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Case Presentation – September 2025

Metastatic Melanoma in the Pleural Cavity

Written by: Pablo Linares, student, Cleveland Clinic Cytology program, Cleveland, Ohio.

Patient Age:  62-year-old male

Specimen Type: Right pleural fluid, ThinPrep® Non-Gyn slide and cell block.

Patient History: Stage IV metastatic melanoma from the posterior left shoulder metastasized to the lungs, brain, liver, mediastinal, retroperitoneal, pelvic, and spine.

Cytologic Diagnosis: Positive for malignant cells. Metastatic malignant melanoma.

Biopsy/Pathologic Diagnosis:

Transbronchial lung biopsies, right middle, and left upper lobe, were positive for melanoma. The left upper lobe fine-needle aspiration was positive for malignant cells consistent with melanoma. IHC stains were positive for S-100 and variably positive for HMB 45, supporting the diagnosis of melanoma.

 Case provided by: Cleveland Clinic, Cleveland, Ohio.

Metastatic Melanoma in the Pleural Cavity

Etiology:

In most cases, melanoma is caused by exposure to ultraviolet (UV) radiation 1. Melanomas may also be caused by inherited genetic changes such as CDKN2A which comprise 22% of all cases 2. Metastatic melanomas are extremely rare and represent about 5% of all secondary malignancies of the lung, but only 2% of patients with metastases have pleural effusions 3.

Clinical Features:

Metastases to the pleural cavity are rare, and it is uncommon to find malignant pleural effusions. Pleural metastatic melanoma may present with pleural thickening. Pleural effusions may be unilateral or bilateral4. Patients may present with continuous coughing accompanied by hemoptysis, breathlessness, and ongoing chest infection 5.

The chest radiograph showed complete opacification of the right hemithorax with subsequent bedside ultrasound showing a right-sided pleural effusion.  The patient had tachycardia and tachypnea.  

Treatment and Prognosis:

For follow-up, video-assisted thoracoscopy, chest CT, and pleural biopsy are paramount. The five-year survival rate for stage four melanoma is 22.5% 6. The patient was given a one-year immunotherapy treatment consisting of ipilimumab and nivolumab. Ipilimumab blocks a checkpoint molecule called CTLA-4 which regulates the growth and activity of T cells. This activates the immune system against melanoma. On the other hand, nivolumab blocks a checkpoint molecule called PD-1 which causes the immune system to find and attack melanoma cells 7. Additionally, the patient had given dabrafenib and trametinib, targeted cancer drugs that can be used to treat melanomas with BRAF mutation. The treatment works as a cancer growth blocker, inhibiting specific cancer-promoting proteins 8. 

Cytology:

Common cytological criteria include binucleation, pale chromatin, large nucleoli, and intranuclear cytoplasmic invaginations. Melanin pigment may or may not be present. In the ThinPrep specimen, the cells showed nuclear enlargement, eccentric nuclei, some nucleoli, melanin pigment, open chromatin, and a high N/C ratio 9. In the cell block, the cells showed melanin, prominent nucleoli, and nuclear enlargement.

Differential Diagnosis:

Based on cell morphology and high rates of pulmonary carcinoma among men, adenocarcinoma of the lung would be considered a differential diagnosis. Additionally, due to the proximity to the pleural cavity, it is more commonly found in effusions. The cells have many typical characteristics of what would be expected in adenocarcinoma. Some cell groups lack markedly differentiated cell borders. The cells look enlarged with apparent nucleoli 10. Some of the cells look eccentric on ThinPrep. Open chromatin can be seen. In certain metastatic sites, hemosiderin-laden macrophages may be confused with melanoma cells pigmented with melanin.

Mesothelioma is another possible differential as it can be quite frequent among men, 75-87%, and it can be found in the pleural cavity 11. Additionally, pleural mesothelioma makes up 70 to 79% of all mesotheliomas 12. However, cytologically this patient’s cells lack typical mesothelioma criteria such as knobby borders, clustering, and large cell size, with no distinct windowing between the malignant cells.

 Another potential differential is reactive mesothelial cells which are commonly characterized by prominent nucleoli, cytoplasmic vacuoles, and eccentric nuclei. Reactive mesothelial cells can result from several factors such as infection, inflammation, radiation, chemotherapy, trauma, foreign materials, and neoplasia 13.

Due to striking cytological similarities between the differentials, IHC stains are extremely helpful in confirming the diagnosis. TTF-1 and Claudin 4 can be used to rule out lung adenocarcinoma if negative. Conversely, WT-1 can be used to rule out mesothelioma if negative.  EMA, CK7, and TERT can all be used to differentiate mesothelioma cells from reactive mesothelial cells14.  To confirm a diagnosis of melanoma, S-100, SOX10, HMB 45 and melanA can be used9.

References:

  1. Peri C. Metastatic Melanoma. WebMD. Published April 26, 2022. https://www.webmd.com/melanoma-skin-cancer/metastatic-melanoma
  2. Fischer R. How Genetics and Family History Contribute to Melanoma Risk – Melanoma Research Alliance. Curemelanoma.org. Published 2023. https://www.curemelanoma.org/blog/how-genetics-and-family-history-contribute-to-melanoma-risk
  3. Ambra Enrica D’Ambrosio, Albonico G, Ignazio Enide, Orazio Mordà, Maisano M, Mondello B. Pleural Melanoma Metastasis. The Annals of Thoracic Surgery. 2021;112(2):e103-e105. doi: https://doi.org/10.1016/j.athoracsur.2020.09.088
  4. Prasad S, Xiong J, Kaur J. Pleural Metastatic Melanoma With Recurrent Malignant Pleural Effusions. Cureus. 2024;16(7). doi:https://doi.org/10.7759/cureus.64366
  5. Cancer Research UK. Symptoms of Advanced Melanoma | Melanoma | Cancer Research UK. Cancerresearchuk.org. Published 2020. https://www.cancerresearchuk.org/about-cancer/melanoma/advanced-melanoma/symptoms-advanced-melanoma
  1. Stage 4 Melanoma. Melanoma Research Alliance. https://www.curemelanoma.org/about-melanoma/melanoma-staging/stage-4-melanoma
  1. Nivolumab (Opdivo®) + Ipilimumab (Yervoy®). Curemelanoma.org. Published 2015. https://www.curemelanoma.org/patient-eng/melanoma-treatment/options/nivolumab-opdivo-ipilimumab-yervoy
  1. Dabrafenib and trametinib. www.cancerresearchuk.org. Published April 26, 2026. https://www.cancerresearchuk.org/about-cancer/treatment/drugs/dabrafenib-trametinib
  1. Mansour B, Donati M. Invasive melanoma. www.pathologyoutlines.com. Published June 22, 2021. https://www.pathologyoutlines.com/topic/skintumormelanocyticmelanoma.html
  2. Underwood C, Musick A, Glass C. Adenocarcinoma Overview. www.pathologyoutlines.com. Published February 27, 2023. https://www.pathologyoutlines.com/topic/lungtumoradenocarcinoma.html
  1. Roden A. Diffuse malignant mesothelioma. www.pathologyoutlines.com. Published March 4, 2021. https://www.pathologyoutlines.com/topic/pleuramesothelioma.html
  1. Selby K. Pleural Mesothelioma: Symptoms, Prognosis & Top Treatments. Mesothelioma Center – Vital Services for Cancer Patients & Families. Published January 21, 2025. https://www.asbestos.com/mesothelioma/pleural/
  2. Bomeisl III PE, Michael CW. Mesothelial Cells, Reactive. Encyclopedia of Pathology. Published online 2017:265-268. doi:https://doi.org/10.1007/978-3-319-33286-4_920
  3. Vickery J, Husain A. Mesothelioma versus adenocarcinoma. www.pathologyoutlines.com. Published May 23, 2022. https://www.pathologyoutlines.com/topic/pleuramesovsadeno.html

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