Bronchoalveolar carcinoma as an unsuspected cause for worsening shortness of breath in a patient with metastatic breast cancer

Abstract

A 70-year-old woman with lung metastases from a breast cancer presented with worsening cough and dyspnoea. She recently had a pleurodesis for a malignant pleural effusion. Chest CT scans demonstrated various radiological changes leading to diagnostic challenges. Differential diagnoses included empyema, pleural disease progression, pulmonary oedema, pneumonitis, lymphangitis and atypical infections. She deteriorated despite a multimodality treatment strategy. Postmortem examination confirmed that lung changes were consistent with a bronchoalveolar carcinoma unrelated to the known metastatic breast cancer. The eventual knowledge of this diagnosis was reassuring to the treating medical team and a comfort to the relatives who witnessed the lack of response to standard treatment.

Background

This case demonstrates the diagnostic challenges encountered in patients with metastatic breast cancer, who present with worsening respiratory symptoms. It highlights that other pathology can occur and when diagnosis is uncertain, postmortem should be considered, even in advanced cases of cancer.

Case presentation

A 70-year-old woman was diagnosed with an early right-sided breast cancer. She underwent mastectomy, but was considered a low risk of disease recurrence. She therefore was not recommended adjuvant chemotherapy or radiotherapy. She completed 5 years of adjuvant tamoxifen. Her medical history was significant for well-controlled hypertension and hypercholesterolaemia. She had never smoked.

Her breast cancer relapsed 18 years after initial presentation with low volume sternum manubria and lung metastatic disease. CT demonstrated right-sided pleural and anterior chest wall infiltration. Her metastatic disease was treated with letrozole and denosumab. CT at 3 months confirmed disease progression, and treatment was switched to everolimus and fulvestrant in the context of a clinical trial. Although this treatment regime was well tolerated and demonstrated disease control, the patient was admitted to hospital soon after with a 3-week history of breathlessness and dry cough. Bronchoscopy was performed at this time, and cytology from this did not reveal any malignant cells. Clinical and CT findings were more consistent with everolimus-induced pneumonitis. Everolimus was stopped and steroid treatment started, with a resolution in symptoms.

During her period off everolimus, she developed progressive chest disease and was given a standard six cycles of 5-fluoruracil, epirubicin and cyclophosphamide chemotherapy. This resulted in stable disease, and after completion she was maintained on exemestane. Her chest disease however relapsed several months later, therefore exemestane was switched to tamoxifen.

Although other sites of disease remained stable for a further 6 months, she developed a recurrent right-sided pleural effusion and went onto have a right pleurodesis which initially stabilised her symptoms. However, approximately a month after pleurodesis, she was admitted with worsening dyspnoea and dry cough in the absence of fevers, night sweats, pleuritic chest pain or haemoptysis. This admission was 16 months after her prior admission with pneumonitis.

Investigations

This patient went on to have a number of radiological and blood investigations. Blood results are summarised in table 1. Sputum samples taken for Gram stain and cultures were normal. Tuberculosis was not tested for as she did not have convincing risk factors.

Table 1.

A summary of blood test results through admission

	Baseline	On admission	1 week post admission	3 weeks postadmission
Hb (g/dL)	13.2	9.5	10.9	10.1
WCC (×109/L)	8.5	12.2	18.7	17.7
Neutrophils (×109/L)	4.6	9.7	18.7	16.5
C reactive protein (mg/L)	3	55	19	84
Creatinine (µmol/L)	65	56	56	34

Hb, haemoglobin; WCC, white cell count.

A CT pulmonary angiogram (CTPA) was performed on admission which ruled out a pulmonary embolism (figure 1). A CT chest, abdomen and pelvis done 2 weeks postadmission, displayed a right loculated pleural effusion with right lower lobe collapse and consolidation. New extensive ground-glass changes were also seen throughout the hemithoraces, particularly on the left (figure 2). These were reported as likely infective or pneumonitic. These were new changes when compared with a CT performed 3 months prior.

Figure 1.

Axial slice of CTPA demonstrating features consistent with progressive right-sided pleural disease with an effusion as well as a pericardial effusion.

Figure 2.

CT of the thorax showing ground-glass changes seen throughout the hemithoraces, more notably on the left.

An echocardiogram showed a small global pericardial effusion and a normal left ventricular ejection fraction.

An ultrasound-guided right pleural aspiration was attempted by a radiologist, however was unsuccessful. Bronchoscopy was considered but the patient was not stable enough for this to be deemed safe, therefore not attempted.

Differential diagnosis

A wide differential of respiratory diagnoses were considered in this case.

Her immunocompromised state and features on imaging raised the suspicion of infectious aetiology. On the basis of her symptoms being similar to that of her previous pneumonitis, this was considered to be her most likely diagnosis. In hindsight, the diagnosis of pneumonitis in this situation was unlikely as there was no re-exposure and radiological re-presentation without exposure was very unlikely.^{1 2} A CTPA had ruled out a pulmonary embolism.

MDT review of her subsequent serial imaging considered likely aetiologies to include progressive chest disease, infection including atypical fungal infection, new/progressive pneumonitis, lymphangitis and pulmonary oedema. Pneumocytis pneumonia (PCP) was considered although clinical and radiological evidence for this was not convincing. Underlying progression of breast cancer in the lungs was the primary consideration of her deterioration.

Treatment

Due to her subacute presentation, the patient was treated for a suspected pneumonitis and an infective process. This was on the basis of initial imaging that suggested both of these and therefore treatment commenced to cover both. Although there have been studies to suggest that giving steroids and antibiotics simultaneously in severe pneumonia can lead to earlier symptom resolution and reduced mortality, the overall benefit remains unclear.^{3 4}

She was given high-dose prednisolone (60 mg initially and weaned down slowly) and antibiotics (initially intravenous co-amoxiclav and oral clarithromycin, then escalated to intravenous meropenem as per discussion with microbiology).

Treatment for PCP was considered but not initiated, as felt unlikely by microbiology given the patient had not been chronically lymphopenic, nor did radiological evidence support this. Fungal infection was considered due to immunosuppression, and intravenous caspofungin was added alongside antibiotics, however formal fungal antigen testing was not performed.

She was given prophylactic low molecular weight heparin through her admission to reduce her ongoing risk of pulmonary emboli.

Outcome and follow-up

She responded to her initial management with an improvement seen in C reactive protein (table 1), although the spike in her white cell count may have been partly attributed to neutrophilia associated with corticosteroid administration. This effect was however short lived, and she deteriorated and unfortunately died.

The diagnostic uncertainty in this case necessitated the need for post mortem which was limited to the thorax. Sections from the right lung revealed diffuse infiltration by metastatic breast adenocarcinoma. Histology from sections of the left lung demonstrated bronchoalveolar carcinoma (BAC; a separate malignant process to her metastatic breast cancer). This was reported as the most likely cause of the new unilateral ground-glass changes on her CT. This was unsuspected as a cause of her symptoms.

Discussion

Patients with breast cancer can present with respiratory complications related both to the underlying cancer and secondary to the therapies used to treat them. In an immunocompromised patient with breast cancer, a range of respiratory infections should be considered including bacterial pneumonia, tuberculosis and atypical infections such as fungi, viruses and PCP. The non-infectious respiratory complications that can arise are metastatic disease which may present with single or multiple nodules, pleural disease or lymphangitis. In addition, other causes such as pulmonary oedema, pulmonary drug toxicity and diffuse pulmonary haemorrhage should be considered.⁵

The diagnosis of respiratory complications involves non-invasive and invasive approaches. Blood and sputum examinations are helpful as initial investigations. Blood examination is useful as an acute leucocytosis in the presence of cough in a patient with cancer raises the suspicion of pneumonia. Positive serum antibodies such as those for histoplasmosis and Aspergillus can suggest active fungal infection. Sputum examination can be helpful in diagnosing disease recurrence, tuberculosis, PCP and in isolating other specific organisms and especially for establishing antibiotics sensitivities.^{5 6}

Radiological patterns help with focusing a differential diagnosis. Where single lobes or segments are affected, this points more towards a bacterial pneumonia. When multiple lobes are affected, infectious processes such as PCP, or non-infectious processes such as drug toxicity should be considered.⁶ Ground-glass opacities within the lungs can be caused by several disease processes including pneumonia, pneumonitis, fibrosis or pre-malignant/malignant conditions such as atypical adenomatous hyperplasia and invasive adenocarcinoma.⁷ In this case, CT of her chest showed consolidation and multifocal bilateral upper zone ground-glass opacities, most notably in the left lung, which made it difficult to narrow the differential.

Invasive procedures used to make a definitive pulmonary diagnosis include bronchoscopy with bronchoalveolar lavage which is particularly useful in the diagnosis of infections such as PCP and fungal pneumonias, especially when combined with transbronchial biopsy. Thoracoscopic surgery is also very useful in obtaining lung tissue, however may not always be feasible in an unwell cancer patient.⁸

BAC is an adenocarcinoma that is characteristic for growing across alveolar walls and lung periphery. It presents with symptoms of cough, sputum production, dyspnoea and pleuritic chest pain. Radiologically, BAC can appear as multiple lobar infiltrates but can also appear patchy or as a solitary nodule. It can therefore mimic pneumonia and non-infective inflammatory conditions such as pneumonitis and interstitial lung disease both clinically and radiologically.⁹ A diagnosis of BAC is best made by histological examination of resected tumour rather than through specimen obtained by transbronchial biopsy which was not a safe option for our patient. In this case, the patient initially responded to antibiotics and steroids but then deteriorated. BAC should be considered as a differential in cases where patients have respiratory symptoms that do not respond or indeed have stopped responding to such treatments.¹⁰

Similar cases have been described by Thompson, as well as Pathak and Rendon with patients presenting with persistent productive cough and dyspnoea. In each of these cases, BAC was ‘masquerading’ as pneumonia and interstitial lung disease, respectively. In the first case, chest imaging revealed mid-lung infiltrates, interstitial prominence and multilobar peripheral air space disease. Imaging in the second case showed ground-glass opacities and honeycombing in both lungs. In both cases, patients failed to respond to antibiotics and/or steroids. Tissue diagnoses obtained later revealed BAC which explained the symptoms and imaging.^{11 12} Similarly, in our case BAC had mimicked other more common respiratory pathologies. We acknowledge that BAC is unlikely to be the entire cause of our patients decline. However, we feel it has been a significant contributor to respiratory decline alongside disease progression of her breast cancer in the lungs. On post mortem, BAC was reported as the most likely cause of new ground-glass changes on CT and unusual presentation of respiratory symptoms, that eventually did not respond to any therapy.

Learning points.

• Bronchoalveolar carcinoma can be both clinically and radiographically indistinguishable from infective and non-infective respiratory pathologies and therefore should be considered in a differential of such cases.

• A wide spectrum of pulmonary complications can arise in patients with metastatic breast cancer with pleural metastases.

• It may be difficult to clinically extricate the multiple aetiologies from each other with diagnostic certainty.

• A multimodality treatment approach to refine and exclude diagnoses may be appropriate.