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Melanuria in a patient with BRAF-mutant metastatic melanoma of unknown primary: Insights on the pathophysiology, differential diagnosis, prognosis, and treatment

Published:December 17, 2022DOI:https://doi.org/10.1016/j.amjms.2022.12.012

      Abstract

      Melanuria is the dark brown discoloration of the urine and an uncommon manifestation in patients with melanoma. It is an ominous sign, usually indicating widespread disease. In this article, through an illustrative case, we discuss the pathophysiological, clinical, and prognostic characteristics of melanuria in melanoma. Moreover, we aim to provide the available data for the prompt diagnosis and treatment of patients presenting with melanuria. We present the case of a 47-year-old man presenting with melanuria and diffure melanosis cutis, who was eventually diagnosed with a BRAF-mutated metastatic melanoma of unknown primary. The patient was started on a BRAF and MEK inhibitor, but he had a rapid disease progression and succumbed to the disease. There is only a limited number of case reports of melanoma patients with melanuria receiving targeted therapies or immune checkpoint inhibitors. In these reports, variable treatment responses have been described. In view of the increasing significance of targeted therapies and immunotherapy for melanoma, more cases are needed to improve our understanding on the prognostic significance of melanuria in the era of novel therapies for melanoma.

      Keywords

      Introduction

      The incidence of melanoma is increasing worldwide, especially in countries with moderate climates and a high percentage of sunny days during the year, alongside an increase of melanoma-related mortality.
      • MacKie RM
      • Hauschild A
      • Eggermont AM
      Epidemiology of invasive cutaneous melanoma.
      Unlike most solid tumors, melanoma affects mostly young and middle-aged people, with a linearly increasing incidence between the ages of 25 and 50 years.
      • Rastrelli M
      • Tropea S
      • Rossi CR
      • et al.
      Melanoma: epidemiology, risk factors, pathogenesis, diagnosis and classification.
      Melanuria refers to the dark brown discoloration of the urine due to increased urine excretion of melanin precursors. Melanuria is not commonly observed in patients with metastatic melanoma, although it is consistently reported to occur in up to 15% of the cases, especially in patients with metastatic visceral disease.
      • Takeda K
      • Kenzaka T
      • Kuroki S
      • et al.
      Melanuria in the diagnosis of metastatic melanoma.
      • Gambichler T
      • Stucker M
      • Kerner K
      • et al.
      Acute kidney injury in a patient with melanuria, diffuse melanosis, and metastatic malignant melanoma.
      • Eide J
      Pathogenesis of generalized melanosis with melanuria and melanoptysis secondary to malignant melanoma.
      This rate might be higher than expected in clinical practice and may include cases in which brown discoloration of urine is not macroscopically apparent, but increased levels of melanin precursors can be detected with laboratory methods. Interestingly, in cases of advanced melanoma, melanuria is often associated with a diffuse skin hyperpigmentation, termed as diffuse melanosis cutis (DMC).
      • Eide J
      Pathogenesis of generalized melanosis with melanuria and melanoptysis secondary to malignant melanoma.
      • Lerner AB
      • Moellmann G
      Two rare manifestations of melanomas: generalized cutaneous melanosis and rapid solar induction of showers of small pigmented lesions. A critical review of the literature and presentation of two additional cases.
      • Sebaratnam DF
      • Venugopal SS
      • Frew JW
      • et al.
      Diffuse melanosis cutis: a systematic review of the literature.
      In this article, we describe the case of a middle-aged melanoma patient presenting with melanuria and DMC who was treated with BRAF- and MEK-inhibitors.

      Case presentation

      A 47-year-old Caucasian male was admitted due to non-productive cough, shortness of breath, malaise, and loss of body weight that began about one month before admission. In addition, the patient noticed dark discoloration of his urine a few days before presentation. His past medical history was unremarkable. The clinical examination revealed diffuse skin hyperpigmentation, crackles in lung auscultation, ascites, and pitting edema of both legs. Moreover, macroscopically dark urine was noticed (Fig. 1).
      A computed tomography (CT) revealed multiple metastatic lesions in the left lung, left pleura, liver, and peritoneum and one metastatic lesion in the cerebellum. The urinalysis revealed melanuria (positive sodium nitroprusside test) and the cytology of the urine showed numerous pigment-containing macrophages and clusters of atypical cells, with large nuclei and irregular nuclear membrane that were strongly positive for HMB-45 and S100 protein (Fig. 2a and b). Eventually, melanoma infiltration was confirmed histologically with a pleural biopsy.
      Fig 2
      Fig. 2A: Urine, May-Grunwald Giemsa stain, x1000. Numerous. pigment containing, macrophages and occasional atypical cells with large, hyperchromatic nuclei and irregular nuclear membrane. B: Urine, Positive immunostaining for Human melanoma black 45, x1000.
      The dermatological, ear, nose, and throat examination and the ophthalmological evaluation did not reveal any suspicious lesions for primary melanoma. Thus, the patient was diagnosed as having melanoma of unknown primary.
      A large volume abdominal paracentesis was performed; the ascitic fluid was dark brown and its examination showed >250 polymorphonuclear leukocytes/mm,
      • Vijuk G
      • Coates AS
      Survival of patients with visceral metastatic melanoma from an occult primary lesion: a retrospective matched cohort study.
      a serum-ascites albumin gradient >1.1, while the cytology revealed melanoma cells in the fluid (Fig. 3a and b).
      Fig 3
      Fig. 3A: Melanoma cells in the ascitic fluid of the patient. May-Grünwald-Giemsa stain, x 1000. B: Ascitic fluid, Positive immunostaining for Human melanoma black 45, x1000.
      Molecular testing on the pleura specimen revealed a BRAF V600E mutation and the patient was started on vemurafenib (BRAF inhibitor) at 960 mg PO q12hr and cobimetinib (MEK inhibitor) at 60 mg PO daily. Under treatment, melanuria subsided temporarily for two weeks, while no response of skin discoloration was observed. In the next two months, the patient's condition deteriorated due to development of severe neurological symptoms owing to brain metastasis; at this point treatment was discontinued and further treatment with immunotherapy was declined by the patient and his relatives. He died two months later.

      Discussion

      Pathophysiology

      In metastatic melanoma, central ischemia of melanoma lesions, immunological responses, and antineoplastic therapies cause cytolysis. This results in the release of melanin precursors and melanosomes in the bloodstream. Urinary melanogens are indolic and phenolic compounds, which are excreted in an elevated amount in the urine of patients with melanoma.
      • Eide J
      Pathogenesis of generalized melanosis with melanuria and melanoptysis secondary to malignant melanoma.
      They constitute colorless melanin precursors or derivatives formed during the synthesis or catabolism of melanin and have been investigated in the past as potential tumor markers for melanoma.
      • Eide J
      Pathogenesis of generalized melanosis with melanuria and melanoptysis secondary to malignant melanoma.
      ,
      • Matous B
      • Bubnova E
      • Budesinska A
      • et al.
      Markers of melanogenesis in malignant melanoma.
      The dark brown color of the urine in melanuria is assumed to arise from autooxidation of pheomelanin (Fig. 4
      • Solano F
      Melanins: skin pigments and much more—types, structural models, biological functions, and formation routes.
      ) in the air after filtration by the glomerulus and extraction in the urine.
      • Eide J
      Pathogenesis of generalized melanosis with melanuria and melanoptysis secondary to malignant melanoma.
      ,
      • Nezirevic Dernroth D
      • Arstrand K
      • Greco G
      • et al.
      Pheomelanin-related benzothiazole isomers in the urine of patients with diffuse melanosis of melanoma.
      The levels of urinary melanogens have been correlated with the extent of melanoma, but since more than 40 melanogens have been detected and because their presence in the urine is also a normal phenomenon, especially in the summer as a result of stimulation of the pigmentary system by ultraviolet radiation, none of them was specific enough as a melanoma marker.
      • Aivaz O
      • Gaertner EM
      • Norton SA
      Metastatic melanoma and melanogenuria.
      ,
      • Yamada K
      • Walsh N
      • Hara H
      • et al.
      Measurement of eumelanin precursor metabolites in the urine as a new marker for melanoma metastases.
      Vanilmandelic acid, homovalinic acid, 5,6-dihydroxyindole-2-carboxylic acid, tryptophan, 5-hydroxyindole-3-acetic acid and indole sulphate are some examples of melanogens that have been identified in the urine of melanoma patients.
      • Valko-Rokytovska M
      • Hubkova B
      • Birkova A
      • et al.
      Specific urinary metabolites in malignant melanoma.
      Fig 4
      Fig. 4The chemical structure of pheomelanin.
      • Solano F
      Melanins: skin pigments and much more—types, structural models, biological functions, and formation routes.
      DMC refers to the dark grey discoloration of the skin and mucosa, sometimes accompanied by darkening of hair, sputum, and peritoneal fluid.
      • Amaral A
      • Diniz LM
      • Lucas EA
      • et al.
      Diffuse cutaneous melanosis: rare complication of metastatic melanoma.
      In histopathological specimens of patients with DMC, melanin deposition can be found in histiocytes and fibroblasts, as well as in extracellular dermal connective tissue.
      • Lerner AB
      • Moellmann G
      Two rare manifestations of melanomas: generalized cutaneous melanosis and rapid solar induction of showers of small pigmented lesions. A critical review of the literature and presentation of two additional cases.
      Interestingly, histiocytes harboring melanosomes show a characteristic perivascular distribution.
      • Sebaratnam DF
      • Venugopal SS
      • Frew JW
      • et al.
      Diffuse melanosis cutis: a systematic review of the literature.
      The exact pathophysiological mechanism of DMC remains unknown. According to one of the most widely accepted theories, DMC arises through absorption and processing of auto-oxidized freely circulating pheomelanin precursors into melanin by dermal histiocytes.
      • Sebaratnam DF
      • Venugopal SS
      • Frew JW
      • et al.
      Diffuse melanosis cutis: a systematic review of the literature.
      ,
      • Fitzpatrick TB
      • Montgomery H
      • Lerner AB
      Pathogenesis of generalized dermal pigmentation secondary to malignant melanoma and melanuria.

      Differential diagnosis

      Dark urine appears in a limited number of possible diagnoses. The differential diagnosis includes melanuria, hemoglobinuria, myoglobinuria, ochronosis (alkaptonuria), and copper or phenol poisoning.
      • Raymond JR
      • Yarger WE
      Abnormal urine color: differential diagnosis.
      In patients with known metastatic melanoma, dark urine may be due to other metabolic causes, such as hemoglobinuria and myoglobinuria, due to drug toxicities, or even severe bilirubinuria in cases of obstructive jaundice due to metastases. Although in patients with known metastatic melanoma melanuria is an easy diagnosis, in patients without such a history, a presentation with dark urine may be challenging.
      The diagnosis of melanuria is based on the macroscopic and microscopic examination of the urine, the ferric chloride tube test, and/or the sodium nitroprusside test. In the ferric chloride tube test, melanin will react with ferric chloride leading to a gray or black precipitate that can be easily differentiated from the reactions produced by other amino acid products. In the sodium nitroprusside (or Thormählen) test, melanin will react with sodium nitroprusside producing a red color of the specimen.
      • Bradley M SG
      Examination of urine.
      The distinctive characteristic of urine with melanin precursors is that it becomes dark after its exposure to oxygen, in contrast to homogentisic acid urine which turns dark after becoming alkaline.
      • Strassinger S DLM
      Urinalysis and Body Fluids.
      As mentioned previously, melanuria is usually caused by urine secretion of melanogens, which are colorless precursors of the melanin pigment. Autooxidation in the air provides the dark brown color of the urine. In these cases, the urine usually is not dark colored when freshly voided.
      • Eide J
      Pathogenesis of generalized melanosis with melanuria and melanoptysis secondary to malignant melanoma.
      The microscopic examination of the urine may reveal the presence of atypical cells, dark brown casts with positive melanin stain, and pigment containing macrophages.
      • Valente PT
      • Atkinson BF
      • Guerry D
      Melanuria.
      After confirming the presence of melanuria, cytology may reveal the presence of melanoma cells in the urine in a significant percentage of cases. Thus, investigation of patients with dark urine in the absence of a known diagnosis of melanoma should include microscopic examination of the urine, sodium nitroprusside test and urine cytology.

      Clinical implications and prognosis

      Melanuria represents an uncommon complication of advanced or metastatic melanoma and is considered to be an ominous sign.
      • Gambichler T
      • Stucker M
      • Kerner K
      • et al.
      Acute kidney injury in a patient with melanuria, diffuse melanosis, and metastatic malignant melanoma.
      ,
      • Raymond JR
      • Yarger WE
      Abnormal urine color: differential diagnosis.
      Interestingly, there is a significant association of melanuria with DMC, as in 77% of all published DMC cases until 2013 presence of melanuria was also reported.
      • Sebaratnam DF
      • Venugopal SS
      • Frew JW
      • et al.
      Diffuse melanosis cutis: a systematic review of the literature.
      The positive association of DMC and melanuria might be theoretically explained by the increased cytolysis rate in patients with disseminated melanoma, which leads to elevated serum concentrations and therefore increased skin deposition or urine excretion of melanin precursors.
      It is currently unknown whether resolution of melanuria upon treatment initiation might represent a favorable prognostic indicator in patients with melanoma. Perez et al. described a patient with melanuria with bone and spleen metastases, whose urine color returned to normal after six cycles of palliative treatment with dacarbazine.
      • Sebaratnam DF
      • Venugopal SS
      • Frew JW
      • et al.
      Diffuse melanosis cutis: a systematic review of the literature.
      It is worth mentioning that in patients with advanced melanoma response rates to dacarbazine have been described to be between 5% and 15%.
      • Perez A
      • Turajlic S
      • Szyszko T
      • et al.
      Generalized melanosis and melanuria in a patient with metastatic melanoma.
      There are only a few reports regarding the use of BRAF-inhibitors or immune checkpoint inhibitors in patients with melanuria. A patient with a BRAFV600E mutant melanoma with DMC and melanuria who showed a good response to treatment with a BRAF inhibitor was reported in 2014.
      • Minocha R
      • Kefford R
      • Uribe P
      • et al.
      Diffuse melanosis cutis in the setting of BRAF(V600E) mutant melanoma and treatment with targeted therapies.
      In another case of BRAFV600E positive melanoma with diffuse hyperpigmentation and melanuria, the patient died two weeks after presentation despite treatment initiation with BRAF inhibitors.
      • Piana S
      • Longo C
      Diffuse melanosis and melanuria.
      In 2019, Yamaguchi and colleagues published a case of melanuria which was responsive to treatment with an immune checkpoint inhibitor as assessed by a macroscopical change of urine color from dark brown to yellow and reduction of urine melanin levels in the Thormählen test. The authors suggested that measurement of urine melanin might be useful in determining treatment response.
      • Yamaguchi T
      • Hoshi M
      • Nagashima K
      • et al.
      A case report on brown urine in treatment with immune checkpoint inhibitor.
      On the contrary, there is a report of two patients with BRAF wild-type melanoma developing melanuria while under treatment with pembrolizumab.
      • Thiem A
      • Schummer P
      • Ueberschaar S
      • et al.
      Early onset of diffuse melanosis cutis under pembrolizumab therapy illustrates the limitations of anti-PD-1 checkpoint inhibitors.
      In conclusion, melanuria is an unusual presentation of metastatic melanoma, usually combined with DMC. The prognosis of these patients is poor, and the median survival depends on the extent of melanoma and response to treatment. In the era of targeted therapies for melanoma, more data are needed to unravel the impact of melanuria on the prognosis of melanoma patients.

      Author Contributions

      P.D., G.P. and E.C.: Writing - original draft, Formal analysis, Software P.D.: Conceptualization, Methodology, Investigation G.P., A.G. and O.B.: Data curation P.M. and G.K.: Data curation, Visualization H.G.: Project administration, Resources, Supervision P.D., E.C. and H.G.: Validation, Writing - review & editing

      Funding

      No funding sources were used.

      Ethics approval and written consent

      Every effort was made to preserve the anonymity of the patient. Moreover, written informed consent from the patient's next of kin was obtained.

      Declaration of Competing Interest

      PD reports personal fees from Roche and Novartis, outside the submitted work. HG reports grants and personal fees from BMS, grants and personal fees from Roche, grants and personal fees from MSD, personal fees from Novartis, personal fees from Amgen, personal fees from Pierre Fabre, outside the submitted work. The remaining authors report no conflict of interests.

      Acknowledgments

      We would like to thank Ms. Evita C. Alexopoulos for copy-editing the final manuscript.

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