Unexpected metastasis of thyroid cartilage involvement from lung adenocarcinoma: A case report

Abstract

BACKGROUND

Thyroid cartilage noncontiguous metastatic involvement is an extremely rare entity due to the absence of vessels within the cartilaginous tissue. A literature review revealed that metastasis from lung cancer is even rarer.

CASE SUMMARY

A 51-year-old male smoker presented with progressive, painful left upper neck lumps for 8 months, accompanied by 10 kg weight loss, poor appetite, and mentation. He had a 30-year history of chronic alcohol use. Following comprehensive imaging studies and pathological examinations, we have identified metastatic lung adenocarcinoma with widespread dissemination to multiple sites including the thyroid cartilage. The final diagnosis is: Lung adenocarcinoma (pT3N3M1c, Stage IVb), epidermal growth factor receptor-mutated (p.E746_S752delinsV). After multidisciplinary team discussion, the patient was initiated on targeted therapy with gefitinib (250 mg/day). At 6-month follow-up, the patient has shown significant clinical improvement with marked reduction in subcutaneous masses in both the cervical and abdominal regions.

CONCLUSION

Monitor for uncommon thyroid cartilage noncontiguous metastases; early detection improves outcomes.

Key Words: Neck neoplasms; Thyroid cartilages; Adenocarcinoma of lung; Case report

Core Tip: This rare case documents thyroid cartilage metastasis from an epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (p.E746_S752delinsV) in a 51-year-old smoker. Despite the avascular nature of cartilaginous tissue, the patient presented with neck masses, weight loss, and widespread metastases (pT3N3M1c, stage IVB). First-line gefitinib achieved remarkable regression of cervical, abdominal subcutaneous, and oropharyngeal lesions at 6 months. Key highlights: (1) Thyroid cartilage metastasis, though exceptionally rare, warrants vigilance in lung cancer; (2) EGFR targeting remains effective even in unusual metastatic patterns; and (3) Multidisciplinary management optimizes outcomes. Early molecular testing is critical for tailored therapy.

INTRODUCTION

The thyroid cartilage is seldom involved in metastatic processes because its cartilaginous structure lacks vascular supply, preventing hematogenous dissemination. Previous reports have described cases of cartilaginous involvement in a melanoma[1], advanced stage carcinoma prostate[2,3], breast[4], but only a few reports of thyroid cartilage metastatic lesions from the lungs have been published[5]. Lung adenocarcinoma (LUAD), which accounts for the majority of non-small cell lung cancer (NSCLC) cases, often presents with metastatic tumors at diagnosis, contributing to its unfavorable 5-year survival outcomes. Although LUAD can metastasize to any part of the body, the nervous and respiratory systems, bone, liver, and adrenal glands are the most common sites for LC metastasis[6]; however, metastasis to the head and neck region is less prevalent as compared to the other sites. Laryngeal metastases usually remain unnoticed and may or may not present with clinical symptoms. Herein, we report a rare case of thyroid cartilage metastasis from a LUAD. We hope that our report will add to the existing literature on this subject.

CASE PRESENTATION

Chief complaints

A 51-year-old Chinese male presented with neck lumps, accompanied by mild pain, that gradually increased in size over the left side of the upper neck region for 8 months.

History of present illness

The patient presented with neck lumps, and multiple subcutaneous masses on his abdominal wall and back. He began experiencing hemoptysis and fatigue for the last month, which was not relieved with conservative treatment. He had no other symptoms, such as choking while drinking, aspiration, difficulty breathing, dysphagia, or hoarseness; however, he had poor mentation and appetite, with a weight loss of 10 kg over the past 6 months.

History of past illness

The patient’s medical history was unremarkable, with no recorded chronic conditions, surgical procedures, or significant traumatic injuries.

Personal and family history

The patient has a 30-year history of smoking and alcohol use. No familial predisposition to neoplastic or heritable conditions potentially associated with the patient's clinical manifestations was identified.

Physical examination

Physical examination revealed multiple enlarged lymph nodes in the left neck regions II and IV, which were approximately 1 cm in diameter, firm in texture, and had limited mobility. Multiple firm, immobile masses were palpable in the chest, abdomen, back, and head, with the largest mass measuring approximately 4 cm in diameter. Laryngoscopy revealed blood-stained secretions in the left piriform sinus, with narrowing of the sinus and disrupted vascular patterns on the lateral wall under the NBI mode. The right piriform sinus and vocal cords showed no abnormalities (Figure 1A). A biopsy was performed concurrently, revealing a squamous epithelial covering with scattered lymphocytes in the stroma, but no definitive tumor was observed. Further imaging studies performed: Enhanced computed tomography (CT), magnetic resonance imaging, and positron emission tomography-CT (PET-CT), along with ultrasound-guided fine needle aspiration biopsy of the oropharyngeal and abdominal masses.

Figure 1 The laryngoscopy in the patient. A: Pre-treatment laryngoscopy: Blood-stained secretions attached to the lateral wall of the left piriform sinus, narrowing of the sinus; B: Laryngoscopy one month post-treatment: With disappearance of blood-stained secretions in the left piriform sinus, narrowing was less pronounced.

Laboratory examinations

The Laboratory tests reveal hypoalbuminemia (26.8 g/L), severely elevated D-dimer (39640 µg/L), mild hypertriglyceridemia (1.99 mmol/L), and low high-density lipoprotein (0.66 mmol/L). Multiple tumor markers are significantly elevated, including carcinoembryonic antigen (11.30 µg/L), CA 125 (57.0 U/mL), CA 15-3 (915.0 U/mL), CA 72-4 (178.00 U/mL), and CYFRA 21-1 (13.7 ng/mL) (Table 1). No significant abnormalities were detected in other tests.

Table 1 Partial laboratory results of the patient.

Test name	Value (Unit)	Reference range
albumin	26.8 g/L (↓)	34.0–53.0
D-dimer	39640 µg/L (↑)	0–550
triglyceride	1.99 mmol/L (↑)	0.50–1.90
high-density lipoprotein	0.66 mmol/L (↓)	1.10–2.00
carcinoembryonic antigen	11.30 µg/L (↑)	< 10
carbohydrate antigen 125	57.0 U/mL (↑)	< 35
carbohydrate antigen 15-3	915.0 U/mL (↑)	< 30
carbohydrate antigen 72-4	178.00 U/mL (↑)	< 6.9
CYFRA 21-1	13.7 ng/mL (↑)	< 3.3

Others relevant examinations

The pathology report showed the following results (Figure 2): Oropharyngeal biopsy revealed fibrous tissues with scattered atypical cells in a nest-like arrangement, with irregularly enlarged nuclei and abundant cytoplasm, consistent with metastatic LUAD; abdominal wall biopsy showed proliferative fibrous tissues with infiltrative growth of atypical cells arranged in glandular or nest-like patterns, with irregularly enlarged nuclei and abundant cytoplasm, which was also consistent with metastatic LUAD.

Figure 2 The pathology of oropharyngeal and abdominal wall biopsy. The immunohistochemical staining results indicate: TTF-1 (+), Napsin A (+). A: (Laryngeal biopsy tissue) Microscopic examination reveals a small amount of striated muscle tissue and fibrous tissue, with scattered atypical cells arranged in nests within the fibrous stroma. The cells exhibit irregular nuclear enlargement and abundant cytoplasm; B: (Abdominal wall biopsy tissue) Microscopic examination shows infiltrative growth of atypical cells within proliferative fibrous tissue, arranged in glandular or nested patterns. The cells demonstrate irregular nuclear enlargement and abundant cytoplasm. The morphologies are consistent with metastatic lung adenocarcinoma.

Programmed death-ligand 1 (PD-L1) expression was negative (tumor proportion score, TPS < 1%). LC next-generation sequencing panel testing identified one somatic mutation, including one with clear or potential clinical significance (EGFR p. E746-S752 delinsV). No hereditary risk-related mutations were detected, and no level II targeted drug mutations were found.

Imaging examinations

The imaging studies showed the following findings (Figure 3): Peripheral-type LC in the left upper lobe with adjacent pleural invasion; multiple metastatic tumors in both lungs; multiple lymph node metastases in the bilateral supraclavicular, mediastinal, left hilum, and neck regions II and IV; bilateral adrenal metastases; multiple bone metastases; dispersed soft tissue nodules in the chest wall; slightly hyperdense masses and nodules in the left temporal and right parietal lobes, with increased metabolism, all suggesting metastasis; and nodules in the left piriform sinus with bone destruction of the thyroid cartilage.

Figure 3 The imaging of the case. A: Axial computed tomography (CT) with contrast image shows nodules in the left piriform sinus with bone destruction of the thyroid cartilage; B: Magnetic resonance imaging shows nodules in the left piriform sinus; C: CT with contrast image shows peripheral type lung cancer in the left upper lobe; D: Positron emission tomography-CT images. Imaging confirmed widespread metastases involving hilar/mediastinal/supraclavicular/cervical lymph nodes, bilateral adrenals, and multiple bones (spine and thyroid cartilage).

MULTIDISCIPLINARY EXPERT CONSULTATION

After multidisciplinary discussion involving thoracic surgery, oncology, radiation therapy, pulmonology, and neurosurgery, the patient was diagnosed with widely metastatic advanced LUAD. Targeted therapy was initiated as the primary treatment.

FINAL DIAGNOSIS

The final diagnosis was LUAD (pT3N3M1c, IVb), with characteristic EGFR exon 19 p.E746_S752delinsV mutation.

TREATMENT

The patient was treated with oral gefitinib (0.25 g, once a day) for targeted therapy.

OUTCOME AND FOLLOW-UP

At the 6-month of follow-up, the patient reported a reduction in the oropharyngeal mass (Figure 1B), with considerable shrinkage of the abdominal, back, and scalp masses, along with notable improvement in mental status and appetite.

DISCUSSION

The thyroid cartilage's avascular structure makes metastatic infiltration a rare phenomenon. We describe an uncommon case of thyroid cartilage metastasis in a 51-year-old man with LUAD. The patient's significantly elevated tumor markers (e.g., carcinoembryonic antigen: 11.30 µg/L, CA125: 57 U/mL) strongly suggest widespread metastatic disease. The thyroid cartilage is most frequently involved by metastatic spread from primary malignancies of proximate anatomical structures, particularly the larynx, vallecula, and pyriform sinus[7]. Laryngeal cartilage metastases are uncommon in clinical practice, predominantly associated with disseminated prostate cancer[8] and melanoma[1], with only rare cases secondary to lung malignancies[9]. Until now, only a limited number of reports have described metastatic lesions to the thyroid cartilage. Age-related ossification of laryngeal structures correlates with elevated metastatic potential, as calcified cartilage develops vascular channels that may facilitate tumor cell colonization[9]. In the present case of advanced LUAD with widespread metastasis, it was unusual that the neck metastasis was centered around the thyroid cartilage, whereas the mucosa of the pharynx and larynx remained normal, with no visible lesions or symptoms. Hence, direct seeding of the tumor cells cannot be considered.

Potential explanations may lie within the hematogenous or lymphatic routes of distant cancer metastases. Hyaline cartilage is known to undergo bony metaplasia and ossification during the aging process and, as the bone has a better vascular supply than the cartilage, Ehrlich[10] hypothesized that this phenomenon could explain the development of a distant metastasis through the hematogenous route. Laryngeal cartilage metastasis starts by micro-metastases within the hematopoietic tissue of the ossified laryngeal parts. Then, they merge to form visible focal tumor nodules, and further growth causes destruction of the laminas. Subsequently, tumor extension is seen into the perilaryngeal soft tissue. Although he is a relatively young man, the tumor progression may have led to increased blood supply and subsequent exacerbation of ossification. Additionally, this patient has a markedly elevated D-dimer level, it primarily result from tumor-associated hypercoagulability (via tissue factor overexpression and fibrinolysis activation) and may serve as a prognostic biomarker for venous thromboembolism risk and disease progression[11].

Secondary laryngeal tumors account for 0.09%–0.4% of all laryngeal tumors[8]. Distal tumors rarely metastasize to the larynx because they are terminally located in the lympho-vascular circulation. The difference in the symptoms between secondary laryngeal and primary tumors is the presence of hemoptysis. Rossini et al[12] conceivable that it is a standard indicator of laryngeal metastasis because these tumors have a highly vascular stroma. As seen in the present case, despite the fact that hemoptysis may be associated with the primary LC, it explains why blood-stained secretions are seen attached to the lateral wall of the piriform sinus, while the other areas lack such secretions.

Evidence from Prescher et al[13] suggests that the thyroid cartilage involvement is suggestive of a poor prognosis as it indicates the presence of extensive metastases. Laryngeal metastases usually remain unnoticed and may or may not present with clinical symptoms. Consequently, these metastases are rarely detected at early stages, typically manifesting only when advanced disease is established, thereby portending an unfavorable prognosis. The same was seen in our case; our patient had no thyroid cartilage involvement symptoms even with the presence of a relatively large mass in the piriform sinus. Additionally, tumors metastasizing to the laryngeal regions are often highly aggressive.

The patient was diagnosed with LUAD exhibiting metastases to the brain, adrenal gland, neck, and widespread bone, classified as unresectable advanced metastatic NSCLC. Epidemiological data indicate that median overall survival (OS) of 18-24 months for patients with unresectable locally advanced or metastatic NSCLC, reflecting the aggressive nature of advanced disease. However, Shi et al[14] proposed that patients with NSCLC harboring sensitizing epidermal growth factor receptor (EGFR) gene mutations demonstrate significantly prolonged median OS compared to wild-type patients (34.7 vs 18.1 months, P < 0.001), largely explained by conferred by EGFR tyrosine kinase inhibitors (EGFR-TKIs) therapy[15].

Shi et al[16] demonstrated that EGFR mutations associated with NSCLC are predominantly located in exons 18–21, with the most common classic sensitizing mutations being exon 19 deletions (EGFR 19del) and the exon 21 L858R point mutation (EGFR L858R). In this case, the patient carried a p.E746_S752delinsV non-frameshift deletion mutation in exon 19. Previous studies have shown that, in treatment-naïve advanced NSCLC patients with sensitizing EGFR mutations, compared to platinum-doublet chemotherapy, first-/second-generation EGFR-TKIs show significantly higher objective response rate and longer median progression-free survival in first-line setting[17-19]. Therefore, this patient was treated with targeted therapy as the first-line approach. As a first-generation EGFR-TKI, gefitinib demonstrates high efficacy against EGFR-sensitive mutations (Ex19del/L858R), offers convenient once-daily oral administration, and exhibits a favorable safety profile with lower incidence of severe adverse events. Its cost-effectiveness and inclusion in national insurance reimbursement, gefitinib was selected as the first-line treatment for this patient.

Immune checkpoint inhibitors, specifically programmed death-1/PD-L1 monoclonal antibodies, have revolutionized the treatment paradigm for advanced NSCLC, advancing from second-line to standard first-line therapy for certain patients. Consequently, PD-L1 testing was performed for this patient. Unfortunately, his TPS was < 1%, rendering immunotherapy unsuitable in this case.

In our case, despite the presence of multiple metastases throughout the body, gene testing revealed an EGFR mutation, which aligns with the NCCN 2024 version 4 guidelines for advanced or metastatic NSCLC[20]. The patient received a targeted therapy with gefitinib. After > 6 months of follow-up, he had significant symptom improvement, with a notable reduction in the size of the abdominal wall, back, neck, and scalp masses, leading to an enhanced quality of life.

CONCLUSION

Although distant metastasis of tumors to the larynx is rare, and even rarer to the thyroid cartilage, it remains possible that micro-metastases could occur through hematogenous routes within hematopoietic tissues during the cartilage ossification process, leading to distant spread, and mainly suggestive of poor prognosis. In the diagnosis and treatment of malignant tumors, it is essential to conduct a thorough history-taking, comprehensive physical examination, and supportive investigations to avoid any potential oversights.