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ORIGINAL ARTICLE
Year : 2019  |  Volume : 67  |  Issue : 3  |  Page : 749-754

A clinicopathologic study of surgically resected metastatic lesions of brain: A single institutional experience


1 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Neurosurgery, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
3 Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
4 Department of Radiation Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

Date of Web Publication23-Jul-2019

Correspondence Address:
Dr. Megha S Uppin
Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad - 500 082, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.263251

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 » Abstract 


Introduction: One of the most common tumors of the brain are metastatic lesions. They can present as cancer of unknown primary (CUP) and require careful determination of the site of origin of the primary. Histopathologic and immunohistochemical analysis helps to determine the primary site.
Aim: To study the clinicopathological features of metastatic tumors of the brain.
Materials and Methods: All cases of surgically resected brain metastasis (solid tumor metastasis) from January 2013 to April 2015 were included in the study. The clinical details including age, gender, clinical features, and location were taken from medical records. The histopathology slides were retrieved and reviewed along with clinical and imaging findings from medical records. Immunohistochemistry was performed wherever necessary.
Results: Out of 1662 resected brain lesions during the study period, 69 accounted for central nervous system metastasis, of which 36 were brain metastasis and 33 were isolated spinal cord metastasis. In the 36 brain metastasis cases, 19 were cases with an unknown primary. Carcinoma lung (47.2%) was found to be the most common primary malignancy. Immunohistochemistry with cytokeratin (CK)7, CK20, and thyroid transcription factor (TTF) 1 as a primary panel in metastatic tumors is highly recommended.
Conclusion: Metastatic tumors accounted for 4.1% of intracranial lesions. Histopathologic pattern and immunohistochemistry aid in the accurate diagnosis of the original site of malignancy.


Keywords: Brain, immunohistochemistry, metastasis, morphology
Key Message: Carcinoma lung is the most common primary showing metastasis to the brain. Immunohistochemistry helps in the diagnosis of the primary in the case of unknown metastasis.


How to cite this article:
Sangati L, Alugolu R, Bhattacharjee S, Vijaya Saradhi M, Sahu B P, Uppin MS, Sadashivudu G, Irukulla MM. A clinicopathologic study of surgically resected metastatic lesions of brain: A single institutional experience. Neurol India 2019;67:749-54

How to cite this URL:
Sangati L, Alugolu R, Bhattacharjee S, Vijaya Saradhi M, Sahu B P, Uppin MS, Sadashivudu G, Irukulla MM. A clinicopathologic study of surgically resected metastatic lesions of brain: A single institutional experience. Neurol India [serial online] 2019 [cited 2019 Dec 15];67:749-54. Available from: http://www.neurologyindia.com/text.asp?2019/67/3/749/263251




Metastasis to the central nervous system (CNS), particularly the brain, is the most commonly encountered intracranial tumor in adults. It is a marker of poor prognosis [1] as involvement of the brain occurs late during the course of metastatic cancer. In some types of cancers such as lung, breast, and melanoma, brain metastases may occasionally be the only presenting feature.[2] The incidence of brain metastasis seems to be on the rise owing to improved imaging modalities, effective chemotherapeutic regimens for systemic malignancies, and a relative increase in the incidence of cancer with ageing.[3] The exact incidence remains largely unknown owing to the under reporting of cases and particularly because not many lesions undergo surgical resection. Cancer of unknown primary (CUP) requires careful determination of the primary site of origin of the tumor for further management. On radiological imaging, metastasis usually presents as multiple space occupying lesions and can be confused with infections or primary brain tumors.[4] Microscopic histology and immunohistochemistry panel form important diagnostic tools to know the morphologic pattern of metastatic malignancy and to point towards a possible primary. Extensive imaging modalities in search of a primary tumor can be expensive and impractical. The common primaries leading to CNS metastasis include non-small cell carcinoma of the lung, as well as primaries from the breast, skin, kidney, and gastrointestinal tract.[5] Sarcomas metastasizing to the CNS are very rare.[6] In this case series, we present the surgical and pathologic findings of brain metastasis in a tertiary care centre from South India.


 » Materials and Methods Top


This is a retrospective study of surgically resected cases of brain metastasis from January 2013 to April 2015. The cases included nonhematologic solid tumor malignancies. The clinical details including age, gender, presentation, and tumor site were taken from the medical records. The histopathology slides were retrieved and reviewed along with clinical and imageological findings. Routine hematoxylin and eosin stained sections of formalin-fixed, paraffin-embedded tissue were reviewed in all cases. Immunohistochemistry (IHC) was performed for cases with an unknown primary to characterize the original site of malignancy. Immunohistochemistry was done on 3-μ paraffin sections on 3-amino propyl ethoxy silane (APES) coated slides using prediluted antibodies with known positive controls by polymer horse radish peroxidase (HRP) detection system. The details of the antibodies used are listed in [Table 1].
Table 1: List of antibodies

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 » Results Top


A total of 1662 surgical resections were done during the study period in which a neuropathological diagnosis was available. Among these, metastasis was identified in 69 (4.1%) cases. Out of the 69 lesions identified as metastasis, 36 were brain and 33 were spinal metastasis. The latter were excluded from the study. [Table 2] summarizes the demographic features of these patients. There was a slight male predominance and most (47.2%) patients were in the 5th decade. The common presenting complaints were headache, pain, weakness, tingling and numbness, hemiparesis, and vomiting. A possible diagnosis of metastasis on preoperative radioimaging was made in 24 (66%) of the cases; whereas, in others, glioma and tuberculosis were the possible differentials. The metastatic lesions were commonly seen in cerebral lobes, with frontal lobe being the most predominant. All were single lesions, except in 2 patients with multiple lesions. One had multiple lesions in the frontal and temporal lobes with a known rectal adenocarcinoma as the primary lesion, whereas the other had multiple brain and spinal lesions with a possible primary in the lung. Already known primary malignancies were documented in 17 (47.2%) patients, whereas in 19 (52.7%) patients, brain metastasis was the first manifestation of the disease. [Table 3] depicts the data of known and unknown primary malignancies. The entire clinical, pathological, treatment, and follow-up details for the primary lung, breast, and other malignancies are given in [Table 4], [Table 5], [Table 6], respectively. The most common primary malignancy with brain metastasis was lung followed by breast, gastrointestinal tract, and thyroid. The common primary in male patients was the lung (71.4%), and in females, was the breast (60%). The primary site was reliably typed on IHC in patients of CUP, and lung was found to be the most common primary site. In 3 patients, the primary site could not be confirmed even after a wide IHC panel. Adenocarcinoma was the most common histologic type noted.
Table 2: Clinical and demographic features of all patients

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Table 3: Distribution of cases with known and unknown primary malignancies

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Table 4: Clinical details with histopathology, treatment and follow up details of patients with primary breast carcinoma

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Table 5: Clinical details with histopathology, treatment and follow up details of patients with primary lung carcinoma

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Table 6: Clinical details with histopathology, treatment and follow up details of patients with other malignancies

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Morphologic patterns

All metastatic carcinomas were adenocarcinomas followed by squamous cell carcinoma. Two cases had small cell carcinoma of the lung. Adenocarcinomas are characterized by glandular arrangements of cells showing cellular atypia and mitosis. Intra- and extracellular mucin could be identified [Figure 1]. Thyroid carcinoma showed colloid-filled follicles with nuclear grooves and pseudoinclusions [Figure 2]. Sarcomas showed spindle cells arranged in interlacing fascicles with frequent atypical mitosis [Figure 3].
Figure 1: (a and b) Tumor cells arranged in glands with intraluminal mucin. H and E × 40 (c) Immunohistochemical positivity for TTF-1. TTF-1 HRP Polymer × 40 and (d) Cytokeratin 7. HRP Polymer CK7 × 40

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Figure 2: (a and b) Tumor cells arranged in papillae with colloid filled follicles. (c) Cellular positivity for TTF-1 and (d) Thyroglobulin

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Figure 3: (a and b) Metastatic sarcoma showing cells arranged in long fascicles with atypia and mitosis. (c) Immunohistochemical positivity for smooth muscle actin. SMA HRP Polymer × 40

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Immunohistochemical analysis

The details of the IHC analysis are given in [Table 7]. The primary IHC panel for CUP cases was CK7/CK20/TTF-1 in which positivity for CK7 and TTF-1 was seen in all lung adenocarcinomas. CK7 and gross cystic disease fluid protein (GCDFP) positivity helped to make the diagnosis of primary breast carcinoma, whereas TTF-1 with thyroglobulin positivity was consistent with thyroid malignancy. The small cell carcinomas were positive for neuroendocrine markers such as synaptophysin in addition to TTF-1, whereas the squamous cell carcinomas showed positivity for high molecular weight cytokeratins (CK5/6).
Table 7: Immunohistochemical positivity for all types of malignancies

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 » Discussion Top


Brain metastasis depicts a poor prognosis and significantly affects the quality of life. This was a comprehensive attempt to study the clinical, pathologic, and IHC features of surgically resected cases of brain metastasis.[7] Brain metastasis significantly contributes to an increased morbidity and mortality irrespective of the type of primary malignancy. Tumor cells reach the brain from the primary site by circulation through venules or lymph channels.[2] Of the body's blood flow, brain receives 15–20%.[8] This fact makes it likely that circulating tumor cells have a greater chance of reaching the brain. The brain metastatic site is determined by the size of the region and its vasculature. Eighty-five percent of brain metastases are found in the cerebrum, as it is the watershed area between the middle and the posterior cerebral arteries.[9] A similar finding was observed in our study where 77.7% of the lesions were in the cerebral hemispheres, 19.4% in the cerebellum, and 2.7% in the brainstem. The signs and symptoms were related to the site of involvement.[10],[11] Most patients presented with headache and pain followed by tingling and numbness, hemiparesis, and vomiting. A comparison with other studies on metastatic lesions of the brain published in the literature is given in [Table 8].
Table 8: Comparison of the present study with similar studies in literature

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Lung is the common primary site in metastatic tumors of brain.[5],[12],[13],[14] The same was seen in our study. Approximately 20–40% patients of non-small-cell lung carcinoma (NSCLC) develop brain metastasis at some point during their illness, usually within 2 years of the primary diagnosis.[15] The histology of adenocarcinoma and the female gender have been found to be more prevalent in long-term survivors of brain metastasis with a lung primary.[16] Modi et al., emphasized the need for resection of metastatic focus in the brain, which improves the overall survival.[17]

Breast is a common site for the primary tumor in the case of metastatic brain lesions in female patients. Age, histology, grade, lymph node status, and human epidermal growth factor receptor 2 (HER2) neu positivity are important predictors of survival.[18] Majority of our patients showed a negative HER2 neu status, which prevented treatment with targeted drugs for attaining an improved survival. The overall survival for HER2 positive patients (18 months) was found to be more than that for the HER2 negative ones (11 months).

In general, lung cancers and melanomas are more likely to be associated with multiple metastases [19] whereas breast, renal, and colorectal carcinomas present as solitary lesions. In our study, all patients had solitary lesions, except the two patients who showed multiple lesions. Solitary metastatic lesions have sharp boundaries and are amenable to surgical resection.[20],[21]

Brain metastasis in sarcomas is rare and is seen more often in undifferentiated sarcomas with prior metastasis. The incidence of sarcoma metastasizing to the brain is <1%.[22] In the single case of sarcoma metastasis in our study, only brain metastasis occurred without evidence of other systemic metastatic disease. These tumors need to be differentiated from primary brain tumors such as a gliosarcoma or a meningeal sarcoma. IHC and the morphologic resemblance to the primary sarcoma can help to differentiate them.

In a large cohort of 2358 patients, Esmaeilzadeh et al., showed that a majority (79.9%) of gastrointestinal malignancies with brain metastasis were from the colorectum with a median age of 58.9 years.[23]

The morphologic subtype of tumor cells can be reliably assessed by the pattern of cellular arrangement.[5] The morphology also helps in excluding primary brain tumors that form a differential diagnosis on preoperative radioimaging. Most metastatic lesions in our study were adenocarcinomas similar to those described in literature.[24] The morphologic subtype helps to decide the IHC panel. Pekmezci and Perry enumerated the IHC panel which can be used for cases of CUP. The panel used in the present study had similar IHC markers.[5]

The use of differential cytokeratins as well as site-specific markers such as thyroglobulin and GCDFP is essential. The subtype of pancytokeratins varies according to the site of malignancy. CK7 is usually expressed in adenocarcinomas of the lung, breast, and upper gastrointestinal tract, whereas CK20 is expressed in colonic adenocarcinomas. TTF-1 has shown 100% sensitivity in lung carcinomas,[24] and thyroglobulin is a site-specific marker for thyroid malignancies.[25] Considering the high frequency of tumors being from lung, a panel including CK7, CK20, and TTF-1 can be used in most metastatic adenocarcinomas of the brain.[26]

In 3 patients, however, the primary tumor remained unclassified. The metastatic tumor was only positive for CK7 whereas TTF-1, CK20, and CDX-2 were negative. Apart from IHC, molecular studies such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in lung carcinoma, and HER2 status in breast carcinoma, help in individualizing the patient's treatment with targeted chemotherapy.

The therapeutic approaches to brain metastases include surgery, whole brain radiotherapy, stereotactic radiosurgery, and chemotherapy.[29],[30] Many factors including the age, performance status, number of lesions, and type of treatment decide the outcome. Aggressive treatment helps to improve the overall survival. In our study, majority of the patients died within a year of diagnosis, confirming the fact that brain metastasis portends a poor prognosis.

In conclusion, we describe the clinicopathologic features of 36 patients with surgically resected brain metastasis. Lung was found to be the most common primary malignancy. Histopathology and immunohistochemistry help to diagnose the primary site as well as to differentiate them from primary brain tumors. The median survival ranged from 3–12.6 months.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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