Irwin M. Braverman

The cutaneous microcirculation: ultrastructure and microanatomical organization.

The cutaneous microcirculation is organized as two horizontal plexuses. One is situated 1–1.5 mm below the skin surface, and the other is at the dermal‐subcutaneous junction. Ascending arterioles and descending venules are paired as they connect the two plexuses. From the upper layer, arterial capillaries arise to form the dermal papillary loops that represent the nutritive component of the skin circulation. There are sphincter‐like smooth muscle cells at the point where the ascending arterioles divide to form the arteriolar component of the upper horizontal plexus. At the dermal subcutaneous junction, there are collecting veins with 2‐cusped valves that are oriented to prevent the retrograde flow of blood. Laser Doppler flowmetry (LDF) has demonstrated vasomotion of red cell flux localized to the sites of ascending arterioles. The simultaneous recording by LDF of red cell flux and the concentration of moving red blood cells from individual sites allows one to construct by computer topographic maps of these two valves. The two maps, based on initial studies using correlative skin biopsy specimens, can define 1‐mm3 volumes of skin that are predominantly arteriolar in composition, predominantly venular in composition, or essentially devoid of all microvascular elements. The electron and light microscopic features that define the microvascular segments, when coupled with the ability of LDF to define the predominant microvascular segments under the probe, will allow one to study both the mechanisms of normal physiological states and the pathogenetic mechanisms underlying pathological skin disorders in which the microvasculature plays a predominant role.

Mycosis fungoides: Clinicopathologic relationships, survival, and therapy in 59 patients with observations on occupation as a new prognostic factor

Clinicopathologic relationships, survival, and therapy were reviewed in 59 patients with mycosis fungoides (MF). An analysis of patient survival disclosed that stage of disease was a significant prognostic variable only if both cutaneous and visceral manifestations were considered in the staging design. The classical three‐stage format, based solely on findings of eczema (I), plaques (II), or skin tumors (III), was not a significant factor in predicting survival. However, the inclusion of lymphadenopathy (IV) and organomegaly (V) or circulating Sézary cells (VI) in an expanded model revealed a significant decline in the probability of survival with increasing stage of disease. Regarding cases where the original histopathologic material was available for review, there was no association between the histologic stage of the specimen and the morphology of skin lesions. These data militate against the use of a staging scheme based on histologic criteria. Among 30 different types of treatment employed during the course of this study, highdose electron beam was superior to all other physical and chemotherapeutic modalities. In a case‐control study considering occupational factors, patients with MF who were employed in manufacturing or construction industries were at significantly increased risk (relative risk = 4.3). Patient survival was reduced considerably for those with industrial backgrounds, suggesting that this subgroup was inclined to have severe disease. The concept that occupational factors may be implicated in the etiology of mycosis fungoides provides a new dimension to previous pathogenic hypotheses that needs further evaluation.

Hypopigmented variant of mycosis fungoides: Demography, histopathology, and treatment of seven cases

BACKGROUND Hypopigmented macules have been described infrequently as a presenting form of mycosis fungoides (MF). OBJECTIVE This study was designed to clarify general characteristics of a hypopigmented MF variant. METHODS Seven new cases were investigated with the use of descriptive epidemiology techniques. Demographic parameters, histopathology, and treatment outcomes were analyzed. These data were combined with those from prior reports to develop a broad composite view of this disease process. RESULTS The median ages in our series were 36 years for disease onset and 39 years at biopsy diagnosis. All patients had brown or black skin. Histologic findings consistently showed a lack of epidermal atrophy and moderate to profound exocytosis. Treatment with PUVA induced rapid and complete repigmentation in six of seven patients. CONCLUSION On the basis of our experience and a literature review, the hypopigmented variant of MF occurs in a younger population than typical forms of the disease and affects persons with dark skin almost exclusively. Microscopic features include lack of epidermal atrophy and moderate to extreme epidermotropism of infiltrating mononuclear cells. The treatment of choice appears to be PUVA.

Progression of pigmented purpura-like eruptions to mycosis fungoides: report of three cases.

The cases of three relatively young male patients with pigmented purpura-like eruptions evolving to mycosis fungoides are described. Initially, the eruptions, both clinically and histologically, very closely resembled pigmented purpuric dermatitis. After a follow-up period averaging 8.4 years, diagnostic histologic changes of mycosis fungoides were observed. Although uncommon, mycosis fungoides should be considered in the differential diagnosis of pigmented purpuric eruptions.

Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides)

PURPOSE Patients with mycosis fungoides [cutaneous T-cell lymphoma (CTCL)] may benefit from adjuvant therapy after completing total skin electron beam therapy (TSEBT). We report the results for T1/T2 CTCL patients treated with adjuvant oral psoralen plus ultraviolet light (PUVA) with respect to overall survival (OS), disease-free survival (DFS), salvage of recurrence, and toxicity. METHODS AND MATERIALS Between 1974 and 1993, TSEBT was administered to a total of 213 patients with CTCL. Records were reviewed retrospectively, and a total of 114 patients were identified as having T1 or T2 disease. Radiotherapy was provided via a 6-MeV linac to a total of 36 Gy, 1 Gy/day, 4 days/week, for 9 weeks. Beginning in 1988, patients were offered adjuvant PUVA within 2 months of completing TSEBT. This was started at 0.5-2 J/m2, 1-2 treatments/week, with a taper over 3-6 months. Therapy then continued once per month. There were 39 T1 and 75 T2 patients. Six T1 (15%) and eight T2 (11%) patients were treated with adjuvant PUVA. A further 49% of the 114 patients received adjuvant systemic therapy, 3% received spot external beam, 4% received adjuvant ECP, 2% received topical nitrogen mustard, 22% received a combination of therapies exclusive of PUVA, and 9% received no adjuvant therapy. Patients were balanced in all subgroups based on pre-TSEBT therapy. The median age of the cohort was 58 (range 20-88), with a median follow-up time of 62 months (range 3-179). RESULTS Within 1 month after completing of TSEBT, 97% of T1, and 87% of T2 patients had achieved a complete remission. Stratified by adjuvant therapy, none of six T1 and one of eight T2 patients who received adjuvant PUVA failed within the first 3 years after completion of TSEBT. A total of 43% of the T1 and T2 patients receiving other or no adjuvant treatment failed within the same time course. The 5-year OS for the entire cohort was 85%. Those who received PUVA had a 5-year OS of 100% versus a 5-year OS for the non-PUVA group of 82% (p < 0.10). The 5-year DFS for the entire cohort was 53%. Those who received PUVA had a 5-year DFS of 85% versus a 5-year DFS for the non-PUVA group of 50% (p < 0.02). By T stage, those with T1 receiving PUVA exhibited no relapses, whereas those with T1 not treated with PUVA had a crude relapse rate of 36%. Median DFS was not reached at 103 months for the T1 adjuvant PUVA patients versus 66 months for the non-PUVA patients (p < 0.01). For those with T2, crude relapse rates were 25% and 55%, respectively, with DFS of 60 (median DFS not reached) and 20 months (p < 0.03). The 5-year DFS for patients salvaged with PUVA was 50%. Toxicity of adjuvant and salvage PUVA therapy was acceptable, with only two patients requiring a reduction in PUVA dosage. CONCLUSION PUVA can maintain remissions in patients with CTCL after TSEBT. There is a significant benefit in DFS but no statistically significant improvement in OS. Prospective, randomized data are needed to confirm these results. PUVA is also effective as a salvage therapy after TSEBT in early-stage patients with recurrence, with acceptable toxicity.

Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy

PURPOSE To evaluate the impact of systemic adjuvant therapies on relapse-free (RFS) and overall survival (OS) of cutaneous T-cell lymphoma (CTCL) patients treated with total skin electron beam therapy (TSEBT). METHODS AND MATERIALS Between 1974 and 1990, TSEBT (36 Gy at 1 Gy/day; 9 weeks; 6 MeV electrons) was administered with curative intent to a total of 163 CTCL (mycosis fungoides) patients using six fields supplemented by orthovoltage boosts (120 kvp, 1 Gy x 20) to the perineum, soles of feet, and apical scalp (120 kvp, 2 Gy x 3). In this group, all patients who achieved a clinical complete response or a good partial response were offered one of two competing regimens of either adjuvant doxorubicin/cyclophosphamide or adjuvant extracorporeal photochemotherapy (ECP). RESULTS When the results for the group who achieved a complete response (CR) to TSEBT were analyzed, OS for T1 and T2 patients was excellent (85-90% at 5-10 years) and not improved by either adjuvant regimen. However, T3 and T4 patients who received either adjuvant doxorubicin/cyclophosphamide (75% at 3 years) or adjuvant ECP (100% at 3 years) had better overall survival than those who received neither adjuvant regimen (approximately 50% at 5 years). The difference between the OS curves for those who received ECP vs. those who received no adjuvant therapy approached statistical significance (p < 0.06), while a significant survival benefit from the addition of chemotherapy for TSEBT complete responders was not observed. Neither adjuvant therapy provided benefit with respect to relapse free survival after TSEBT. CONCLUSIONS These results suggest that an adjuvant nontoxic regimen of extracorporeal photochemotherapy may prolong survival in advanced stage CTCL patients who have achieved a complete remission after TSEBT. The combination of doxorubicin/cyclophosphamide had no significant impact on overall survival in those patients who achieved CR to TSEBT, and neither adjuvant therapy had an impact on relapse free survival for all T-stages. Such results are the basis for the current development of a prospective, randomized trial studying the impact of ECP after TSEBT in patients with advanced stage CTCL.

Additional courses of total skin electron beam therapy in the treatment of patients with recurrent cutaneous T-cell lymphoma

BACKGROUND Recurrent cutaneous T-cell lymphoma (CTCL) is managed with a variety of modalities. Repeat treatment with additional courses of total skin electron beam therapy (TSEBT) has not been formally evaluated. OBJECTIVE Our purpose was to evaluate the efficacy and toxicity of additional TSEBT for recurrent CTCL. METHODS A total of 14 patients were treated with TSEBT and received at least two courses, with five of those patients receiving a third course. Patients were offered additional TSEBT if they suffered recurrence despite other therapy if the extent of the recurrence precluded localized radiation. The median follow-up was 36 months. RESULTS The median dose for the entire group was 57 Gy. Thirteen patients (93%) achieved a complete response (CR) after the initial course. After the second course, 12 patients (86%) had a CR; of the five patients who underwent a third course, three (60%) achieved a CR. The median disease-free interval after the first course of therapy for those with a CR was 20 months and 11.5 months after the second course. Median survival after the second course was 15 months. All patients had xerosis, pruritus, desquamation, mild erythema, epilation, and anhidrosis of the skin. CONCLUSION Patients with recurrent CTCL recalcitrant to other forms of therapy or too diffuse for treatment with localized radiation fields are candidates for additional TSEBT. This therapy is effective and well tolerated with an acceptable risk profile.

Familial multiple lipomatosis: Report of a case and a review of the literature

Familial multiple lipomatosis is a hereditary syndrome of multiple lipomas occurring in a particular distribution. It is clinically distinct from multiple symmetric lipomatosis with which it is frequently confused in the dermatologic literature. A case of familial multiple lipomatosis is reported and a review of this condition is presented in an effort to resolve the confusion in the literature about familial multiple lipomatosis and multiple symmetric lipomatosis.

Age of onset, pattern of distribution, and histology of aneurysm development in a genetically predisposed mouse model

The blotchy mouse has an X chromosome mutation affecting crosslinking of collagen and elastin, which results in aneurysmal dilatation of the aorta. The age of onset, patterns of distribution, and histologic features of these lesions have not been characterized in detail in previous studies. Male normal and blotchy mice 1 to 8 months of age were killed and latex was injected into the left ventricles to facilitate exposure, examination, histologic sampling, and photography of the aorta. Aneurysms were not detected in any normal animals but the affected animals had a progressive increase in the incidence of aneurysms with age, reaching 100% by 6 months. Most aneurysms occurred in the ascending aorta, with some also present in the descending thoracic and abdominal segments. Some animals had multiple aneurysms. Histologically the blotchy mice aortas exhibited disrupted elastic lamellae and thickening of the interlamellar spaces. These spaces contained conspicuously pleomorphic smooth muscle cells, confirmed by electron microscopy. These changes occurred as early as 21 days, when there was no gross evidence of aneurysmal development. Aortic aneurysms develop in blotchy mice in a consistent fashion, with characteristic gross and histologic changes. These animals provide a practical model for further studies of aneurysmal disease, including possible therapeutic interventions to prevent aneurysm development.

White spots in tuberous sclerosis

Hypopigmented macules were present in 18 of 23 patients with tuberous sclerosis. The lesions, which averaged 1 to 3 cm. in diameter, were usually oval with irregular margins. One patient also had partial albinism, and 3 patients had hundreds of finely stippled hypopigmented spots on thir legs. Hypopigmented macules are usually present at birth or appear early in the newborn period and are probably the earliest detectable cutaneous sign of tuberous sclerosis. In a control study, none of 55 neurologically handicapped children had white spots. A single hypopigmented macule was found in 1 of 100 neurologically normal children also examined.