Lentiginous Melanocytic Hyperplasia Overlying Dermatofibroma

There are occasional reports of proliferative epidermal changes overlying dermatofibromas. We report the first case to our knowledge of a dermatofibroma with overlying lentiginous melanocytic hyperplasia.     

Recovery of cardiopulmonary reflexes in monkeys undergoing heart-lung transplantation

After heart-lung transplantation in primates, cardiopulmonary reflexes were tested and shown to be present. The Hering-Breuer and cough reflexes were tested, as well as responses to an inhaled respiratory stimulant, vasodilator, and an intravenous anticholinesterase and antimuscarinic agent. Recovery of these responses, except to the anticholinesterase agent, suggests that reinervation occurs in autotransplanted organs in primates. The Hering-Breuer reflex was present at 1.9 and 2.2 months after the operation in two animals subjected to autotransplantation. These cardiopulmonary reflex responses were also demonstrated in two allograft recipients studied at 15 and 16.9 months after the operation. Return of protective reflexes such as coughing may be an important mechanism to prevent aspiration pneumonitis and other complications in humans.     

Detection of DNA-psoralen photoadducts in mammalian skin

An immunofluorescence (IF) method for the detection of 8-methoxypsoralen (8-MOP) photoadducts to DNA has been developed to assess nuclear damage in keratinocytes and melanocytes after psoralen plus UVA (PUVA) treatment, both under in vitro and in vivo conditions. Cryostat sections of the albino and pigmented guinea pig and human skin were used for in vitro studies to establish minimal and maximal drug concentration and UVA dosimetry for the detection of DNA-8-MOP photoadducts. Limits of detection were as low as 10 ng/cm2 8-MOP and 1 J/cm2 UVA for skin sections and sodium bromide-split epidermal sheets. Guinea pigs treated with topical PUVA revealed positive IF stain in epidermal cell nuclei at a threshold dose of 100 micrograms/cm2 8-MOP and 13 J/cm2 UVA. Pretreatments of cryostat cuts with ethanol and alkali before IF test enhanced the sensitivity of detection in vivo about 10-fold and enabled us to follow the repair of DNA damage after treating normal guinea pig skin with a dose of 50 micrograms/cm2 8-MOP plus 6 J/cm2 UVA. The most interesting findings were as follows: A sensitive method to detect PUVA-induced nuclear damage in epidermal and dermal cells was developed. PUVA treatment induced nuclear DNA damage to melanocytes as well as to adjacent keratinocytes, and melanocytes appeared to be 10 times less vulnerable to photo-damage than keratinocytes. There was a greater propensity for the proliferative cells to be damaged by PUVA. PUVA induced nuclear damage up to 700 micron depth in the dermis. The usefulness of the IF test in detecting DNA damage in microgram and ng amounts in vivo and in following the repair of damaged DNA induced by PUVA.     

Malignant melanoma with desmoplasia and neurotropism

Desmoplastic (DMM) and neurotropic (NMM) malignant melanoma are two variants of the vertical growth phase of malignant melanoma. Both lesions commonly present clinically as firm nodules that are often mistaken for fibromas. Histologically, they are associated with a pleomorphic spindle cell population of cells that widely infiltrate the dermis. An accompanying fibrosis is present. DMM usually lies beneath a lentiginous proliferation of a typical melanocytes, whereas NMM may arise without obvious epidermal involvement. Because the lesions infiltrate widely, adequate therapy results only when complete extirpation is performed. Otherwise, there may be recurrence. Recurrent lesions act more aggressively.     

Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes.

Cutaneous melanoma is a common melanocytic neoplasm that can quickly metastasize to regional lymph nodes. Currently, prognosis is determined by measuring tumor thickness but more reliable markers for metastatic spread are urgently needed. We investigated whether the extent of tumor lymphangiogenesis can predict melanoma metastasis to sentinel lymph nodes. We quantified the extent of tumor lymphangiogenesis, as well as other factors, in excised primary tumors and in sentinel lymph node biopsy samples from 45 patients with primary cutaneous melanoma. The results were correlated with histological and clinical outcome. Primary melanomas from patients whose tumors had metastasized to the sentinel lymph nodes contained prominent 'hot spots' of increased lymphatic vessel density, compared to nonmetastatic tumors. Multivariate risk analysis revealed that the lymphatic vascular area of primary melanomas, an index of tumor lymphangiogenesis, was the most sensitive prognostic marker for sentinel lymph node metastasis, and was even able to more accurately predict which tumors were metastatic to sentinel lymph nodes than the currently used method of measuring tumor thickness. Highly lymphangiogenic melanomas maintained their lymphangiogenic activity after metastasis to the sentinel lymph node. The extent of tumor lymphangiogenesis is a highly sensitive (83%) and specific (89%) prognostic marker of lymph node metastasis. Assessment of lymphangiogenesis in primary melanomas may be a more effective approach than the currently used technique of measuring tumor thickness in selecting patients with early metastatic disease for aggressive therapy.     

Nitrotyrosine causes selective vascular endothelial dysfunction and DNA damage

Vascular endothelial dysfunction is recognized as a contributor to a wide array of cardiovascular disease states, but the initiating events involved are incompletely defined. Elevated plasma levels of free 3-nitro-L-tyrosine (3NT, biomarker of peroxynitrite formation) have been measured in settings of endothelial dysfunction, but its pathologic significance is unknown. We tested the hypothesis that clinically demonstrated concentrations of 3NT can induce vascular and endothelial dysfunction in vitro. Further studies evaluated involvement of DNA fragmentation and/or apoptosis as a potential mechanism. Preincubation of rat thoracic aorta segments with 3NT (100, 250 microM) resulted in selective, concentration-dependent impairment of acetylcholine (ACH) maximal response, with no change in KCL, phenylephrine, nitroprusside, or ACH EC50 effects (ACH Emax, 53+/-2, 42+/-5, 31+/-2%; Control, 100 microM, 250 microM 3NT). Vascular segments treated with 3NT also demonstrated concentration-dependent DNA damage, assessed using DNA nick-end labeling techniques (TUNEL staining), compared with control (TUNEL-positive nuclei/linear mm: 5.4+/-1.2, 13.7+/-1.2, 16.9+/-3.2; Control, 100 microM, 250 microM 3NT), which was confined to the endothelial layer. Equimolar tyrosine had no significant effects. Frequency of positively stained nuclei was statistically correlated to extent of endothelial dysfunction (p < 0.01). Free 3NT is apparently more than a benign biomarker in vivo, and may contribute to vascular endothelial dysfunction through promotion of DNA damage and/or apoptosis.     

Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand

Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and flt3-ligand (FL) induce the development of dendritic cells (DCs). To compare the functional properties of DCs stimulated by these cytokines in vivo, we used retroviral-mediated gene transfer to generate murine tumor cells secreting high levels of each molecule. Injection of tumor cells expressing either GM-CSF or FL resulted in the dramatic increase of CD11c+ cells in the spleen and tumor infiltrate. However, vaccination with irradiated, GM-CSF-secreting tumor cells stimulated more potent antitumor immunity than vaccination with irradiated, FL-secreting tumor cells. The superior antitumor immunity elicited by GM-CSF involved a broad T cell cytokine response, in contrast to the limited Thl response elicited by FL. DCs generated by GM-CSF were CD8alpha- and expressed higher levels of B7-1 and CD1d than DCs cells generated by FL. Injection sites of metastatic melanoma patients vaccinated with irradiated, autologous tumor cells engineered to secrete GM-CSF demonstrated similar, dense infiltrates of DCs expressing high levels of B7-1. These findings reveal critical differences in the abilities of GM-CSF and FL to enhance the function of DCs in vivo and have important implications for the crafting of tumor vaccines.     

Endocrine Mucin-Producing Sweat Gland Carcinoma: An Uncommon Presentation

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, often underrecognized, low-grade sweat gland carcinoma of the skin of the eyelid. To date, only 20 cases of this carcinoma have been reported, most frequently in Caucasian females with an average age of 70 years. Although the diagnosis is primarily made with immunohistochemical stain, compared to endocrine ductal carcinoma in situ, clinical detection serves as a potentially curative treatment. Further, its benign appearance clinically makes this tumor often misdiagnosed and undertreated. This disease commonly presents in Caucasian women of advanced age, aiding in the diagnosis of this tumor, which presents an even more critical diagnosis in a patient with a rare presentation. In the available literature, we could find no case of EMPSGC in younger African American women. The following case is the first case presented in the literature. Here, we present a case of an atypical presentation of the tumor in a young African American female, as well as a review of literature on the pathophysiology, clinical presentation, and treatment of EMPSGC.