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Report on a case of liver-originating malignant melanoma of unknown primary

  • Zheng Yuan , Hai-yan Guo , Wei-ting Lu , Yao-hui Wang , Jing He , Fan Zhang , Jun-yong Che EMAIL logo and Fei Qiao EMAIL logo
Published/Copyright: October 23, 2023
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Open Life Sciences
From the journal Open Life Sciences Volume 18 Issue 1

Abstract

Malignant melanoma (MM) frequently occurs in the skin or mucosa, whereas malignant melanoma of unknown primary (MUP) is diagnosed in patients with lymph nodes or visceral organs as the site of origin, where it is challenging to detect the primary lesion by comprehensive examination. MUP is possibly related to the spontaneous regression of the primary lesion. In addition, primary hepatic melanoma (PHM) usually refers to the primary MM occurring in the liver, with no typical primary lesions and no manifestations of tumor metastasis. A 61-year-old male patient with liver as the site of origin was diagnosed with MM by Melan-A, HMB-45, and S-100 immunohistochemistry staining of liver biopsy tissue. Based on a comprehensive examination, no basis was found for melanoma in sites such as the skin, mucosa, five sense organs, brain, digestive tract, respiratory tract, or genitalia, and the patient was subsequently diagnosed with MUP. MMs require a comprehensive inspection, beginning with the liver, to search for the primary lesion; if the primary lesion is not found, the possibility of PHM or MUP should be considered.

Keywords: diagnosis; liver; malignant melanoma; unknown primary

1 Introduction

Malignant melanoma (MM) is a strongly aggressive cancer that occurs primarily at the junction of epidermis and dermis, or in regions abundant in melanocytes such as the skin, mucosa, ciliary body of the eye, iris, choroid, and meninges [1]. With more than 95% of cases of MM originating in the skin, skin MM metastases occur most frequently in the liver, lungs, bones, and brain. When a patient is diagnosed with metastatic MM, the primary lesion should be identified in time, but there are still some cases of melanoma of unknown primary (MUP) that involve lymph nodes or visceral organs and are not located in the skin [2]. In this study, a patient with MUP manifesting primarily as liver lesions was diagnosed and treated, as reported below.

2 General information

The patient was a 61-year-old male retiree who was in excellent health and had no history of skin and eye diseases or related treatment, no toxic exposure, no addiction to tobacco or alcohol, and no family history of hepatocellular carcinoma.

2.1 Clinical features

The chief complaint was abdominal distension accompanied by loss of appetite and weight loss for more than a month. Symptoms included abdominal distention, poor appetite, nausea, weakness, and progressive weight loss. On physical examination, no obvious melanocytic nevi were discovered on the skin and mucosa of the entire body. Palpation revealed that the site, a width of four transverse fingers below the xiphoid process of the liver, was harder, hypersensitive, and nodular.

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The research related to human use complied with all the relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration, and has been approved by the Ethics Committee of Affiliated Hospital of Nanjing University of Chinese Medicine.

2.2 Blood test

Blood routine examination was basically normal; liver function: GOT 50 U/L (10–50 U/L), GPT 69 U/L (10–40 U/L), Glb 35.0 g/L(35–52 g/L), Alb/Glb 1.03, AKP 859 U/L (40–130 U/L), GGT 623 U/L (8–61 U/L), TBil 42.60 µmol/L (<24 µmol/L), DBil 27.60 µmol/L (<5 µmol/L), ChE 2126 U/L (5,900–12,220 U/L); PCT: 2.10 ng/mL (<0.046 ng/mL); HBsAg, HBcAb, and HCV antibodies were negative; tumor markers: CA19-9 49.2 IU/mL (<37 IU/mL), FER 724 ng/mL (23.9–336 ng/mL), AFP 1.34 IU/mL (<10.9 ng/mL).

2.3 Imaging examination

Abdominal computed tomography (CT) enhancement suggests hepatomegaly, diffuse space-occupying lesions of the liver, uneven enhancement in the arterial phase, and splenomegaly; abdominal MRI reveals diffuse space-occupying lesions of the liver (Figure 1); positron emission tomography/CT (PET/CT) reveals diffuse modules in the liver, multiple nodules in the spleen, multiple bone density changes, slightly larger retroperitoneal lymph nodes, multiple nodes in the left parotid gland and neck and the right cardiophrenic angle region, nodules in both arm muscles, and fluorodeoxyglucose uptake enhancement in all these areas, and thus a malignancy was considered (Figure 2).

Figure 1 MRI shows diffuse space-occupying lesions of the liver, T1WI high signal (a), T2WI low signal (b), DWI high signal (c), and unequal enhancement of foci in the arterial phase (d).
Figure 1

MRI shows diffuse space-occupying lesions of the liver, T1WI high signal (a), T2WI low signal (b), DWI high signal (c), and unequal enhancement of foci in the arterial phase (d).

Figure 2 PET-CT shows an increase in the SUV uptake value in multiple parts of the body (a), such as the liver and spleen (d), sternum and vertebrae (b), and other parts of the bone (c).
Figure 2

PET-CT shows an increase in the SUV uptake value in multiple parts of the body (a), such as the liver and spleen (d), sternum and vertebrae (b), and other parts of the bone (c).

2.4 Diagnosis

Pathology of liver biopsy tissue: appearance: black, under the microscope: a malignancy with pigmentation (Figure 3); immunohistochemical (IHC) of paraffin section: Melan-A (++), HMB45 (++), S-100 (++), P16 (scattered+), Ki67 (about 25%), CgA (−), Syn (−), CK-P (−), BRAF (V600E) (+), indicating MM. Gastroenterological endoscopy results were negative. The ophthalmology, otorhinolaryngology, and dermatology consultations revealed no primary lesion at the corresponding site. Malignant lesions were excluded by biopsy pathology after a thorough physical examination, which revealed an oval, blue-gray pigmented nevus of approximately 0.3 cm in length and diameter on the skin posterior behind the left scapula (Figure 3). The patient was finally diagnosed with MUP with multiple hepatic, splenic, bone, and muscular metastases, based on the above data, and no basis was found for melanoma in such sites as the skin, mucosa, five sense organs, brain, digestive tract, or genitalia.

Figure 3 Liver histopathology (HE ×100) reveals nestlike cellular infiltration, accompanied by more pigmentation and nuclear enlargement with evident heteromorphism (a); the histopathology of pigmented nevi posterior to the left scapula (HE ×100) indicates benign cutaneous nevus (b).
Figure 3

Liver histopathology (HE ×100) reveals nestlike cellular infiltration, accompanied by more pigmentation and nuclear enlargement with evident heteromorphism (a); the histopathology of pigmented nevi posterior to the left scapula (HE ×100) indicates benign cutaneous nevus (b).

2.5 Treatment and prognosis

The patient was treated once with 200 mg of pembrolizumab monoclonal antibody, followed by target therapy. At a 5 month follow-up, the patient complained of a modest improvement in abdominal distension and weakness but continued to have a poor appetite, and imaging re-examination suggested no obvious changes in intrahepatic lesions.

3 Discussion

MUP, with an incidence of approximately 3% in MM, is defined as metastatic melanoma detected under the skin and in lymph nodes or other visceral organs, with no obvious indications of the primary lesion [3,4,5]. DasGupta et al. proposed the diagnostic criteria for MUP in 1963 [6] based on which the following cases were excluded: (1) patients who did not undergo a comprehensive physical examination, including anus, genitalia, and eye examinations; (2) patients with a history of orbital dissection; (3) patients who underwent surgical or non-surgical procedures for birthmarks, freckles, chronic paronychia, or skin lesions without undergoing pathological examinations; and (4) patients who developed enlarged lymph nodes and scars in the skin with lymphatic drainage. In this study, the patient had no history of dermatology or ophthalmology diseases or treatments; no clear skin or mucosal lesions were identified during a comprehensive physical examination; the gastrointestinal source was excluded using a gastroenterological endoscope; and eye lesions were excluded using an ophthalmic consultation. The patient fulfilled the diagnostic and exclusion criteria for MUP.

Regression of the primary focus is the most likely reason for the pathogenesis of MUP to remain unclear [7]. The frequency of complete regression of primary skin MM is assumed to range between 3.7 and 8.7% [8]. Males are more susceptible to regression than females [9]. There is an argument that males are more likely to ignore early primary melanoma in the skin before its regression and metastasis. Therefore, it is necessary to identify the MM in which the primary focus has completely regressed, and thoroughly check the skin of all patients diagnosed with MM [10]. Some studies have recommended the following MUP examinations [11]: comprehensive examination of skin and mucosal surfaces; ophthalmologic examination, otorhinolaryngologic examination (nasal cavity); gastrointestinal endoscopy (oral cavity, esophagus, anus); gynecologic examination (vulva, vagina, cervix, uterus); brain, neck, chest, and abdominal CT scanning; other possible sites include the gallbladder and ovaries.

Initial consideration was given to the rare diagnosis of primary hepatic melanoma (PHM), for which only a few reports exist [12,13]. Melanophores originate from neural crest cells, a transiently migrating population of stem cells [14]. Extracutaneous MM is believed to be caused by melanoblasts accompanying the mucosa, stroma, and neurovascular bundles or neuroectodermal rest cells migrating to these sites [15]. Therefore, primary visceral MM is theoretically valid. Due to the absence of unified diagnostic criteria for PHM, some scholars argue that the diagnostic criteria [16] should include the three primary conditions and one secondary condition listed below. Three primary conditions: (1) support from hepatic histopathology; (2) absence of evidence of melanoma in other sites; and (3) no history of skin lesions of unknown type or eye surgery. One secondary condition: a single lesion or multiple lesions with at least one lesion larger than 5 cm in diameter. The patient in this study met the above primary diagnostic conditions, but he failed to meet the secondary condition because he had multiple diffuse space-occupying lesions of the liver with a diameter of less than 5 cm and no primary focus. At the same time, the imaging findings of this patient do not conform to the common features of PHM: single or multiple cystic-solid space-occupying lesions in the liver [17]. Therefore, the patient could not be diagnosed with PHM.

MRI is the preferred imaging technique for detecting the liver and spleen metastases of MM [18]. In addition, studies indicate that systemic MRI is 100% sensitive, 100% specific, and 100% accurate in the diagnosis of hepatic metastases of melanoma [19]. Normal MM that contains melanin may exhibit a paramagnetic effect during an MRI examination, which may shorten T1 and T2 relaxation times and display a high T1WI signal and a low T2WI signal [20]. The patient in this investigation exhibited this feature. Thus, the MRI examination is extremely beneficial for the recognition and diagnosis of MM lesions of the liver. Of the 24 MUP patients reported, 11 patients underwent PET that showed no primary focus, possibly because the primary focus was too small or had spontaneously regressed [21]. This suggests that PET is less effective in discovering the primary tumor site of melanoma but is useful for detecting metastatic lesions and developing treatment regimens.

In terms of prognosis, the mean survival of MUP patients with lymphatic metastasis is 24–165 months, and that of MUP patients with visceral metastasis is 3–13.2 months [3], suggesting that the latter have shorter overall survival [22]. In terms of treatment, patients with MUP should be actively treated according to the same standards as patients with metastatic disease whose primary disease has been completely treated, and resectable lesions should be surgically removed as much as possible. In the event of lymphatic metastasis, lymph node dissection should also be conducted [21]. However, the patient in this study could not receive surgical resection due to hepatic diffuse metastasis with metastases in other sites and was treated primarily with immunotherapy and targeted therapy, combined immune checkpoint inhibitors of cytolytic T lymphocyte-associated antigen 4 and programmed death 1 could be considered as a therapeutic regimen [23].

4 Conclusion

MM originating from the liver necessitates the accumulation of a comprehensive medical history, a thorough physical examination, and a corresponding auxiliary examination in order to search for the primary lesion. If the primary lesion cannot be identified, PHM or MUP should be considered.

  1. Funding information: This research was funded by Guiding Project of Jiangsu Provincial Science and Technology Department (No. BY2022016).

  2. Author contributions: Conception and design of the research: Fei Qiao, Jun-yong Che. Acquisition of data: Zheng Yuan, Hai-yan Guo, Wei-ting Lu, Jing He, Fan Zhang, Yao-hui Wang; analysis and interpretation of the data: Yao-hui Wang; statistical analysis: Zheng Yuan, Jun-yong Che; obtaining financing: Fei Qiao; writing of the manuscript: Zheng Yuan; critical revision of the manuscript for intellectual content: Hai-yan Guo, Wei-ting Lu; all authors read and approved the final draft.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2023-06-07
Revised: 2023-09-01
Accepted: 2023-09-11
Published Online: 2023-10-23

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
https://doi.org/10.1515/biol-2022-0750
Keywords for this article
diagnosis; liver; malignant melanoma; unknown primary
Creative Commons
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  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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