Endobronchial, laryngeal and mediastinal melanoma: a rare constellation of metastatic disease

Abstract

A 45-year-old man presents with acute respiratory failure. Imaging revealed a left mainstem endobronchial mass with subcarinal lymphadenopathy, but no other evidence of a primary tumour. An incidental laryngeal nodule was found during bronchoscopy. Biopsies of this lesion by nasopharyngoscopy and subcarinal lymph nodes via mediastinoscopy were performed. Histopathological and immunohistochemical examination showed evidence of melanoma in both samples. Mutational analysis identified the presence of a BRAF^V600E mutation. The patient underwent bronchoscopic ablation of the left mainstem endobronchial tumour with laser therapy followed by initiation of encorafenib and binimetinib combination therapy. The patient remains alive at 4 months after initial presentation of disease. This case adds to the body of literature highlighting the clinical heterogeneity and challenges of the management of metastatic pulmonary melanoma. To the best of our knowledge, this simultaneous constellation of metastasis has not been described before.

Background

Endobronchial melanoma is an uncommon manifestation of metastatic disease that comprises 4.5% of all endobronchial metastases^{1 2} and presents at a median of 48 months after initial melanoma diagnosis.³ The incidences of laryngeal and mediastinal metastases are reported to be 1.1%⁴ and 16%,⁵ respectively. Mortality of metastatic melanoma to the lungs is poor, demonstrating a 1-year survival rate of 9%–19%.⁶ Respiratory failure caused by metastatic lesions is the most common cause of death in patients with pulmonary melanoma.⁷

Recognition of these uncommon manifestations of melanoma is crucial for timely surgical intervention and initiation of immunotherapy. Complete surgical resection of limited metastases may prolong survival in select patients.⁸ However, prognosis following surgical resection remains poor due to the presence of micrometastases and recurrence of disease.⁹ Further, anti-programmed death protein-1 (PD-1)¹⁰ and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)¹¹ antibody immunotherapy for metastatic melanoma has shown improvement in overall survival compared with traditional chemotherapy.

Given the rarity of these individual anatomical manifestations and the complex treatment implications, we describe a case and management of metastatic melanoma presenting with simultaneous left mainstem endobronchial lesion, subcarinal lymph node and epiglottic involvement presenting 156 months after initial resection of localised cutaneous melanoma of the lower extremity.

Case presentation

A 45-year-old Ecuadorian man presents to our emergency room with a 2-month history of intensifying non-productive cough, left-sided pleuritic chest pain and a sensation of breathlessness. There are no clear precipitating or alleviating factors. He reports having gangrene of his left foot in 2003, due to complications from cutaneous melanoma, that was resected with clean margins. He reports that he received adjuvant chemotherapy but could not recall the precise regimen. He works in construction and has known industrial exposures to dust, fumes and metal exposure. Otherwise, he does not have a tobacco or alcohol use history, tuberculosis exposure or any known relevant family history.

Investigations

Initial vital signs were significant for acute respiratory failure with a SaO₂ of 89% room air that merely improved to 93% on 4 L of nasal cannula. Physical examination was notable for asymmetric chest excursion, dullness to percussion and absence of breath sounds over the left lung fields. Arterial blood gas demonstrated primary respiratory alkalosis and hypoxemic respiratory failure at pH 7.46/PaCO₂ 31/PaO₂ 58/bicarbonate 22.0. Complete blood count, chemistries and coagulation parameters were within normal limits.

Chest X-ray demonstrated near white-out of the left hemithorax with spared areas of lung aeration at the apex concurrent with ipsilateral tracheal deviation (figure 1). Thoracic ultrasonography showed the absence of pleural effusion. CT revealed atelectasis of the lingula and the left lower lobe due to an endobronchial mass in the left mainstem bronchus. Further, there was concurrent subcarinal lymphadenopathy (figure 2).

Figure 1.

Chest X-ray. (A) Posteroanterior film showing near complete opacification of left hemithorax with sparing of the left lung apex and ipsilateral tracheal deviation. (B) Lateral view. There is evidence of a partially occluded left mainstem bronchus (red circle).

Figure 2.

CT of the chest with contrast. (A) Axial cut in lung window demonstrating 6 mm soft tissue nodule at the entrance of the left mainstem bronchus. More distally, the entire left mainstem bronchus and lobar bronchi of the left lung are complete occluded. Calcified right pulmonary nodules are also seen. (B) Axial cut in mediastinal window highlighting a large subcarinal soft tissue mass measuring 5.1×5.6×5.5 cm, that is, causing splaying of the pulmonary arterial bifurcation and splaying of the carina. This mass is contiguous with a left-sided precarinal lymph node measuring 2.6×2.4×2 cm.

Microbiological investigations demonstrated a positive interferon-gamma release assay for Mycobacterium tuberculosis (MTb) but with a negative nucleic acid amplification test for MTb. Three consecutive sputum acid-fast stain were negative for MTb. Also, HIV p24 antigen and HIV-1 and HIV-2 antibody testing were negative.

Flexible bronchoscopy under general anaesthesia was performed. While passing the vocal cords, the presence of a dark blue pigmented nodule was visualised over the left laryngeal surface of the epiglottis. In the left mainstem bronchus, immediately distal to the carina by about 3 cm, was the presence of a 4 cm fungating, haemorrhagic and tan-coloured mass that nearly obstructed the airway and prevented the scope from passing, despite visualisation of the distal airway (figure 3).

Figure 3.

Bronchoscopic view of the tan-coloured endobronchial tumour obstructing the left mainstem bronchus.

Brush cytology of the endobronchial mass was performed. In light of profuse haemorrhage caused by the brushing, biopsy of the mass was deferred. Transbronchial needle aspiration was performed of the subcarinal lymph nodes. However, these samples were unrevealing for malignancy.

Alternate biopsy sites of potential metastases were pursued. Nasopharyngoscopy was performed and detailed the presence of an irregularly shaped, dark blue coloured, sessile nodule on the superior left laryngeal surface of the epiglottis (figure 4). A biopsy of the vocal cord nodule was performed and histopathology revealed evidence of brown melanin pigment among epitheliod and fusiform cells among a loose fibrous background (figure 5). Subsequent immunohistochemistry analysis confirmed this lesion to be a melanoma.

Figure 4.

Nasopharyngoscopic view of the dark blue coloured left vocal cord nodule.

Figure 5.

Laryngeal nodule pathology. H&E stain (×200) demonstrating a neoplasm composed of fusiform and epitheliod cells in a loose fibrous background with brown pigment.

Because of the possibility of two distinct malignancies, mediastinoscopy was performed. Tissue biopsy of the subcarinal lymph nodes also revealed a neoplasm consisting of epitheliod and fusiform cells but sans visible brown pigment (figure 6). Subsequent immunohistochemistry analysis also confirmed this lesion to be a melanoma.

Figure 6.

Subcarinal lymph node pathology. H&E stain (×200) demonstrating a neoplasm composed of fusiform and epitheliod cells in a loose fibrous background. No pigment is seen.

Table 1 shows full details of immunohistochemical analyses of both lesions.

Table 1.

Solid tumour immunohistochemical analysis of the biopsied tissue sites

	Laryngeal nodule		Subcarinal lymph node
S-100	Positive	S-100	Positive
HMB45	Positive	CK5/6	Negative
AE1/AE3	Negative	AE1/AE3	Negative
Melan A/Mart - 1	Positive
Chromogranin A	Negative

S-100—neural crest derivatives—including melanoma; HMB45—melanoma-associated marker; Melan A/Mart-1—melanoma-associated marker; AE1/AE3—monoclonal antibodies to cytokeratin; chromogranin A—neuroendocrine marker; CK5/6—squamous and mesothelial cells.

CK5/6, cytokeratin 5/6; HMB45, human melanoma black 45.

The diagnosis of recurrent and metastatic melanoma to the left mainstem bronchus, left vocal cord and the mediastinum was established.

Differential diagnosis

The primary differential diagnosis for an obstructive endobronchial lesion is a tumour, whether malignant or benign. Squamous cell carcinoma of the lung would the prime differential in a patient who has had known exposures to toxic airway exposures in his workplace. However, the history of being a non-smoker makes this less likely. Other benign tumours (eg, hamartoma, chondroma, lipoma, leiomyoma, mucus gland adenoma, papilloma) can also be entertained as possibilities.

Although endobronchial metastases are less common manifestations of pulmonary metastases, it remains a distinct possibility given the patient’s prior history of malignant melanoma. Lymphoma (Hodgkin and non-Hodgkin), colorectal cancer, melanoma and renal cell cancer are all known malignancies that metastasise to the bronchi.

Treatment

With aggressive chest physiotherapy, the patient demonstrated improvement in oxygen saturation, work of breathing and aeration of the left lung on chest radiography. However, the patient remained unable to perform strenuous physical activity without developing dyspnea. Because the persistent near occlusion of the left mainstem bronchus was not likely to resolve spontaneously, the patient was referred to interventional pulmonology at an affiliated tertiary care centre for further evaluation and management of his central airway obstruction (CAO).

Outcome and follow-up

After interventional pulmonology evaluation, the patient underwent bronchoscopic ablation with laser therapy via rigid bronchoscopy. Following this, his left lung fully re-expanded and the patient’s oxygenation and functional status improved significantly. Subsequently, he was referred to medical oncology. Mutational analysis revealed the presence of an activating BRAF^V600E mutation. The patient was initiated on encorafenib 450 mg once a day and binimetinib 45 mg two times per day.

At 5 months after initial diagnosis, the patient remains alive and has tolerated this therapy without significant morbidity or toxicity and there has been no radiographic or clinical evidence of progression of disease.

Discussion

A review of the literature has revealed several cases of primary or metastatic melanoma occurring at the individual anatomical sites of the larynx,¹² mediastinum^{13 14} and bronchus.^15–17

Our case is unique for two reasons. First, the simultaneous presentation of three distinct anatomical sites of metastasis has been noted earlier in this report. Second, the late recurrence duration of 15 years is an uncommonly long period of time. In a retrospective analysis of 1372 stage I and II melanoma survivors who survived >10 years, only 5.6% of these patients had a recurrence at least 10 years after initial diagnosis.¹⁸

Regarding treatment of pulmonary metastatic melanoma, there are no consensus treatment guidelines or large clinical trials to guide the specific management of endobronchial, laryngeal or mediastinal metastases. Hence, treatment algorithms and data from the studies using immunotherapy for metastatic or unresectable melanoma in cases of pulmonary involvement.^{19 20}

Surgical management

Complete surgical resection via pulmonary metastasectomy to reduce the tumour burden is advocated prior to initiation of chemotherapy. Among patients with pulmonary metastases, data from the International Registry of Lung Metastases showed improved 5-year and 10-year survival rates after complete metastasectomy compared with incomplete resection (22% vs 0% and 16% vs 0%, respectively).²¹ A database of 289 patients with metastatic pulmonary nodules found a median survival of 1 year.²² Other studies have identified 5-year survival rates in the range of 5%–33%^{23 24} and a mean survival of 7.3 months.²⁵ Regarding endobronchial metastases, there are limited survival data. A recent retrospective study by Chaussende et al revealed a median survival of the studied population of 6 months.²⁶ Also, there are case reports of limited survival with durations of as short as 3 months.²⁷ However, even among patients who undergo surgical metastasectomy, the prognosis of patients with malignant melanoma of the lung is generally poor because the lesion often metastasises soon after surgery⁹ and recurrences have been documented despite adequate surgical resection and systematic lymph node dissection.^{16 28}

In accordance to the American College of Chest Physicians guidelines regarding palliative care in lung cancer,²⁹ our patient underwent an ablative therapy for his CAO. There are several strategies available used to secure the airway and debulk the obstructing tumour mass. These include laser resection, cryotherapy, electrocautery, photodynamic therapy, argon plasma coagulation, external beam radiation and brachytherapy. Our patient underwent laser resection of the endobronchial tumour and this quickly achieved patency and security of the airway. In light of advanced metastatic disease in other anatomical locations, an individualised decision to defer adjunctive therapy with electron beam radiation therapy was made.

Despite the immediate efficacy of this laser ablation, definitive outcome data are limited. Among retrospective case series, most of which primarily involved primary lung malignancy, laser therapy has been attributed to improvement in airway patency in the majority of cases^30–32 and has also facilitated extubation in patients with CAO-associated respiratory failure.³³ In the largest of these studies involving 1838 patients,³⁰ laser therapy was associated with improved airway patency and improvement of respiratory symptoms in 90% of the study patients. However, the effects were short lived as the median time to a repeat laser procedure was 102 days.

Regarding laryngeal metastases, there are no clear surgical treatment guidelines. One review of 39 cases of laryngeal metastases, spanning from 1900 to 2010, have described the use of total laryngectomy and more modern techniques of laser excision.¹² However, outcome data are lacking in this case series. Similarly, there are no clear surgical treatment guidelines for the management of mediastinal lymph node metastases. Expert opinion on the basis of case series advocate for complete surgical resection of involved lymph nodes.^34–36

Chemotherapy and immunotherapy

Dacarbazine, an imidazole carboxamide, was initially the only chemotherapeutic agent that showed efficacy in the treatment of metastatic melanoma.³⁷ However, its response rate and median survival were studied to be in the range of 7%–12% and 5.6–7.8 months, respectively.^38–40

Immunotherapy has become the mainstay of therapy for malignant melanoma therapy and has largely supplanted the use of dacarbazine due to superior efficacy and median survival rates. The use of IL-2 and interferon-alpha are approved for use for unresectable disease. However, these therapies have had limited application in light of large side effect profiles,⁴¹ despite anecdotal reports of success in achieving a remission in pulmonary melanoma.¹⁷

Recently in the last decade, new immunotherapeutic agents have been made available for use in metastatic and unresectable melanoma. Ipilimumab, a murine monoclonal antibody targeting CTLA-4, combined with dacarbazine, the use of ipilimumab has been shown to improve 5-year survival rates.¹¹ Vemurafenib, an oral BRAF^V600E mutation inhibitor, was shown to improve 6-month survival rates by 20% compared with dacarbazine.⁴² Nivolumab and pembrolizumab are ‘checkpoint inhibitors’ that target PD-1. Nivolumab demonstrated an 11.5% reduction in recurrence and death compared with ipilimumab in a population of patients with stage IIIB/C or stage IV melanoma with complete resected primary disease.⁴³ Pembrolizumab demonstrated significant and improved 6-month progression-free survival rates compared with ipilimumab (47.3% vs 26.5%).⁴⁴ Most recently on June 2018, the Food and Drug Administration (FDA) approved encorafenib and binimetinib as combination therapy for metastatic or unresectable melanoma with BRAF^V600E or BRAF^V600K mutations. In the phase III COLUMBUS trial, these two agents were shown to have a median progression-free survival rate of 14.9 months compare to 7.3 months for patients receiving vemurafenib.⁴⁵

Conclusion

Despite the increasing repertoire of immunotherapy for metastatic and unresectable melanoma, the prognosis of patients with pulmonary metastatic melanoma remains dismal with a median survival of 189 months and a 5-year survival of 21%.²⁴ Further, there is only a 6-month median overall survival rate in patients with metastatic endobronchial melanoma.²⁸ Given these poor survival rates, the expeditious use of immunotherapy, surgical resection and radiotherapy may be able to confer a survival advantage and possibility improved functional quality of life.

To summarise, we present a unique case of simultaneous involvement of these anatomical locations to highlight the unpredictable spatial and temporal heterogeneity of the pattern of melanoma metastases. Our case highlights the concept that melanoma cannot be regarded as cured even after primary resection and clearance of margins. Therefore, any patient with a history of melanoma and pulmonary symptoms warrants an aggressive and prompt diagnostic workup.

Learning points.

• Recurrent metastatic melanoma can present with great spatial and temporal heterogeneity and can simultaneously involve multiple areas of the upper and lower airways.

• Interventional pulmonology techniques for endobronchial tumour destruction can result in improvement of lung aeration and function.

• Checkpoint inhibitors, including anti-programmed death protein-1, cytotoxic T-lymphocyte-associated antigen 4 and BRAF kinase inhibitor immunotherapy, offer promise as treatment options for pulmonary melanoma metastases that prolongs survival compared with traditional chemotherapy.

• The most important determinant of long-term survival in pulmonary metastatic melanoma is achieving a complete resection of metastatic disease.