Metastatic melanoma and melanogenuria.

We report a case of a 70-year-old Hawaiian man with an exophytic black nodule on the left suprascapular region of several years' duration. Histopathologic examination of the excised lesion showed a nodular melanoma with 17-mm Breslow thickness. The patient had firm fixed lymph nodes circumferentially around his neck. He underwent palliative cervical lymph node dissection to remove the compressive nodes but declined further therapy. One year later, the patient's skin was noted to have a generalized uniformly gray-brown color. Physical examination showed ulcerated masses on his trunk, right arm, and both axillae. A urine specimen initially was dark yellow but turned black after exposure to air at room temperature and ambient light for several minutes. Black urine, termed melanuria, is a rare finding in patients with disseminated melanoma. In melanogenuria, the urine is yellow and darkens as the colorless melanin precursors oxidize in the presence of air. Detection of these urinary melanin precursors may someday help determine the prognosis of melanoma and monitor response to treatment.

[Diffuse brown discoloration of skin, mucosa and urine]. / Diffuse Braunfärbung von Haut, Schleimhaut und Urin.

A 45-year-old woman presented with diffuse melanosis, icteric sclera and melanuria. Physical examination revealed a massive nodular melanoma with ulceration and satellite metastases on the back. Further investigation showed distant cutaneous and visceral metastasis. After palliative debulking along with postoperative multidrug chemotherapy, the patient has shown objective disease regression for more than 11 months. However, it remains to be seen if disease regression will translate into increased survival.

The color of urine: then and now-a comprehensive review of the literature with emphasis on intracytoplasmic pigments encountered in urinary cytology.

The color of urine, once considered by uroscopists to give the most important clues to the diagnosis, still can provide some diagnostic clues in modern medicine. Pigmented cells are an uncommon and surprising find in urine cytology and can at the same time provide important diagnostic clues or represent a dangerous pitfall. We present a review of the significance of pigmented cells in urine cytology. The presence of intracellular pigment granules; their color, size, shape, and variation in size and shape; as well as their staining reactions with special stains can provide useful diagnostic insight, especially when interpreted in the cytologic context (type of pigmented cell and its degree of atypicality) and patient's clinical context. The main differential diagnosis of cytoplasmic pigmented granules includes hemosiderin, lipofuscin, and melanin, each having a different pathogenesis and significance. The goal of this paper is to describe the morphological, histochemical, and ultrastructural characteristics of the pigments seen in urinary cytology, and to review the benign and malignant conditions associated with them.

Acute kidney injury in a patient with melanuria, diffuse melanosis, and metastatic malignant melanoma.

Diffuse melanosis with melanuria is a rare complication of metastatic malignant melanoma that is associated with a very poor prognosis. Acute kidney injury secondary to melanuria has not been reported previously. We describe a patient with malignant melanoma, diffuse melanosis, and melanuria who developed acute kidney injury that was clinically indicated by an increase in urinary excreted metabolites in the serum. Histopathologic examination of kidney tissue revealed damage to tubules associated with disseminated intra-tubular melanin deposits. Diffuse melanosis with melanuria may lead to morphologic and functional kidney changes and warrants careful monitoring of kidney function in affected malignant melanoma patients.

Diffuse cutaneous melanosis: rare complication of metastatic melanoma.

Diffuse cutaneous melanosis is a rare complication of metastatic melanoma related to a worse prognosis. There are few cases reported in the literature. Its pathogenesis has not been completely elucidated, although studies have suggested certain mechanisms for its occurrence. It is clinically manifested as a blue-gray discoloration of the skin and mucous membranes in a cephalo caudal progression and usually associated with melanuria. Skin and mucosa histopathology reveals only the presence of melanophages in the dermis, mainly perivascular, and free interstitial melanin. We report the case of a 68-year-old male with metastatic melanoma, diffuse hyperpigmentation of the skin and melanuria.

Nude mouse model of the melanosis syndrome.

The occurrence of diffuse hyperpigmentation secondary to a xenografted human malignant melanoma was observed in nude mice. The patient from whom this cell line was established developed cutaneous hyperpigmentation after his disease became disseminated. Light and electron microscopy studies were performed on skin and organ biopsy specimens from the hyperpigmented mice. These studies indicated that this melanoma-associated melanosis was secondary to the release of pigment granules from the xenografted tumors and to the uptake of these granules by macrophages throughout the body, including those located in the dermis.

Identification of 5-hydroxy-6-indolyl-O-sulfate in urine of patients with malignant melanoma.

It has previously been shown that enzymatically hydrolyzed urine of patients with malignant melanoma contains 5,6-dihydroxyindole (5, 6DHI ). In this study we describe the elucidation of the entire structure of urinary 5, 6DHI -conjugate. Differential hydrolysis of melanotic urine revealed that, in contrast to beta-glucuronidase, sulfatase can liberate 5, 6DHI from its conjugated form. 5, 6DHI -sulfate was synthetized by reacting 5, 6DHI with sulfur trioxide trimethylamine complex. Thin-layer chromatography (TLC) documented its close similarity to the Thorm ahlen -positive compound usually entitled "C." Gas chromatographic-mass spectrometric (GC-MS) analysis of methylated and subsequently hydrolyzed synthetic 5, 6DHI -sulfate showed that the synthetic product consisted of a mixture of 5-hydroxy-6-indolyl-O-sulfate and 6-hydroxy-5-indolyl-O-sulfate (with a certain amount of 5, 6DHI -disulfate). 5, 6DHI -sulfate was purified with use of DEAE-cellulose column chromatography from melanotic urine. Methylation of this conjugate with deuterated dimethylsulfate and subsequent GC-MS analysis of the hydrolyzed product provided evidence that 5, 6DHI from melanotic urine was almost exclusively sulfated in position 6. It was concluded (1) that 5, 6DHI is excreted as a 6-O-sulfate, and (2) that this compound is consistent with Thorm ahlen -positive compound "C".

Trichochromes in the urine of melanoma patients.

The urine of patients with melanoma metastases and increased urinary excretion of 5-S-cysteinyldopa was examined for trichochromes. Five of 16 patients showed urinary excretion of trichochromes B and C. None excreted trichochromes E or F. All patients showing trichochrome excretion had very large amounts of cysteinyldopa in their urine.

Clinical comparison of adriamycin and a combination of methyl-CCNU and imidazole carboxamide in disseminated malignant melanoma.

The effects of adriamycin were compared to a combination program of methyl-CCNU and imidozole carboxamide (DTIC) in 44 patients with disseminated malignant melanoma. There were objective clinical responses in 6 of 21 patients with the combination of DTIC and methyl-CCNU who received this program as primary treatment and none in 23 patients receiving adriamycin as primary treatment. Secondary responses were not observed with either treatment regimen. Toxicity with the combination program included leukocyte depression (less than 3,000/cu mm) in 25% and platelet depression (less than 100,000/cu mm) in 40% compared to 52% leukocyte depression and 16% platelet depression after adriamycin. There were no responses after the combination treatment program in the absence of myelosuppression. There was nausea and vomiting in virtually all patients, which was moderately severe in one third of the patients receiving the combination and in only 10% of those receiving adriamycin. Alopecia developed in all who received adriamycin but in only 15% of the combination treatment group. The combination treatment response of 28% was of the same order as most response rates previously reported in this disease. This randomized controlled clinical trail found adriamycin without clinical benefit and not worthy of further trial in patients with disseminated malignant melanoma.

Role of the clinical laboratory in the diagnosis and management of malignant melanoma.

The biosynthesis of melanin from tyrosine is reviewed as the basis for assessment of laboratory tests that might potentially aid in the diagnosis and management of patients with malignant melanoma. These tests include qualitative and quantitative assays for the intermediates in metabolism of melanin and catecholamines, enzyme assays, metal ion analyses, and, most recently, immunoassays. Although currently no role exists for the clinical laboratory in the early diagnosis of malignant melanoma, serial quantitative analyses of total or individual melanogens or of catecholamine metabolites in urine or plasma specimens may be of value in the management of patients with this disorder. Immunologically based methods for the diagnosis and management of malignant melanoma hold some promise for the future.

A new coagulation defect associated with a case of melanomatosis.

A marked abnormality of the intrinsic coagulation system was observed in a patient with melanomatosis and frank melanuria. With successful treatment of the tumour there was a parallel improvement in the clotting abnormality. This defect was shown to be a deficiency of factor XI together with a previously unrecognised factor. This is distinct from either Fletcher or Fitzgerald factors and appears to act between factors XI and X in the coagulation sequence.

Impaired levodopa response in Parkinson's disease during melanoma therapy.

A patient with melanoma and sporadic positive melanuria developed Parkinson's disease. Treatment with levodopa failed to modify tumoral progress. However, during chemotherapy with dacarbazine, the patient experienced a significant impairment to levodopa response.

Identification of Thormählen-positive compound "B" in urine of patients with malignant melanoma.

The identification of the entire structure of the Thormählen-positive compound B from melanotic urine is described. The compound was separated from other Thormählen-positive compounds using DEAE-cellulose column chromatography. On the basis of differential enzymic hydrolysis followed by gas chromatography-mass spectrometry analysis and comparison with synthetically prepared compounds it is possible to conclude that the Thormählen-positive compound B is a mixture of O-sulphate 5-hydroxy-6-methoxyindole and 6-hydroxy-5-methoxyindole with predominance of the latter.

The identification of Thormählen positive melanogen "A" from the urine of melanoma patients as 6-methoxy-5-indolylglucosiduronate.

The Thormählen positive melanogen previously determined as "A" has been isolated from melanotic urine by means of column chromatography on Amberlite IR 45, DEAE cellulose and Dowex 50. According to its behavior during a study with 1H--NMR spectra it has been found that the isolatd compound is 6-methoxy-5-indolyglucosiduronate, the metabolite of 5,6-dihydroxyindole. The possible formation and biotransformation of this compound is discussed.

Excretion of melanogens and zinc during the growth of melanoma in hamsters.

Melanogens which are considered as probable precursors or their metabolites in the metabolic pathway toward melanin are excreted in an increasing amount during the melanotic melanoma growth in hamsters. Moreover, an increased excretion of zinc was observed. The evaluation of dependence between zinc and Thormählen positive melanogens excretions during the melanoma growth suggests an exponential type of dependence. Likewise as in the case of human melanoma the hyperzincuria proved to be a laboratory sign of tumor disease progression in Syrian hamsters as well. The cause of an increased zinc excretion during the melanoma growth seems to consist in an increased lysis of pigment cells. The presumed destruction of tumor cells was not accompanied by a higher excretion of magnesium, though. Concentration of creatinine proved to be a useful mean for expressing of standard excretion of various substances also in hamsters.

Comparison of the excretion of different types of melanogens in the melanoma patients.

Urinary melanogens are indolic and phenolic compounds which are excreted in an elevated amount in the urine of melanoma patients. Urinary melanogens can be divided into two principal groups according to their behavior during Thormählen test--Thormählen positive melanogens (TPM) and Thormählen negative melanogens (TNM). When comparing TPM and TNM (represented by homovanillic and vanillactic acids) urinary excretion in stage III of melanoma patients we have found two significantly different relations for melanogens excretion, i. e. predominating TPM urinary excretion in melanotic forms of melanomas and predominating homovanillic acid and vanillactic acid urinary excretion in amelanotic forms of melanomas. We assumed that it could be an indirect evidence of the different catalytic activity of either cresolase or catecholase activities of tyrosinase.

Melanuria.

The urinary cytologic findings in a patient with metastatic malignant melanoma, diffuse melanosis and melanuria are presented. The melanosis was diagnosed from the clinical appearance of a generalized slate-blue skin discoloration, which is probably caused by dermal deposition of excess melanin pigment. The melanuria was characterized microscopically by the presence of amorphous, dark-brown casts, which stained positively for melanin pigment, and numerous pigment-laden macrophages.

Diffuse melanosis secondary to disseminated malignant melanoma.

A patient with melanosis and melanuria in whom disseminated malignant melanoma was found is described herein. The primary malignant process was not detected in the skin. Light and electron microscopic examinations, as well as cytochemical studies, revealed numerous melanin-containing macrophages in the skin.