Thankamma Ajithkumar
Case history
A 60-year-old woman presented with a 4-week history of mass in the right breast. A screening mammogram 6 months before had shown no evidence of any mass lesion. Her mother had had breast cancer at the age of 60. A mammogram showed a suspicious lesion in the upper outer quadrant of right breast. An ultrasound confirmed a superficial 1.3cm irregular mass with no associated axillary lymphadenopathy. Biopsy of the breast mass showed a carcinoma of ductal origin, which was negative for oestrogen (ER), progesterone (PgR), and gross cystic disease fluid protein-15 (GCDFP-15), and positive for thyroid transcription factor 1 (TTF-1).
Questions
1. What is the pathological diagnosis?
2. How will you proceed?
Answers
1. What is the pathological diagnosis?
The negative immunohistochemistry for ER, PgR, and GCDFP-15 suggests that it is a metastasis to the breast rather than a primary breast cancer. Although ER/PgR negativity does not rule out a primary breast cancer, GCDFP-15 helps to identify metastatic breast cancer in the absence of a previous history of breast cancer and/or in tumours which are negative for ER and PgR. A positive GCDFP-15 suggests primary breast cancer of ductal origin but a negative result does not exclude it due to a low sensitivity of 60–75%.
TTF-1 is a tissue-specific transcription factor expressed in epithelial cells of the lung and the thyroid. Some 70–80% of primary lung adenocarcinomas express TTF-1. A literature review showed that only four out of 419 breast cancers expressed TTF-1 (Maounis et al. 2010). Therefore the most probable diagnosis is metastatic non-small cell lung cancer (NSCLC).
2. How will you proceed?
This woman needs a chest X-ray and CT staging of the thorax, abdomen, and pelvis to look for a lung primary and to rule out further metastatic disease.
The chest X-ray and CT scan are shown in Fig. 4.1.
Fig. 4.1
Question
3. What do the images show?
Answer
3. What do the images show?
The chest X-ray shows a right hilar mass. Since the right heart border is well defined, the lesion will be arising posterior to the heart. The axial CT images show a stellate mass in the right breast (metastasis) and an irregular mass in the right lower lobe (primary tumour).
The scan also showed a 1.3cm right hilar node and 1.2cm subcarinal node (not shown in Fig. 4.1). There was no disease elsewhere.
Question
4. What is the further management?
Answer
4. What is the further management?
This patient has a radiological T2N2M1b lung cancer. It is important to establish the true extent of the metastatic disease, and there are at least two clinical scenarios with potentially different treatment approaches. These include:
1. Disseminated metastatic disease with involvement of mediastinal nodes and possibly other occult disease, when treatment is palliative with systemic chemotherapy.
2. Oligometastatic disease—the only sites of disease are in the lung and breast with the nodes being reactive. In this situation a more radical approach should be considered.
Therefore further investigations should include a PET scan, a biopsy from the lung lesion to confirm a lung primary and to correlate with the breast pathology, and epidermal growth factor receptor (EGFR) mutation status.
A PET scan showed intense fluorodeoxyglucose (FDG) uptake in the breast lump (SUV 11.5), lung mass (SUV 12), right hilar nodes (SUV 4.3), and subcarinal nodes (SUV 4.6) but without other uptake. Figure 4.2 shows FDG uptake in the breast lump, the lung mass, and hilar nodes.
A biopsy from the lung tumour showed a poorly differentiated adenocarcinoma with areas of necrosis. The tumour cells were strongly positive for TTF1 and negative for ER and GCDFP-15. EGFR mutation testing was not available at the time this patient was diagnosed.
Fig. 4.2 (See also colour plate section)
Question
5. How will you proceed?
Answer
5. How will you proceed?
The features of the lung tumour correlate with those of the breast lump, suggesting the diagnosis of breast metastasis from adenocarcinoma of lung. The PET scan suggests possible involvement of the hilar and subcarinal nodes.
18FDG PET/CT has an established role in the staging of NSCLC. It distinguishes malignant lung tumours from benign lesions more accurately than CT or PET alone.
PET/CT can detect malignant disease in normal-sized lymph nodes and therefore is more sensitive than CT scan alone. With regards to nodal staging, PET/CT has an equal or superior negative predictive value (i.e. the probability of not having the disease when the scan is negative) to mediastinoscopy. Therefore if lymph nodes are negative on PET/CT, a mediastinoscopy is not needed for confirmation. However, a PET scan has a poor positive predictive value with a high chance of false-positivity, leading incorrectly to upstaging of the disease. Thus, PET-positive regional nodes require histological confirmation to prove or refute metastasis.
PET/CT has a greater sensitivity than CT scan alone in detecting metastatic disease, except for brain and possibly liver metastases. Ideally, this woman should have a mediastinoscopy with histopathological examination of the PET-positive nodes to confirm or rule out nodal disease.
The multidisciplinary team decided not offer a mediastinoscopy, but recommended proceeding with four courses of chemotherapy with carboplatin and pemetrexed.
After four courses of chemotherapy CT restaging reported that the right lower lobe tumour had decreased in size from 3.4cm × 5.6cm to 2.6cm × 3.7cm with no change in the size of either the left hilar node or the subcarinal node. The breast metastasis decreased in size from 1.4cm × 1.3cm to 9mm × 11mm.
Questions
6. What is your further management?
7. Is there any role for surgery in this patient?
Answers
6. What is your further management?
In view of the decrease in size of the lung tumour and breast lump, with no change in the size of the nodes, it is reasonable to assume that the nodal disease is false positive on PET. Therefore the patient should be offered a mediastinoscopy to reassess the mediastinal nodes.
7. Is there any role for surgery in this patient?
Generally, patients with stage IV NSCLC have incurable disease. Patients with oligometastatic disease represent a distinct subset of patients with metastatic disease and a number of retrospective series have examined the role of surgical resection in patients with oligometastases. Following surgical resection of solitary brain metastases the 5-year survival is 11–30% and following adrenelectomy for solitary adrenal metastases the 5-year survival is 26%.
Reports of successful surgical resection in oligometastatic NSCLC at sites other than brain and adrenal are sparse. Breast metastasis (either synchronous or metachronous) from NSCLC is very unusual and patients have a poor prognosis, with most patients dying within in a year of diagnosis. Due to the rarity of the situation, there is no clear evidence to recommend surgery in this patient. Therefore any recommendation for an attempted surgical resection would be based on a perceived clinical benefit extrapolated from the literature on oligometastatic disease at other sites.
Mediastinocopy with samples from stations 4R and 7 did not show any evidence of malignancy. MRI of the brain was normal and CT staging did not show progression. She underwent a right lower lobectomy and excision of the solitary breast metastasis. Pathology showed ypT2aN0 R0 resection of lung and an Rx resection of the breast metastasis (due to a diathermized edge).
Fifteen months after surgery she presented with features suggestive of a stroke. CT and MRI of the brain showed a solitary left frontal lesion suggestive of a metastasis.
Questions
8. What is your management?
9. Should this patient have been offered PCI after surgery?
Answers
8. What is your management?
The patient needs to be started on high-dose steroids to minimize any cerebral oedema. Further staging with a CT scan of chest, abdomen, and pelvis is recommended to rule out systemic disease. Provided her ECOG performance status is good (0–1) and she has no systemic disease, she should be managed similarly to patients presenting with a single brain metastasis with surgery, radiotherapy, or a combination of both (see p. 54).
9. Should this patient have been offered PCI after surgery?
There is no proven role for PCI in NSCLC. Previous randomized trials have shown that although PCI decreases and/or delays brain metastases there is no survival benefit and there are concerns over long-term toxicity. These data have been confirmed by the report of the RTOG 0214 trial (Gore et al. 2011). Therefore this patient should not have been offered PCI.
Progress and follow-up
CT staging did not show any systemic disease, and hence the patient underwent complete resection of the single metastasis followed by whole-brain radiotherapy. She remains well without recurrent disease at 18 months follow-up, which is 3.5 years after her initial presentation.
Further reading
Gomez DR, Niibe Y, Chang JY. Oligometastatic disease at presentation or recurrence for nonsmall cell lung cancer. Pulmonary Medicine 2012; doi: 10.1155/2012/396592 [online only].
Gore EM, Bae K, Wong SJ, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. Clinical Oncology 2011; 29: 272–278.
Ji FF, Gao P, Wang JG, et al. Contralateral breast metastasis from pulmonary adenocarcinoma: two case reports and literature review. Thoracic Disease 2012; 4: 384–389.
Maounis N, Chorti M, Legaki S et al. Metastasis to the breast from an adenocarcinoma of the lung with extensive micropapillary component: a case report and review of the literature. Diagnostic Pathology2010; 5: 82 [online only].
Pfannschmidt J, Dienemann H. Surgical treatment of oligometastatic non-small cell lung cancer. Lung Cancer, 2010; 69: 251–258.