Spectrum of metastatic neoplasms of the brain: A clinicopathological study in a tertiary care cancer centre
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.232333
Source of Support: None, Conflict of Interest: None
Keywords: Brain metastases, central nervous system metastases, immunohistochemistry, metastatic carcinoma
Brain metastases (BM) are devastating lesions with a huge impact on the survival and quality of life of patients. The World Health Organisation (WHO) has defined metastatic tumors of the central nervous system (CNS) as “tumors that originate outside the CNS and spread secondarily to the CNS via the hematogenous route (metastasis) or by direct invasion from adjacent tissues.”
Metastatic tumors are the most common CNS neoplasms. The incidence of metastases to the brain is estimated to be about 170,000/year in the USA, an incidence 10 times higher than that of primary malignant brain tumors. It has been reported that between 20% and 40% of patients with systemic cancer will develop metastases involving the CNS during the course of their disease.
The morbidity and mortality rates are high in patients who develop BM. In adults, metastases to the brain most commonly arise from primary tumors of the lung (50–60%), breast (15–20%), skin (melanoma) [5–10%], and gastrointestinal (GI) tract (4–6%)., The most common sources in children, in a descending order, are leukemia, lymphoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma.
The increase in the incidence of BM is likely a result of improved therapeutics resulting in increased survival after the initial diagnosis has been established, an aging patient population, and improved screening and diagnostic methods, leading to the earlier detection of the lesion and the initiation of treatment., With the emergence of newer and better imaging techniques, confirmatory diagnosis of the brain neoplasm by histopathology has become easier. However, up to 15% of all patients with BM have no clearly detectable primary site despite an extensive evaluation.,, Immunohistochemical analysis is most helpful for determining the exact nature and origin of the metastatic neoplasm and for distinguishing primary from secondary CNS tumors in some cases.,,
This study was conducted at the Department of Pathology at our institute. Data for 4 years were retrieved from the records both retrospectively (January 2012 to December 2013) and prospectively (January 2014 to December 2015). Hematolymphoid and meningeal tumors were excluded. Hematoxylin and eosin (H and E) stained slides were reviewed (n = 69), and in cases with an unknown primary (n = 46), immunohistochemistry (IHC) was advised. The panel of markers was chosen based on the histomorphology on the H and E sections. IHC was done in cases with an unknown primary where paraffin blocks were available (n = 39).
IHC was done on 3-μ paraffin sections taken on 3-amino propyl ethoxy silane (APES) coated slides, using prediluted antibodies, with known positive controls, by the polymer horse radish peroxidase (HRP) IHC detection system, using the manufacturer's instructions. The slides were stained with 3, 3'-diaminobenzidine tetra hydrochloride (DAB) chromogen, counterstained with hematoxylin and mounted. The details of the antibodies used are given in [Table 1].
During the study period, we encountered 69 cases of metastatic brain neoplasms. The male-to-female ratio was 1.2:1. The age of the patients ranged from 21–80 years, and the mean age was 51.75 years. Majority of the cases were encountered in the fifth and sixth decades. Most of the patients presented with symptoms of raised intracranial pressure, which included headache (n = 52; 75.4%) and vomiting (n = 43; 62.3%), as well as seizures (n = 21; 30.4%). The most common presentation was with headache followed by vomiting and seizures. Twenty-three cases (33.3%) had a known primary malignancy. Among these, lung cancer was the most common primary (9 cases) followed by breast cancer (6 cases). In the remaining 46 (66.7%) cases, the primary was unknown. Paraffin blocks were available in 39 out of 46 cases, on which IHC was done. After the IHC, lung cancer (53.8%) was the most common primary to be detected followed by breast cancer (17.9%) and colorectal cancer (10.3%). Adenocarcinoma of the lung was the most common subtype of lung cancer followed by small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma. We did not encounter any cases of squamous cell carcinoma of the lung as a source of BM in our study. Details of the different subtypes of primary malignancies encountered are outlined [Table 2]. IHC was inconclusive in two cases where a morphologic diagnosis of metastatic adenocarcinoma and metastatic poorly differentiated carcinoma was given. On studying the metastatic brain neoplasms and their IHC findings, lung cancer was found to be the most common primary malignancy (n = 30; 48.4%) followed by breast cancer (n = 13; 21%), colorectal cancer (n = 6; 9.6%), and skin cancer (melanoma) [n = 3; 4.8%]. Other sites of primary malignancy included the kidney (n = 2; 3.2%), oesophagus (n = 2; 3.2%), urinary bladder (n = 2; 3.2%), prostate (n = 1; 1.6%), and ovary (n = 1; 1.6%). The lung was the most common site of primary in both men (47.4%) and women (38.7%). In 9 cases (13%), we could not determine the primary site of malignancy, as paraffin blocks were not available in 7 cases and IHC was inconclusive in 2 cases. Photomicrographs of the different malignancies and their corresponding IHC profiles are given in [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7].
We also determined the proportion of metastatic brain neoplasms and found that they accounted for 4.9% of all malignant brain neoplasms in our centre, which is a referral centre for radiotherapy of brain tumors.
Despite considerable progress in diagnostic modalities and therapeutics, successful treatment of cancer remains a major challenge. This increase in incidence can be attributed to the growth of the world's aging population and the fact that cancer remains a leading cause of mortality worldwide. BM are frequently discovered in cancer patients and are said to be far more common than primary brain tumors. Approximately 25% of patients who die from cancer have CNS metastases which are detected at autopsy, of which approximately 15% are in the brain, and in approximately 10% patients, brain is the only site of CNS metastases.
Traditionally, a pathologist's role in the diagnosis of a brain metastasis has been to determine the absence of a high-grade glial neoplasm followed by a simple diagnosis of “metastatic neoplasm” or a “metastatic carcinoma.” For many years, the diagnosis of BM was based only on the examination of H and E stained slides, and in the event of suspicion of an adenocarcinoma, special stains such as the mucicarmine stain were used to demonstrate the presence of mucin. However, identification of the possible primary neoplasms was difficult, especially in poorly differentiated neoplasms, resulting in difficulty in determining the origin of the neoplasm when there was no history of a previous malignancy. Identification of the possible primary neoplasms was difficult in asymptomatic patients with an occult primary neoplasm. With the advent of IHC in the 1980s, it became easier to determine the primary tumor and to provide an early and adequate therapy to patients with BM, resulting in an increased survival of these patients.
An important factor affecting the incidence of metastatic brain tumors is the histology of the primary tumor. In general, the primary tumors which serve as sources of BM (in descending order) are those arising in the lung, breast, skin, kidney, and gastrointestinal (GI) tract.,,,,
Other factors that have been reported to affect the incidence of BM are the stage of the primary malignancy, age, sex, and race.,
The age at diagnosis of the primary malignancy has a significant effect on the incidence of BM. Metastatic brain tumors are more common in adults, with their incidence peaking in the age group of 50–80 years.,, Although majority of the patients with BM belong to the older population with cancer, younger adult patients with cancer may have a higher proportion of BM. This might be because of differences in biology and a more aggressive cancer phenotype in younger adult patients.
Only two Indian studies on the histopathology of metastases in the CNS with immunohistochemical findings have been published till date. Patnayak et al., conducted an 11-year retrospective study of 40 cases of BM in a tertiary care centre in South India, and found that adenocarcinoma (56.67%) was the most common source of metastases to the brain. The lung was the most common source of metastatic adenocarcinoma followed by the thyroid and prostate among the cases with a known primary. However, in approximately 47% of cases harbouring a metastatic adenocarcinoma, the primary site was unknown. Metastatic squamous cell carcinoma was the next in frequency (16.67%) followed by metastatic melanoma (of the skin) [6.67%], metastatic germ cell tumor (6.67%), and metastatic neuroendocrine carcinoma (lung; 3.33%). Ten percent of BM were undifferentiated. Sharma et al., conducted a study of 74 cases of BM from an unknown primary over a period of 64 months and found the lungs to be the most common primary for BM of unknown origin (n = 51; 68.9%). They also found that the use of IHC helped them to identify the primary tumor in 86% of BM cases with an unknown primary. The present study also shows the lung to be the most common site of primary tumor (48.4%).
The proportion of BM in the present study was 4.9%, which is lower than that seen by Jaiswal et al., in a study conducted at the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru. The figure was also lower than that seen in the Western literature., This can be attributed to various reasons. Our institute is an oncology referral centre, where postoperative radiotherapy is offered but no neurosurgery is performed. Many patients with BM diagnosed elsewhere do not opt for further workup and treatment at all after learning about the dismal prognosis of their condition. The poor economic status of most patients could be the main reason for this. However, compliance towards postoperative radiotherapy for primary brain tumors is much better. The present series is also based entirely on surgical pathology material because no autopsy samples were available. The frequency of BM from lung and breast cancers in our study was similar to that cited in the existing literature. However, BM from colorectal cancer was found to be more frequent than BM from melanoma and renal cancer, in contrast to the existing data.,,,,
In lung cancer, the histological subtype is the most important risk factor for the development of BM. Patients with small cell lung cancer (SCLC) have the highest risk (approximately 70%) for developing BM. It is because of this that SCLC is the only subtype with a clear indication for prophylactic whole brain radiation to prevent the development of BM. We had two cases of SCLC (7% of all lung primaries), both of which were diagnosed by IHC in cases with an unknown primary.
The incidence of BM varies from 5–30% among patients with metastatic breast cancer. This is dependent on the molecular subtype, whose surrogate IHC markers are steroid receptor status [estrogen receptor (ER), progesterone receptor (PR)], HER2 overexpression status, and rate of proliferation. HER2 overexpression is reflected in intense membranous overexpression of the HER2 receptor and is frequently associated with the development of BM. The triple negative subtype of breast carcinoma is defined by the absence of hormone and HER2 receptor overexpression, and is associated with the highest propensity for development of BM., However, in our study, almost all the cases were positive for ER (Allred score = 3 or more) and PR (Allred score = 3 or more), except one which was triple negative. HER2 overexpression was seen in 4 cases (score = 3+), equivocal in 2 cases (score = 2+), and negative in one case (score = 1+) [triple negative case]. Multiple metastases were seen in a known case of invasive carcinoma breast, no special type.
BM from colorectal cancer account for 1.4–4.8% cases of BM.,, We found that BM from colorectal cancer constituted 8.7% of all our cases. This figure could be explained by the increased survival of patients with colorectal cancer due to improved treatment methods, and hence, an increased likelihood of developing BM as a late complication.
Cutaneous melanoma accounted for 4.8% of BM in our study. This is much lower than the incidence of 40% found in Western studies.,,,, Apart from the lower incidence of melanoma in our population, the lack of autopsy cases could account for this finding. In the study conducted by Patnayak et al., a melanoma accounted for 5% of the cases, which is similar to our findings, whereas Sharma et al., did not encounter any case of BM from a melanoma.,
BM from clear cell renal cell carcinoma accounted for 3.2% of the cases. Their reduction could be due to the improved systemic treatment strategies including antiangiogenic tyrosine kinase inhibitors. Sharma et al., found that renal cell carcinoma accounted for 2.7% of the cases of BM, which is similar to our findings.
Rare causes of BM are ovarian cancer, prostate cancer, bladder cancer, and gastroesophageal cancer. This was concordant with our findings.
BM are often the first signs of an occult malignancy and their accurate diagnosis can help point towards the site of the primary malignancy, which can then guide optimal treatment. In the present study, most of the BM represented metastases of unknown origin (MUOs), with IHC determining the primary, most commonly in the lung, breast, and colorectum. Hence, the role of the pathologist is of utmost importance because a definitive diagnosis can be made with an easily available ancillary test such as IHC.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2]