2020 NPB-16

This case was originally published in 2020. 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.

The patient is a 55-year-old man who presented with left facial droop, headache, and altered mental status. Brain MRI revealed a large right frontal mass with heterogeneous contrast enhancement, edema, blood products, and right-to-left shift. The patient was taken to surgery for resection of the lesion.

Tissue Site
Brain

The whole slide image provided is an H&E-stained section of the right frontal lobe resection specimen.

The diagnosis in this case is metastatic large cell neuroendocrine carcinoma. H&E-stained sections (Image A and Image B) show a high-grade neoplasm with areas of hemorrhage and necrosis invading brain parenchyma. The tumor cells are densely packed and show no glandular differentiation. They have heterochromatic, pleomorphic nuclei, and display abundant mitoses and apoptotic bodies. There is strongly-positive immunostaining for pancytokeratin (Image C), CD56 (Image E), and synaptophysin (Image F). The tumor cells in this case also show positive immunoreactivity (but to a lesser degree) for chromogranin (Image D) and TTF1 (Image G). This immunoprofile and histopathologic appearance establish the diagnosis and suggest a lung primary site of origin.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors thought to arise mostly from endodermal precursor cells. They have the ability to produce hormones and other secreted molecules (prostaglandins, histamine, bradykinin, substance P, catecholamines, and, notably, serotonin) and have similarities with nerve cells, such as cytoplasmic granules and exocytotic machinery. However, the majority of NENs are hormonally silent. NENs primarily arise from the gastrointestinal tract (55%) and bronchopulmonary system (30%) but can occur in virtually any organ. In roughly 13% of metastases, the primary location is unknown.

The age-adjusted incidence rate of NEN rose from 1.09 per 100,000 individuals in 1973 to 6.98 per 100,000 in 2012 across all sites, stages, and grades, or around 5% each year. This increase is ascribed to more sensitive diagnostic methods.

NENs can be recognized by their characteristic cytologic and IHC neuroendocrine features. NENs are a heterogeneous group of tumors as they exhibit different organ-specific characteristics and biological behavior. NENs encompass both well-differentiated NE tumors (NETs) and poorly-differentiated NE carcinomas (NECs), as they both share common histologic, immunophenotypic, and ultrastructural neuroendocrine features. NETs are composed of cells characterized by round or oval nuclei with “salt and pepper” chromatin and variably-eosinophilic, granular cytoplasm. NECs are divided into small cell carcinomas and large cell NECs based on nuclear-to-cytoplasmic ratio (N:C ratio) which is lower in large cell NEC than in small cell carcinoma. Also, large cell NECs often show greater pleomorphism.

Chromogranin A and synaptophysin are currently considered the most specific IHC markers for NENs. CD56 is a sensitive, but not a highly-specific marker; most primary CNS tumors are immunoreactive. Dot-like pancytokeratin staining is highly suggestive of NENs. IHC for insulinoma associated protein 1 (INSM1) has been found to stain a broad spectrum of NENs and is felt to have comparable or better sensitivity and specificity than older markers. A variety of markers can help suggest the site of origin for a metastatic NEN. CDX2 is a homeodomain-containing transcription factor that indicates probable intestinal differentiation. TTF1 is a homeodomain-containing nuclear transcription protein that is involved in the organogenesis of the thyroid gland and lung as well as the development of the neurohypophysis and the ventral brain. PAX8 is a transcription factor involved in thyroid and kidney development. Isl-1 is a homeobox-gene transcriptional factor expressed in all endocrine, but not exocrine, pancreatic cells. Pancreatic NENs may also express the progesterone receptor (PR), pancreatic and duodenal homeobox 1 (PDX-1), and the neuroendocrine secretory protein 55 (NESP55). Finally, Ki-67 labeling index is accepted by the WHO as an independent prognostic marker for NENs and is felt to be the most reliable prognostic factor of gastroenteropancreatic (GEP) group of NENs.

NETs are graded in three tiers as G1 (low-grade), G2 (intermediate-grade), and G3 (high-grade). It is not necessary to grade NEC as these are always high-grade. Mitotic count, Ki-67 proliferative index, and the presence or absence of necrosis are the main three prognostic relevant grading parameters. Because NENs are a diverse group of tumors, grading should be contingent on the anatomic site. Grading of metastatic foci is controversial.

• NEC are regarded as high-grade, but as they represent a separate tumor family, there is no need for formal grading.
• aThe category of G3 atypical carcinoid in the lung is not a validated entity and is not recognized in the 2015 WHO classification. Currently such tumors are classified as small cell lung carcinoma (SCLC) or large cell neuroendocrine carcinoma (LCNEC). High-grade NET with features of atypical carcinoid similar to the G3 tumors of the pancreatic/gastrointestinal tract are rare in the lung, not well characterized, and need further study.
• bNot recommended as small cell lung carcinoma (SCLC) is too well ingrained in clinical practice, and some SCLC lack commonly-used neuroendocrine markers.

*Table modified from Rindi G, Klimstra D, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31:1770-86. Reused under license CC BY 4.0.

Although NETs were traditionally thought to exhibit benign behavior, metastatic and malignant potentials have now been well established. In addition to differentiation and proliferation rate, metastatic disease is a major prognostic factor in NETs. While lymph node, liver, and bone metastases occur relatively frequently, brain metastases in NETs are rare, with an estimated incidence of 1.5% to 5%, and likely occur mostly in advanced disease.

The differential diagnosis of NEN metastases to the CNS includes primary brain tumors and other metastases. The primary CNS tumors with similar appearance include gliomas, embryonal tumors, and lymphomas. The histologic and IHC features of metastatic tumors are similar to their primaries. They spread mainly via the hematogenous route. Lung, breast, and skin (melanoma) are the most common sites of origin for CNS metastases.

Small cell lung carcinoma (pulmonary NEC, small cell-type) is the most likely of the NENs to metastasize to the brain and usually shows TTF1 and CK7 immunoreactivity. Breast carcinomas are often CK5/6, CK7, GATA3 positive, and TTF1, CK20, and S100 are non-immunoreactive. Melanoma is the third most common tumor type to metastasize to the brain and is generally S100, HMB45, and Melan A/MART1 positive.

Treatment of metastatic NEN includes surgery, stereotactic radiosurgery, whole-brain radiotherapy (WBRT), or chemotherapy as single therapies or in combination. No prospective, randomized therapeutic trials for NEN metastasis to the brain are currently available.

• NENs may arise in almost any organ and in soft tissues.
• NENs share common neuroectodermal phenotypes, including general NEN markers (chromogranin A, synaptophysin, pancytokeratin), but may express additional markers suggestive of site of origin.
• Organ-specific features inform grading and nomenclature.
• Depending upon organ system, mitotic rate, Ki-67 labeling index, and necrosis are prognostically useful, but grading is controversial in metastases.

1. Louis DN, Perry A, Reifenberger G, et al. World Health Organization Classification of Tumors of the Central Nervous System. 4th ed. Lyon, France: International Agency for Research on Cancer; 2016:803-20.
2. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31:1770-86.
3. Rosai J. The origin of neuroendocrine tumors and the neural crest saga. Mod Pathol. 2011;24:S53-7.
4. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335-42.
5. Krug S, Teupe F, Michl P, Gress TM, Rinke A. Brain metastases in patients with neuroendocrine neoplasms: risk factors and outcome. BMC Cancer. 2019;19:362. doi:10.1186/s12885-019-5559-7.
6. Leoncini E, Boffetta P, Shafir M, Aleksovska K, Boccia S, Rindi G. Increased incidence trend of low-grade and high-grade neuroendocrine neoplasms. Endocrine. 2017;58(2):368-79.
7. Choe J, Won Kim K, Jung Kim H, et al. What is new in the 2017 World Health Organization classification and 8th American joint committee on cancer staging system for pancreatic neuroendocrine neoplasms? Korean J Radiol. 2019;20(1):5-17.
8. Kyriakopoulos G, Mavroeidi V, Chatzellis E, Kaltsas GA, Alexandraki KI. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. Ann Transl Med. 2018;6(12):252.
9. Mallory GW, Fang S, Giannini C, Van Gompel JJ, Parney IF. Brain carcinoid metastases: outcomes and prognostic factors. J Neurosurg. 2013;118(4):889-95.
10. Pekmezci M, Perry A. Neuropathology of brain metastases. Surg Neurol Int. 2013;4(suppl 4):S245-25.
11. Lloyd RV, Osamura RY, Klöppel G, Rosai J. WHO Classification of Tumours of Endocrine Organs. 4th ed. Lyon, France: International Agency for Research on Cancer; 2017:209-40.