What could be the primary malignancy in a patient presenting with sudden hoarseness of voice and metastasis to the liver, lung, and bones?

Primary Malignancy with Hoarseness and Liver, Lung, and Bone Metastases

Lung cancer, specifically small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), is the most likely primary malignancy in a patient presenting with sudden hoarseness of voice combined with metastases to the liver, lung, and bone. 1

Rationale for Lung Cancer as Primary

Hoarseness as a Key Localizing Symptom

• Hoarseness indicates left recurrent laryngeal nerve palsy, which occurs when tumors or malignant lymph nodes in the aorto-pulmonary window or mediastinum compress the nerve as it courses deep into the thorax under the aortic arch. 1

• This specific anatomical relationship makes lung cancer (particularly left-sided tumors) the most common cause of hoarseness from recurrent laryngeal nerve involvement. 1

• The right recurrent laryngeal nerve is less commonly involved because it does not traverse extensively into the chest. 1

Metastatic Pattern Strongly Suggests Lung Primary

• Brain, bone, liver, adrenal glands, and pleura are the most common sites of metastatic disease in both SCLC and NSCLC. 1, 2

• SCLC is characterized by early development of widespread metastases, with patients frequently presenting with bone pain, liver involvement, and neurologic compromise. 1

• Bone metastases occur in 6-25% of lung cancer patients at presentation, with vertebral bodies being the most common site. 2

• Liver metastases from lung cancer often present with weakness and weight loss, though liver function tests typically remain normal until advanced stages. 2

• The combination of liver, lung (suggesting intrapulmonary metastases or multiple primaries), and bone involvement is classic for advanced lung cancer. 1, 2

Differential Diagnosis Considerations

Small Cell Lung Cancer (SCLC)

• SCLC accounts for approximately 14% of lung cancers and is characterized by rapid doubling time, high growth fraction, and early widespread metastases. 1

• Preferential metastatic sites include brain, liver, adrenal glands, bone, and bone marrow. 1, 3

• Nearly all cases are attributable to cigarette smoking. 1

Non-Small Cell Lung Cancer (NSCLC)

• NSCLC commonly presents with a large hilar mass and bulky mediastinal lymphadenopathy, which can cause hoarseness through mediastinal invasion or lymphadenopathy in the aorto-pulmonary window. 1

• The metastatic pattern to liver, lung, and bone is consistent with NSCLC. 1, 2

Other Primaries to Consider (Less Likely)

• Breast cancer: Can metastasize to liver, lung, and bone, but laryngeal metastases causing hoarseness are extremely rare (less than 20 cases reported). 4, 5

• Renal cell carcinoma: Can metastasize to these sites but hoarseness from laryngeal involvement is uncommon. 5

• Thyroid cancer: Can show strong TTF-1 positivity (similar to lung adenocarcinoma) and metastasize to lungs and bone, but the clinical presentation with hoarseness would more likely be from direct local invasion rather than recurrent laryngeal nerve palsy from mediastinal disease. 6

• Colorectal cancer: Frequently metastasizes to liver and lungs but has a distinctive immunohistochemical profile (TTF-1 negative, CK7 negative, CK20 positive, CDX-2 positive) and hoarseness would be atypical. 6

Diagnostic Approach

Immediate Imaging

• CT chest with IV contrast is essential to identify the primary lung lesion, assess hilar and mediastinal lymphadenopathy, and characterize pulmonary metastases. 1, 2

• PET/CT should be performed to assess the full extent of metabolic activity in all metastatic sites and help distinguish primary from metastatic lesions. 1

• Brain MRI with contrast should be obtained given the high frequency of brain metastases in lung cancer (lung is the primary site in 70% of cancers presenting with symptomatic brain metastases). 2

Tissue Diagnosis

• Biopsy the most accessible metastatic site (liver, bone, or lung lesion) to establish both diagnosis and stage simultaneously. 1, 2

• If mediastinal lymphadenopathy is present, EBUS-guided needle aspiration has a diagnostic yield of 93% and specificity of 100%. 1

• Immunohistochemistry is critical: TTF-1 positivity strongly suggests lung primary, while CK7/CK20 patterns help distinguish from gastrointestinal or other primaries. 1, 6

Laryngoscopy

• Direct laryngoscopy should be performed to visualize vocal cord paralysis and rule out direct laryngeal involvement (which would suggest a different primary or metastatic disease to the larynx itself). 1

• True laryngeal metastases are rare and typically appear submucosal with intact overlying mucosa, most commonly in the supraglottis, requiring deep biopsies for diagnosis. 5

Critical Pitfalls to Avoid

• Do not assume hoarseness is from direct laryngeal involvement without imaging the chest and mediastinum first. The most common cause of hoarseness in this clinical scenario is recurrent laryngeal nerve palsy from mediastinal disease, not laryngeal metastases. 1

• Do not delay tissue diagnosis with prolonged observation given the extent of metastatic disease. Prompt biopsy is essential for treatment planning. 1

• Do not assume all lung nodules represent metastases in a patient with known extrapulmonary cancer. In patients over 55 who smoke, 58% of lung nodules are actually new primary NSCLC rather than metastases. 6 However, in this case with no known primary and the specific symptom of hoarseness, lung cancer as the primary is most likely.

• Do not rely solely on radiographic patterns without tissue confirmation. While the metastatic pattern strongly suggests lung primary, immunohistochemistry is essential to confirm the diagnosis and guide targeted therapy. 1