus simulating malignant melanoma

Many cases reported as malignant melanomas arising in benign congenital melanocytic nevi in the neonatal period have not shown evidence of metastases after several years of follow-up. These lesions were probably pathologically misdiagnosed, thus creating a controversy regarding the precise incidence. This article describes the case of an infant with a giant melanocytic nevus simulating malignant melanoma to illustrate the proper criteria for diagnosis of this condition so extensive and unnecessary therapy procedures can be avoided.     

Histological evaluation of coronary plaque in patients with variant angina: relationship between vasospasm and neointimal hyperplasia in primary coronary lesions

OBJECTIVES: This study was designed to determine whether coronary vasospasm in patients with variant angina pectoris (VAP) may produce focal organic lesions at the site of vasospasm that would contribute to disease progression. BACKGROUND: Recent clinical angiographic and experimental studies have demonstrated the potential role of vasospasm in the worsening of organic coronary stenosis. METHODS: We studied histologically the coronary plaques obtained at atherectomy in 202 patients with moderate to severe coronary stenosis. This population included 22 patients with VAP, 100 patients with chronic stable angina and 80 patients with restenosis following angioplasty or atherectomy. Diagnosis of VAP was based on both the clinical feature of angina at rest associated with ST elevation and a positive response to acetylcholine provocation test. RESULTS: The most common histological appearance in 92% of patients with stable angina was hypocellular fibroatheromatous plaques, whereas neointimal hyperplasia was the characteristic feature of the plaque observed in 90% of patients with restenosis. The coronary specimens at the site of spasm in 15 of the 22 patients (68%) with VAP demonstrated intimal injuries such as neointimal hyperplasia (15), thrombus formation (2), and intimal hemorrhage (3). Neointimal hyperplasia was significantly more common in the patients with VAP as compared with those with stable angina (68% vs. 8%; p < 0.0001). A rapid progression of organic stenosis within three years was angiographically found in 5 of the 22 patients with variant angina. In all five cases, neointimal hyperplasia was the main contributor to the worsening of the organic lesion at the site of spasm. These histological findings in patients with VAP extremely resembled those in restenosis. Except for vasospasm, no factors significantly predicted the presence of neointimal formations in primary coronary lesions. CONCLUSIONS: Coronary vasospasm may provoke vascular injury that leads to the formation of neointima in VAP patients similar to that seen with restenosis. Coronary spasm may thus play a key role in the rapid coronary stenosis progression in certain patients with VAP.     

Quantification of vascularity in nodular melanoma and Spitz's nevus

Spitz's nevi are acquired benign melanocytic skin tumors. Usually they are differentiated from nodular melanoma by clinical and histopathological criteria. Since Spitz's nevi are one of the most common simulators of nodular melanomas their bizarre histopathology may cause diagnostic confusion and make it difficult to differentiate these two melanocytic tumors. One of the histologic features shared by Spitz's nevus and nodular melanoma is prominent vascularity. The ability of malignant melanoma to induce angiogenesis is well established whereas benign melanocytic tumors do not have a prominent overall vascularity. The purpose of this study was to find out whether the degree of vascularity of nodular melanomas differs significantly from that of benign Spitz's nevi. In this study the number of microvessels and the vessel area were determined in 23 Spitz's nevi and 16 nodular melanomas. The number of microvessels and the vessel area were determined on Ulex Europaeus agglutinin I-stained sections by computer-assisted image analysis. Two methods of measurement were used, namely systematic and selective sampling. Measurement of the whole tumor specimen (systematic sampling) revealed a vessel count of 10.83/field (SD +/-5.97) for Spitz's nevi whereas nodular melanomas exhibited a significantly lower (p=0.04) vessel count of 6.44/field (SD +/-3.85). This difference was even more pronounced when the vessel area (Spitz's nevi: 17.85x10-4mm2, SD +/-10.32; nodular melanomas: 7.88x10-4mm2, SD +/-5.23) was investigated (p < 0.001). The difference in vessel area and vessel count was insignificant for areas exhibiting the greatest vascularity (selective sampling). Measurement of vessel count and vessel area lead us to conclude that Spitz's nevi have a significantly higher vascularity than do nodular melanomas. Our results thus indicate that angiogenesis in these pigmented lesions is not correlated with malignancy.     

Technetium-99m-tetrofosmin for parathyroid scintigraphy: comparison to thallium-technetium scanning

The efficacy of 99mTc-tetrofosmin for the detection of parathyroid lesions was investigated prospectively in patients with hyperparathyroidism referred for surgical treatment. METHODS: Twenty-seven patients with primary and 18 with tertiary hyperparathyroidism were studied. Twelve patients had undergone one or more previous neck explorations. Static imaging with 201Tl was performed first, immediately followed by a 30-min 99mTc-tetrofosmin dynamic study. Delayed views of up to 3 hr postinjection were also obtained. Technetium-99m-pertechnetate was used for thyroid delineation. The tetrofosmin/99mTc-pertechnetate subtraction scan (TF/TC), the single-tracer washout technique and the thallium/technetium subtraction (TL/TC) were compared. Quantification of relative uptakes of tracers in the thyroid and abnormal parathyroids was accomplished by measuring activity within regions of interest. Kinetics of tetrofosmin in the thyroid and abnormal parathyroids were studied by evaluating the plots of the parathyroid to thyroid ratios against time as well as by calculation of the half-clearance times from the slow component of the time-activity curves. RESULTS: The overall sensitivity, specificity and accuracy of TF/TC and TL/TC were 76%, 92% and 83% and 52%, 85% and 65%, respectively. The respective sensitivities were 87% and 70% for adenomas and 72% and 46% for hyperplasia. The parathyroid-to-thyroid activity ratios of tetrofosmin were significantly higher than those of thallium (p < 0.001). The tetrofosmin single-tracer washout study was less accurate than the subtraction technique (overall sensitivity and specificity, 70% and 69%, respectively). The washout properties of tetrofosmin in abnormal parathyroids were not substantially different from those in the thyroid, with a few exceptions (p = 0.4). No correlation of half-clearance times with parathyroid size, degree of early uptake, parathyroid hormone levels or histology could be established. Comparing adenomas to hyperplasia in respect to tetrofosmin retention, a statistically significant difference was observed (p = 0.005). CONCLUSION: Technetium-99m-tetrofosmin is suitable for parathyroid imaging. The kinetic properties of this agent in parathyroid and thyroid tissues do not warrant differential washout protocols. The diagnostic impact of the observed difference in tetrofosmin kinetics between parathyroid adenomas and hyperplasia requires further investigation.     

Nursing staff perceptions of the use and reduction in the use of physical restraints

Substance P (SP) is a neuropeptide found in both the central and peripheral nervous system. In the skin, SP-containing neurons stimulate the release of histamine from connective tissue mast cells (MC). SP also can potentiate neoangiogenesis and induce dermal fibrosis. MC-derived histamine has potent vasoactive effects, is angiogenic, and promotes tissue fibroplasia. In addition to histamine, MC contain many other angiogenic factors and a variety of cytokines, growth factors, and proteolytic enzymes implicated in tissue remodeling, and normal as well as tumor-associated neoangiogenesis. Many MC-derived factors, including histamine, can enhance melanoma cell growth directly. MC often concentrate around cutaneous melanomas which also frequently are associated with angiogenesis and peritumoral fibrosis. The precise mediators of these responses have not been well defined. We evaluated by immunohistochemistry cutaneous lesions representing stages of progression of malignant melanoma and its precursor lesions for the expression of SP. SP was expressed in 17/25 (68%) primary invasive malignant melanomas, 2/5 (40%) metastatic melanomas, 6/10 (60%) melanomas in situ, 7/12 (58%) atypical (dysplastic) nevi, and 4/10 (40%) spindle and epithelioid cell (Spitz) nevi, but was not detected in any (0/11, 0%) acquired benign melanocytic nevi (p<0.05). Invasive melanomas were immunolabeled in both the intraepidermal and the dermal components of the lesions. For those atypical and Spitz nevi which expressed SP, most of the immunoreactive melanocytes were located at the dermal-epidermal junction overlying areas of papillary dermal fibrosis. The results show differential expression of SP among cutaneous melanocytic lesions and suggest that the expression of this neuropeptide together with other factors may contribute to some of the host responses associated with these lesions.     

Enhanced expression of Ki-67, topoisomerase IIalpha, PCNA, p53 and p21WAF1/Cip1 reflecting proliferation and repair activity in UV-irradiated melanocytic nevi

To investigate the effect of ultraviolet (UV) irradiation on the expression of cell cycle-associated proteins, melanocytic nevi from healthy volunteers were partially covered, irradiated with a defined UV dose, and excised 1 week thereafter. The irradiated and the protected parts were examined separately by conventional microscopy and immunohistochemistry using the antibodies Ki-S11 (Ki-67), Ki-S7 (topoisomerase IIalpha), PC10 (proliferating cell nuclear antigen [PCNA]), DO-7 (p53), 6B6 (p21WAF1/Cip1), and the melanocytic marker HMB-45. DNA nick-end labeling was used as a marker of apoptosis. Irradiation resulted in morphological changes and increased HMB-45 reactivity. Proliferation, as assessed by Ki-67 and topoisomerase IIalpha expression, was also clearly enhanced in the UV-exposed areas. This was confirmed by the appearance of occasional mitotic figures. PCNA expression levels markedly exceeded those of the proliferation markers and did not correlate with the latter in most cases. p21 immunolabeling indices were also consistently augmented after UV exposure; hence it is likely that growth-inhibitory mechanisms partly compensate for the proliferative impulse, and the disproportional rise in PCNA expression probably reflects DNA repair activity. Enhanced p53 immunostaining in four cases suggests that the induction of p21 after irradiation may be p53 mediated, whereas no concomitant apoptotic events were observed. We conclude that UV light can stimulate the proliferative activity of melanocytes in melanocytic nevi, but that simultaneously cell cycle inhibitors are activated to permit DNA repair.