This case was originally published in 2018. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A previously healthy 55-year-old man with a three-week history of headaches presents to the emergency department with new-onset emesis and balance problems. MRI reveals a 3 cm enhancing lesion with a cystic component in the right cerebellar hemisphere (Image A).

Tissue Site
Right cerebellar hemisphere

Image A: MRI of the brain: axial FLAIR.

Image A: MRI of the brain: axial FLAIR.

The whole slide image provided is an H&E stained slide of the right cerebellar hemisphere from a resection.

  1. What is the BEST diagnosis?

    1. Epithelioid glioblastoma

    2. Metastatic melanoma

    3. Metastatic adenocarcinoma

    4. Pleomorphic xanthoastrocytoma

    5. Primary CNS anaplastic lymphoma

  2. Which of the following IHC markers is MOST specific for this neoplasm?

    1. GFAP

    2. Melan A

    3. S100

    4. INI1

    5. Vimentin

  3. Which of the following non-CNS neoplasms has the highest propensity to metastasize to the CNS?

    1. Adenocarcinoma of the breast

    2. Gastrointestinal stromal tumor

    3. Hepatocellular carcinoma

    4. Papillary thyroid cancer

    5. Squamous cell carcinoma of the cervix

View Answer Key

Neoplasms metastatic to the brain represent an increasingly larger number of biopsies/resections seen by surgical pathologists as compared to primary CNS neoplasms. CNS metastases can be the presenting findings for patients with cancer. Radiographic studies often can accurately distinguish metastatic disease from primary CNS neoplasms based in part on the presence of multiple lesions in the former. Even in solitary lesions, characteristic radiographic enhancement patterns, contours, or other features can bring metastasis into the differential diagnosis. The primary mode of entry for metastasis is via blood vessels, though extension from cranial and peripheral nerves or bone is possible.

In descending order of incidence, the most common primary sites for brain metastases are lung, breast, skin (melanoma), kidney, and gastrointestinal tract. However, many other neoplasms can also rarely metastasize to the brain. Metastases can be of highly variable differentiation patterns and are often poorly differentiated, making identification of the primary origin difficult. Fortunately, the ever-increasing IHC armamentarium at the pathologist's disposal can help suggest a site of origin. A systematic and stepwise approach to immunoprofiling the lesion is recommended based on H&E histomorphology as well as clinicoradiographic information. A first-line IHC panel could include: pan-cytokeratin, GFAP, S100, and CD45. Based on findings from the initial panel, a more extensive second round of testing may be needed.

Melanoma metastatic to the CNS can be one of the more challenging diagnoses to make. Melanoma has been called “the great mimicker” as it can resemble carcinomas, sarcomas, lymphomas, and gliomas. Melanomas often present as multifocal lesions in the CNS and can show leptomeningeal spread. Identification of brown melanin pigment can assist with the diagnosis, but its absence does not rule out the diagnosis as amelanotic forms exist (Image B). Tumor cells can range from a spindled sarcomatous appearance to an epithelioid look with abundant pink cytoplasm, large nuclei, and giant cherry-red nucleoli (Image C). Like most other metastases, melanomas often show sharp brain-tumor interfaces (Image B), but rarely they can have a more diffusely infiltrating pattern like gliomas. Fortunately, most melanomas will express antigens allowing positive immunostaining for markers such as S100, Melan A, and HMB45. While a sensitive marker for melanoma, S100 is also found in normal neural cells, schwannomas, and astrocytomas (Image D, upper half is melanoma while lower half is reactive brain tissue). Melan A (Image E) and HMB45 are more specific for melanoma, but their sensitivity can sometimes be decreased in metastases. SOX10, a nuclear transcription factor found in neural crest, melanocytes, Schwann cells, and glia can also be a sensitive marker for melanoma and is generally not seen in most other metastatic neoplasms. Melanomas will not be immunopositive for Pancytokeritin markers (Image F) or GFAP (Image G, upper half of panel is reactive brain tissue, lower unstained half is melanoma). Multiple markers must often be employed to confirm the diagnosis.

Image B: H&E stain.

Image B: H&E stain.

Image C: H&E stain.

Image C: H&E stain.

Image D: S100, IHC stain.

Image D: S100, IHC stain.

Image E: Melan A, IHC stain.

Image E: Melan A, IHC stain.

Image F: Pan-cytokeratin, IHC stain.

Image F: Pan-cytokeratin, IHC stain.

Image G: GFAP, IHC stain.

Image G: GFAP, IHC stain.

Establishing a diagnosis of metastatic melanoma by histology and IHC is essential to guide further molecular characterization and therapy. Various studies have suggested that almost half of the individuals with stage IV melanoma will develop brain metastases. Surgery and radiation therapy have been at the forefront of treatment for metastatic melanoma to the CNS, though with fairly limited therapeutic effect. Targeted therapy and immunotherapy are becoming increasingly important and effective in recent years. About 40% to 50% of metastatic cutaneous melanomas contain a mutation in BRAF, the most frequent of which are valine-to-glutamic acid, valine-to-lysine, and valine-to-aspartic acid substitutions at codon 600 (V600E, V600K, and V600D, respectively). These mutations lead to enhanced cell growth and proliferation through activation of the mitogen activated protein kinase (MAPK) pathway. A number of BRAF inhibitors have been developed and together with small-molecule inhibitors of related downstream pathways are now routinely used to significantly improve survival of patients with metastatic melanoma. Similarly, immunotherapies based on antibodies against the checkpoint inhibitors cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-ligand 1 (PD-L1), and programmed cell death protein-1 (PD-1) are being increasingly used. Broader therapeutic options are now providing meaningful improvements in survival and quality of life for this once near-uniformly fatal disease.

Metastatic melanoma

Take Home Points

  • Metastases to the brain can be the first harbingers of systemic disease. Therefore, a systematic and stepwise approach to IHC panels is helpful in guiding the clinical team to further investigate the location of the tumor's primary origin.
  • Melanomas metastatic to the brain can have many different appearances on standard H&E-stained sections and are sometimes amelanotic. They can even mimic primary CNS neoplasms.
  • Ancillary molecular characterization of metastatic melanoma is crucial to directing treatment with new immunomodulatory therapies.


  1. Lin F, Liu H. Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med. 2014;138(12):1583-610.
  2. Pekmezci M, Perry A. Neuropathology of brain metastases. Surg Neurol Int. 2013;(4):S245-55.
  3. Westphal D, Glitza Oliva IC, Niessner H. Molecular insights into melanoma brain metastases. Cancer. 2017 Jun 1;123(S11):2163-75.

Answer Key

  1. What is the BEST diagnosis?
    A. Epithelioid glioblastoma
    B. Metastatic melanoma
    C. Metastatic adenocarcinoma
    D. Pleomorphic xanthoastrocytoma
    E. Primary CNS anaplastic lymphoma
  2. Which of the following IHC markers is MOST specific for this neoplasm?
    A. GFAP
    B. Melan A
    C. S100
    D. INI1
    E. Vimentin
  3. Which of the following non-CNS neoplasms has the highest propensity to metastasize to the CNS?
    A. Adenocarcinoma of the breast
    B. Gastrointestinal stromal tumor
    C. Hepatocellular carcinoma
    D. Papillary thyroid cancer
    E. Squamous cell carcinoma of the cervix