Keywords:
Non-small-cell lung carcinoma - Neoplasm metastasis - Case report - Metastasis to
breast.
Descritores:
Carcinoma pulmonar de não pequenas células - Metástase neoplásica - Relato de caso
- Metástase da mama.
INTRODUCTION
Metastases from non-breast malignant neoplasms to the breast are rare and account
for approximately 4% of all malignant breast tumors, affecting patients with an average
age of 57.4 years[1]
[2]. Of the primary tumors most commonly reported as metastasizing to the breast are
hematopoietic neoplasms, malignant melanoma, and lung carcinoma[1]
[3]
[4]. While lung carcinoma is among the most common of all malignant ftumors[5] it is an infrequent site of metastatic lesions[3]
The prognosis of patients with metastatic lung cancer to the breast is reserved: over
80% of diagnosed cases of solid tumor metastatic to the breast die within a year[3]
[4]
The following case report is of a 65-year-old female patient, an 80 pack-year smoker
for 40 years. During a gynecological check-up a lump was detected in the breast and,
with further investigation, the patient was diagnosed with primary lung cancer with
breast metastases. The case report was evaluated by the ethics and research committee
of Mãe de Deus Hospital in Porto Alegre - RS (Brazil) and has been approved under
the registration number 14372172014.
CASE REPORT
Female patient, 65 years old, black, with no family history of breast or lung cancer.
Na 80 pack-year smoker for 40 years. During a physical gynecological examination,
the patient presented a palpable nodule in the outer quadrant of the right breast.
A subsequent mammography showed a 2.5 cm nodule in outer quadrant of the right breast,
BIRADS = 5. The patient was referred for staging through chest X-ray, which showed
4 cm nodule in the right lung. Later, a CT scan confirmed a spiculated and infiltrative
solid mass measuring 4.3 x 3.3 cm, with its epicenter in the middle lateral segment,
infiltrating the adjacent oblique fissure and invading the anterior basal segment
of the lower lobe. To investigate other possible active foci of the disease, a PET-CT
was performed ([Figure 1]), confirming irregular hypermetabolic lesion, measuring 2.7 cm, in the outer quadrant
of the right breast and a hypermetabolic lesion, 4.3 cm in diameter, in the right
lower lobe (SUV 11). The patient underwent concurrent setorectomy and bi-lobectomy.
Pathologic examination showed a diagnosis of moderately differentiated non-small cell
lung cancer, without peritumoral invasion. The immunohistochemical analysis of the
breast and lung material is shown in[Table 1].
The test used for EGFR and ALK was done by PCR amplification and direct sequencing[6]. The diagnostic conclusion was non-small cell lung cancer metastatic to the breast.
Both lesions were resected with free margins. Resected mediastinal lymph nodes were
negative for metastatic cells.
The patient received adjuvant chemotherapy, six cycles of carboplatin (AUC 6) and
pemetrexed (500mg/ m2 ) (every 21 days)[7]. Tolerance was excellent, and the maintenance of pemetrexed for six months was proposed[8]
[9]. The patient has undergone regular PET-CT examination since the immediate postoperative
period and at four-monthly intervals. There is no suspicion of recurrence. The patient
is currently only in follow-up, with no evidence of neoplasia ([Figure 2]).
Figure 1 Preoperative PET-CT (17/05/2012) showed lesions in the breast and lung.
DISCUSSION
Metastases to the breast from other organs are rare, with a prevalence of 1.7 to 6.6%
of breast tumors. Primary sites that metastasize to the breast are lymphomas, melanomas,
lung, ovary, stomach, and more rarely, kidney, liver, pancreatic, pleural and endometrium
carcinomas. In children and adolescents, rhabdomyosarcoma is one of the cancers that
most metastasize to the breast. In male patients, although rare, a relationship has
been shown between this phenomenon and prostate adenocarcinoma. The discovery of a
lump in the breast of a patient with a history of cancer may complicate the diagnosis
and treatment. Therefore, identifying whether the tumor is primary or metastatic is
essential to avoid an unnecessary mastectomy, for example[10].
Table 1
Markers of the lesion in the right breast
|
Marker
|
Positive
|
Negative
|
|
TTF-1
|
x
|
|
|
Ki-67 (50% of cells)
|
x
|
|
|
CK7
|
x
|
|
|
AE1 + AE3
|
x
|
|
|
Progesterone receptor (PR)
|
|
x
|
|
Estrogen receptor (ER)
|
|
x
|
|
BRST-2, GCDFP-15
|
|
x
|
|
C-erbB-2
|
|
x
|
|
CDX-2
|
|
x
|
|
EGFR
|
|
x
|
|
ALK
|
|
x
|
|
CK20
|
|
x
|
Figure 2 PET-CT conducted 80 months after surgery and chemotherapy. No evidence of recurrence.
Women are five to six times more likely to be affected by metastasis in the breast
than men. There are no predisposing factors clearly associated with this condition.
While the hormonal issue remains debatable, a higher occurrence of metastasis to the
breast is seen in adolescent females and pregnant and lactating women. In men, it
is more common in patients undergoing hormone therapy due to prostate cancer. The
suggestive mechanism of this phenomenon is that estrogen could increase vascularity
and the stromal mass of the breast, which would be a predisposing factor for the development
of metastases[10].
A retrospective study conducted at the Memorial Hospital for Cancer and Allied Diseases
evaluated 4000 patients with breast cancer between 1961 and 1970. Fifty-one of whom
(1.2%), 44 women and 7 men, had metastases in the breast. In this study, the primary
site that generated most metastases was lymphoma (n = 16), followed by melanoma (n
= 14) and lung carcinoma (n = 6). The study revealed that mastectomy did not substantially
extend the survival of patients, except in situations where the metastasis was very
large and was deeply infiltrated in the breast[11].
In the study by Surov et al., the radiology center of the Halle-Wittenberg Martin-Luther University enrolled
6,668 patients diagnosed with some metastasis between January 2000 and December 2009.
Of whom, 51 had metastasis to breast with primary tumors in extra-mammary sites. The
group consisted of 43 women and 8 men with an average age of 61 years. Of the 51 cases
of metastasis, the most common primary tumors were melanoma, ovarian, gastric, kidney
and sarcoma. Lung cancer, accountted for only 0.89% of the cases that produced metastasis
to the breast[12].
Clinically, most breast metastases are reported as being fast growing, painless mass
with no retraction of the skin or nipple. In Surov's study, metastasis to the breast
more often appeared as a solitary nodule than as multiple lesions. Sixty percent (60%)
of patients with metastatic breast were accidentally diagnosed during staging for
the primary cancer, wherein subsequent biopsy confirmed the diagnosis in 70% of cases.
Only 31% of the patients had a painful solitary nodule or multiple nodules, with or
without axillary lymphadenopathy[12].
In the reported case, the patient remained asymptomatic and the diagnosis was made
during routine clinical examination.
In imaging examinations, the suggestive finding of metastasis to the breast is the
presence of one or more rounded nodes in the breast which are difficult to distinguish
them from other small nodules, cysts or fibroadenomas. Attention should be paid to
metastasis to the breast when there is already another metastasis in a region of soft
tissue. Another factor favoring the hypothesis of metastasis is rapid nodular growth
between two mammograms. Finally, when the first notable abnormality is increased skin
thickness, this may indicate an invasive metastasis via the lymphatic system[13].
The histological diagnosis of metastasis to the breast is more difficult than the
diagnosis of primary breast tumor. In most cases, the definitive diagnosis is made
by biopsy. However, biopsy is not always conclusive. In such cases, attention should
be paid to the periductal and/or perilobular distribution of malignant cells in the
absence of intraductal and/or lobular carcinoma in situ, characteristics which suggest metastasis to the breast originating elsewhere. The
role of surgery in the case of metastatic disease should be considered[11]
[14].
In addition to histological characteristics, there are various markers that help distinguish
breast metastases arising from lung carcinoma and a primary breast tumor. In such
cases, immunohistochemistry can be helpful in reaching a correct diagnosis. Thyroid
transcription factor-1 (TTF-1) is expressed in 68-80% of cases of lung adenocarcinoma,
while no case report in the literature has reported its presence in breast adenocarcinomas.
The marker for estrogen receptor (ER) is rarely responsive in lung cancer (negative
in the present case). Finally, mammaglobin is expressed in 48% to 72% of breast adenocarcinomas,
but is negative in lung adenocarcinomas. Consequently, the use of a panel of markers
including ER, PR (progesterone receptor) and mammaglobin is recommended, because none
of them is 100% accurate in distinguishing the primary site of the tumor. Our case
represents a typical case of primary tumor in the lung, with ER negative, PR negative,
and TTF-1 positive ([Table 1]). Instead of using the mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15)
was used, which is less sensitive but more specific than mammaglobin in identifying
primary breast tumors ([Table 1])[15]. Some publications attribute to TTF-1 a sensitivity of 93% for non-small-cell lung
tumors (as in our case) and 63% for others. In primary breast tumors, ER is expressed
in 80% and PR in 60% of cases. GCDFP-15 is expressed in 45-53% of breast carcinomas[13]
[14].
An EGFR mutation search was considered to test the possibility of adenocarcinoma.
ALK gene undergoes rearrangement in 2-7% of patients with non-small cell lung cancer.
Its frequency increases in young and non-smoking patients, and occurs almost exclusively
in adenocarcinomas. In a phase I/II study, the use of crizotinib represented a response
rate of 61% in 149 ALK positive patients[16]. The use of crizotinib appears to offer new hope for the positive ALK group, since
it has proved to be more beneficial than the previous standard treatment, consisting
in the use of carboplatin/cisplatin and pemetrexed ( p < 0.0001)[17].
In our case, a mutation search was conducted in the patient, However, both ALK and
EGFR were negative, therefore the treatment was not directed towards these targets.
Although malignant metastases to the breast are rare, when a breast tumor is identified
it is important to confirm the site of the primary tumor. The importance of identifying
and differentiating the primary and secondary sites is necessary to properly direct
treatment in order to avoid the patient having to undergo unnecessary and possibly
harmful procedures. In the present case, despite the prognosis of patients with metastatic
lung cancer to breast be reserved - more than 80% of diagnosed cases of solid metastatic
tumor to the breast die within a year - the patient presented good evolution.
Bibliographical Record
Pedro Marchiori Cacilhas, Kelly Mallmann Silva, Monique Wickert, Allan Arrieira Azambuja.
Primary lung cancer metastatic to the breast: case report of a patient in remission.
Brazilian Journal of Oncology 2019; 15: e-20190022.
DOI: 10.5935/2526-8732.20190022
