Miliary pattern on chest imaging as a presentation of EGFR-negative primary lung adenocarcinoma

Abstract

A 64-year-old African American man, with a history of prostate adenocarcinoma treated in 2009 and a greater than 50-pack-year tobacco smoking history, presented with 2–3 weeks of non-productive cough, frontal headache and generalised myalgias and arthralgias. CT was positive for diffuse, miliary opacities in bilateral lung fields. He was diagnosed with stage four lung adenocarcinoma, negative for epidermal growth factor receptor (EGFR) gene mutation. The patient was unable to tolerate therapy and passed away approximately 4 months after his diagnosis. Previous case reports and research have suggested an association between EGFR gene mutation and miliary patterned lung metastases in non-small cell lung cancer. This case suggests that the mechanism by which miliary patterned metastases occur is more complex than purely mutation of the EGFR gene. Further study may elucidate novel molecular targets for treatment, especially in patients with rapidly progressive disease such as the patient we describe.

Background

Diffuse miliary nodules on lung imaging are an accepted sequela of metastatic disease.^{1 2} Far more common, would be a diagnosis of miliary tuberculosis given the global burden of tuberculosis disease.³ Miliary pattern on chest imaging as a presenting finding of primary lung adenocarcinoma is an atypical finding, and there is minimal data in the literature that suggests why this may be. It has been hypothesised that there may be an association between epidermal growth factor receptor (EGFR) positive non-small cell lung cancers (NSCLC) and miliary patterned lung metastases,^4–7 however our patient was negative for EGFR. This case provides an example of an uncommon presentation of primary lung adenocarcinoma.

Case presentation

A 64-year-old man presented with 2–3 weeks of non-productive cough, frontal headache, and generalised myalgias and arthralgias. He had no history of fevers, chills, weight loss, night sweats or anorexia. He had a history of prostate adenocarcinoma treated with whole pelvis radiation, brachytherapy and adjuvant hormonal (therapy completed in 2009) and hepatitis C treated with ledipasvir and sofosbuvir in 2015.

His prostate adenocarcinoma, status post therapy, was regularly followed by an outpatient oncologist. Prostate-specific antigen was regularly tested and remained within normal limits since patient completed therapy. The patient’s serum calcium was also regularly monitored and remained within normal limits.

His social history was notable for more than 50 pack years of tobacco cigarette use; polysubstance use with intravenous heroin, intravenous cocaine and alcohol; a distant incarceration history; and construction work—now retired. He had no significant travel history or other exposure history.

His deceased father had prostate and lung cancer.

Investigations

• Chest X-ray.

• CT of the chest (figure 1).

• QuantiFERON TB Gold test.

• Sputum acid-fast bacilli smear and culture.

• Endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS TBNA) of lymph node (figure 2).

• MRI of the brain.

• Complete, whole-body X-ray bone survey.

• Fluorodexoyglucose-positron emission tomography with CT correction skull base to mid-thigh.

Figure 1.

Cross-sectional slice from contrast enhanced CT chest demonstrating miliary patterning of pulmonary lesions.

Figure 2.

Pathology from transbronchial needle aspiration of lymph node exhibiting hyperchromatic and irregular nuclei with high nuclei-to-cytoplasm ratio. Features consistent with adenocarcinoma.

Differential diagnosis

The differential diagnosis in patients presenting with respiratory symptoms and miliary lesions on chest imaging include TB, other pulmonary infections, metastatic disease (lung adenocarcinoma, thyroid carcinoma, renal cell carcinoma, breast carcinoma, malignant melanoma, pancreatic malignancy, osteosarcoma and trophoblastic disease), interstitial lung disease, sarcoidosis and hypersensitivity pneumonitis.

Outcome and follow-up

The patient was diagnosed with stage 4 adenocarcinoma of the lung. Immunostaining of biopsied tissue supported this, which was positive for thyroid transcription factor 1 and negative for p40, chromogranin or synaptophysin; suggesting primary lung adenocarcinoma. Molecular evaluation was negative for EGFR mutation, anaplastic lymphoma kinase mutation and ROS1 receptor tyrosine kinase mutation, and had 5%–10% programmed death-ligand 1 expression. Of note, we were unable to establish a histological sub-type of the patient’s lung adenocarcinoma, as the patient never underwent core biopsy of his malignancy.

Brain MRI showed at least six punctate and small foci of subcortical contrast enhancement suspicious for metastatic disease. The patient received whole brain radiation therapy with minimal improvement. Throughout the majority of the patient’s workup he denied bone pain, imaging was negative for bony lesions and serum calcium remained within normal limits; a complete, whole-body X-ray bone survey was read by radiology as having no evidence of osseous metastasis. Approximately 1 month after his bone survey, the patient had significant reduction in functional status and began to report diffuse body pain. Further imaging suggested new metastases to bone and liver.

Ideally, the patient would have been treated with a combination of pembrolizumab, carboplatin and pemetrexed based on Langer et al.⁸ Unfortunately, the patient was never able to initiate therapy secondary to the rapid progression of his disease. He passed away approximately 4 months after his diagnosis, while en route to inpatient hospice.

Discussion

Miliary opacities on radiographic imaging refer to innumerable, small 1–2 mm pulmonary nodules scattered throughout the lungs. Globally, one of the most common causes of such a pattern on imaging is miliary tuberculosis. However, patients with primary lung adenocarcinoma may also present with similar findings. Uncommonly, metastases from other malignancies may also present with a miliary pattern including thyroid carcinoma, renal cell carcinoma, breast carcinoma, malignant melanoma, pancreatic malignancy, osteosarcoma and trophoblastic disease. Our patient’s pathological diagnosis was primary lung adenocarcinoma, garnered from an EBUS TBNA of a lymph node. Of note, the patient passed away prior to the performance of a core biopsy of the patient’s malignancy. As such a histological subtype of the patient’s lung adenocarcinoma cannot be defined.

A miliary pattern on chest imaging as a presenting finding of primary lung adenocarcinoma is atypical, and there are minimal data in the literature indicating why this may be. Our case is similar to five patients described by Umeki et al ⁹ although he described cases of bronchogenic carcinoma.⁹ Umeki’s suggestion was that the miliary lung metastases in his patients originated via bone metastases from primary bronchogenic carcinoma. Our patient did not have evidence of bone metastases on imaging during his initial presentation, and to that end never underwent bone and/or bone marrow biopsy. The patient’s prostate adenocarcinoma was routinely monitored and showed no evidence of recurrence, arguing against a secondary malignancy to the patient’s lung adenocarcinoma as a cause for metastases.

Subhashchandra et al describe a non-smoking, young woman who presented near identically to our patient and underwent a similar workup, although without molecular analysis of the described patient’s malignancy.¹⁰ In our patient’s case, he had a significant smoking history, but quit 4 years prior to his diagnosis.

It has been hypothesised that there may be an association between EGFR positive NSCLC and miliary patterned lung metastases.^4–7 In fact, Laack et al ⁵ suggested never-smoking NSCLC with miliary pattern of pulmonary metastases be recognised as a clinically relevant subgroup. They described a ‘specific molecular phenotype facilitating tumour cell homing to the lungs’ and in five similar patients identified identical deletions in exon 19 of the EGFR gene. The described patients all had dramatic responses to EGFR tyrosine kinase inhibitors. On the other hand, our patient’s lung adenocarcinoma was negative for EGFR gene mutation.

Our patient represents a case of lung adenocarcinoma with miliary-type pulmonary metastases, negative for EGFR gene mutation and with a significant smoking history. NSCLC is commonly known to have predilection to metastasize to liver, bone, brain and adrenal glands. Although uncommon, a miliary pattern of pulmonary metastases from NSCLC is a recognised phenomenon. The scientific literature reports that in most cases a miliary pattern of pulmonary metastases is associated with EGFR gene mutation, and potentially a more specific deletion at exon 19. Our case suggests that the mechanism by which miliary patterned metastases occur is more complex than purely mutation of the EGFR gene. Further study may elucidate novel molecular targets for treatment, especially in patients with rapidly progressive disease such as the patient we describe.

Learning points.

• Primary lung adenocarcinoma can present with a miliary pattern on chest imaging.

• Case reports have described an association between epidermal growth factor receptor (EGFR) gene mutation and non-small cell lung cancers presenting with miliary patterned metastases, but our patient demonstrates a case of such a presentation without EGFR gene mutation.

• Further study of the mechanism by which miliary metastases in lung adenocarcinoma are produced, may elucidate novel targets for treatment, especially in rapidly progressive cases such as the one we describe.