2019 NPA Minisymposium

This minisymposium was originally published in 2020. The information provided in this minisymposium 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 minisymposium.

Skull lesions are not uncommonly encountered by both neuropathologists and general surgical pathologists alike; therefore, awareness of the broad differential diagnosis of such lesions and possessing a sound understanding of an approach to this differential is important. There have also been recent advances in the molecular understanding of many of these entities. The wide differential includes nonneoplastic and both primary and secondary neoplastic entities. Clinical history and radiographic studies are often helpful in narrowing the differential diagnosis.

When approaching the differential diagnosis of a skull lesion, it is helpful to consider the patient’s age, location of the lesion, focality, and more specific imaging characteristics. For example, skull lesions occurring more commonly in the pediatric age group include Langerhans cell histiocytosis (LCH), fibrous dysplasia, aneurysmal bone cyst, metastatic neuroblastoma, and Ewing sarcoma, while chordoma, chondrosarcoma, plasma cell neoplasia, and metastases from breast, lung, prostate, skin, and kidney are more common in adults. Lesions commonly seen in the skull base (eg, chordoma, chondrosarcoma) differ from those more commonly seen in the calvarium (eg, metastases, plasma cell neoplasia, LCH) and the petrous apex (eg, cholesterol granuloma). The presence of multiple lesions might suggest metastases or plasma cell myeloma, while many other entities are more typically unifocal. CT and MRI can provide disparate, useful information when narrowing the differential. CT can demonstrate bone lysis and sclerosis, involvement of the two skull tables and diploë, calcification within the lesion, and sclerotic margins. MRI is useful in evaluating for extraosseous involvement of either soft tissues or the brain parenchyma.

Once tissue is available for examination, broad classification into either nonneoplastic or neoplastic category should be performed. Nonneoplastic entities include infections and other inflammatory lesions. Neoplastic entities encompass both benign and malignant, as well as both primary and secondary tumors (Figure 1). While many of the histologic diagnoses are fairly straightforward, in some instances there may be histologic overlap between entities, and arriving at an accurate diagnosis can be challenging. Three such patterns will be explored further: tumors with chordoid morphology, small round blue cell tumors, and lesions with giant cells.

The prototypical tumor with chordoid morphology is of course the chordoma. Chordomas are malignant bone tumors that display notochordal differentiation. Because they arise from notochordal remnants, they are typically found in midline locations, with the skull base, sacrococcygeal bones, and other vertebral bodies each accounting for approximately one-third of cases. Histologically, chordomas often display lobulated architecture and are comprised of cords and nests of physaliphorous cells with clear bubbly cytoplasm embedded in abundant myxoid matrix. Nuclear pleomorphism and mitotic activity can vary from low-grade to high-grade, but low-grade features predominate. Necrosis may be encountered. Histologic variants include chondroid chordoma (in which the extracellular matrix resembles hyaline cartilage) and dedifferentiated chordoma (in which areas of classic chordoma are seen along with a high-grade undifferentiated spindle cell tumor or osteosarcoma component). Chordomas display immunoreactivity for cytokeratin, EMA, and S100. Brachyury is a more specific marker for chordoma and can be used to distinguish it from other tumors in the differential, including chondrosarcoma, most carcinomas, and chordoid meningioma. It should be noted, however, that brachyury expression has also been identified in a substantial proportion of germ cell tumors and small cell carcinomas of the lung, and rarely in other carcinomas and sarcomas. Furthermore, immunoreactivity can be lost in decalcified tissues, and it is not typically expressed in the dedifferentiated component of dedifferentiated chordomas. In addition to its use as a diagnostic marker, brachyury may also be a prognostic marker; some studies have shown that patients with skull base chordomas expressing brachyury have a significantly shorter progression-free survival as compared to those with tumors not expressing brachyury.

The differential for the chondroid variant of chordoma includes chondrosarcoma. Both can occur in the skull base region, although chondrosarcoma is typically located more laterally, while chordoma is midline. Chondrosarcoma is graded on a scale of I to III, with most skull base chondrosarcomas being low-grade. Molecular studies have recently identified two subgroups of chondrosarcoma: central and periosteal chondrosarcomas, which harbor IDH1/2 mutations; and peripheral chondrosarcomas, which display EXT1 or EXT2 inactivation. Skull base chondrosarcomas are considered a type of central chondrosarcoma and studies have shown approximately 50% harbor mutations in IDH1/2. Unlike diffuse gliomas, in which the most common mutation is IDH1 R132H. This particular mutation has been detected in only approximately 17% of chondrosarcomas, with other substitutions such as R132C, R132G, R132L, and R132S being more common. The IDH immunostain is therefore less useful in chondrosarcoma than in gliomas, and sequencing for IDH1/2 mutations is more beneficial. IDH1/2 mutations are not seen in chordomas, and brachyury expression is not seen in chondrosarcomas.

The differential for chordoma may also include metastatic carcinoma, especially carcinomas with mucinous features. A clinical history of carcinoma and IHC should generally distinguish the two. While both may show immunoreactivity for cytokeratin, S100 is commonly positive in chordoma but typically negative in carcinomas. Brachyury is generally considered more specific for chordoma, but as mentioned above, immunoreactivity has been seen in some epithelial malignancies, including fairly commonly in germ cell tumors (embryonal carcinoma and seminoma) and small cell carcinoma of the lung, and very rarely in other carcinomas.

Intraosseous meningioma is uncommon, and intraosseous chordoid meningioma even more so, but this should still be considered in the differential of skull tumors with chordoid histology. Chordoid meningiomas are expected to display immunoreactivity for EMA, similar to chordoma, but they may also show progesterone receptor and diffuse somatostatin receptor type 2A (SSTR2A) immunoreactivity and are essentially negative for cytokeratin, S100, and brachyury. Moreover in many cases, areas of more classic meningothelial meningioma may also be seen within the tumor.

Finally, chordoma must be distinguished from benign notochordal cell tumors, which can be found in intraosseous locations similar to those of chordoma. In addition, benign notochordal cell tumors can be located intradurally; examples in the dorsum of the clivus are termed ecchordosis physaliphora. Benign notochordal cell tumors are comprised of vacuolated cells similar to chordoma, but do not exhibit the lobular architecture, fibrous septae, and myxoid matrix typical of chordoma.

Small round blue cell tumors involving the skull include hematolymphoid malignancies, namely plasma cell neoplasms and non-Hodgkin lymphomas, Ewing sarcoma, metastatic small cell carcinoma or metastatic neuroblastoma, small cell osteosarcoma, and mesenchymal chondrosarcoma.

Plasma cell neoplasms include both plasma cell myeloma (previously multiple myeloma) and solitary plasmacytoma of bone. Both are clonal proliferations of neoplastic plasma cells, with plasma cell myeloma being multicentric and plasmacytoma being unicentric; distinction requires clinical and radiographic correlation. In most cases, tumor cells resemble normal plasma cells with an eccentrically placed nucleus, condensed chromatin, indistinct nucleolus, abundant basophilic cytoplasm, and perinuclear hof or clearing. Some cases however, may exhibit a small lymphocyte-like appearance or may be more poorly differentiated, exhibiting a blastic appearance with prominent nucleoli, vesicular chromatin, and high nuclear:cytoplasmic ratios. The histologic differential diagnosis can include both reactive plasma cell proliferations, such as those seen in infections including syphilis, mycobacteria, and trypanosomiasis, as well as other neoplastic entities including non-Hodgkin lymphomas, poorly-differentiated carcinomas, neuroendocrine carcinomas/tumors, and round cell sarcomas. IHC can be helpful in this distinction. CD138, CD38, and MUM-1 are excellent plasma cell markers but do not distinguish reactive from neoplastic plasma cells. IHC or in situ hybridization for kappa and lambda light chains can establish light chain restriction and therefore clonality. It should also be noted that CD138 can be expressed in some carcinomas, albeit generally not as strong and diffuse as in plasma cell neoplasms.

Primary non-Hodgkin lymphoma of bone may occasionally present as a skull lesion, with diffuse large B-cell lymphoma (DLBCL) being the most common type encountered. Morphology is typically similar to DLBCL seen elsewhere, but occasionally there can be extensive fibrosis and spindling of cells, mimicking a sarcoma. While both are considered small round blue cell tumors, the nuclei of lymphoma typically demonstrate more pleomorphism than is generally seen in Ewing sarcoma. In the 2016 revision of the WHO classification of lymphoid neoplasms, stratification of DLBCL into germinal center and nongerminal center subtypes is now required, as this may affect treatment. IHC methods, such as the Hans algorithm, are considered acceptable for subtyping DLBCL. In addition, IHC coexpression of MYC and BCL2 has been identified in a subset of DLBCLs, most of which do not harbor MYC/BCL2 chromosomal alterations. These so-called “double-expressor” lymphomas have a worse prognosis than DLBCL without coexpression but a better prognosis than “high-grade lymphoma with rearrangements of MYC and BCL2 and/or BCL6.” Other subtypes of lymphoma, including other mature B-cell lymphomas, anaplastic large cell lymphoma, and rarely Hodgkin lymphoma, can also be primary bone lesions. Primary bone lymphoma must be distinguished from the much more common secondary bone involvement by a nodal or other extranodal lymphoma.

Ewing sarcoma is a small round cell sarcoma most commonly seen in children and adolescents characterized most often by a reciprocal translocation, t(11;22)(q24;q12), that fuses EWSR1 to FLI1, creating the EWSR1-FLI1 oncoprotein. Alternate translocations that fuse EWSR1 to other ETS family members are seen in a minority of cases. While Ewing sarcoma most commonly involves long bones, the skull can occasionally be involved. Histologically, Ewing sarcoma is characterized by sheets of small round blue cells with fine chromatin and scant glycogen-rich, and therefore PAS-positive, cytoplasm. Classic Ewing sarcoma does not show neuroectodermal differentiation, but some cases may show Homer Wright rosettes or immunophenotypic evidence of neural differentiation. Diffuse membranous CD99 immunoreactivity and FLI-1 immunoreactivity are characteristic of Ewing sarcoma. As many as 30% of cases show some cytokeratin immunoreactivity. It should also be noted that CD99 is not entirely specific for Ewing sarcoma, as lymphoblastic leukemia/lymphoma and myeloid sarcoma may also show a staining pattern identical to that seen in Ewing sarcoma.

Bone lesions containing giant cells are many and varied and could include nonneoplastic entities such as sarcoidosis, granulomatous infections, and cholesterol granuloma, as well as neoplastic entities including histiocytic neoplasms (LCH, Erdheim-Chester disease (ECD)), giant cell tumor (GCT) of bone, aneurysmal bone cyst, osteoid osteoma/osteoblastoma, osteosarcoma, and chondroblastoma.

LCH is a clonal neoplastic proliferation of Langerhans cells. Clinical manifestations are highly varied, ranging from a unifocal lesion to disseminated multisystem disease. Isolated bone lesions are the most common presentation, with the calvarium being the most frequently involved site. The pituitary gland and other central nervous system (CNS) locations can be involved less commonly. CNS involvement may include tumor-like lesions as well as LCH-associated neurodegenerative disease, the latter of which is characterized by demyelination, neuronal loss, and gliosis without histiocytic infiltration. In contrast, tumor-like lesions in the CNS as well as the classic bone lesions are histologically characterized by aggregates of Langerhans cells, which characteristically display ovoid or reniform nuclei with indented, irregular nuclear membranes, and often nuclear grooves. These neoplastic Langerhans cells are admixed with inflammatory cells including eosinophils, lymphocytes, neutrophils, plasma cells, and multinucleated giant cells. The diagnosis can be confirmed by demonstrating immunoreactivity for CD1a and CD207 (Langerin) in the Langerhans cells. These cells are also often immunoreactive for S100 but negative for CD68. Identification of the pathognomonic Birbeck granules by electron microscopy is rarely necessary anymore. Recent studies have found BRAF V600E mutations in approximately half of LCH cases. Mutations in other MAPK pathway members are seen in some cases without this BRAF mutation. A recent revised classification of histiocytoses categorizes LCH and ECD into the Langerhans-related group of histiocytoses, as both entities have similar molecular features and up to 20% of patients with ECD also have LCH lesions.

GCT of bone is a locally aggressive primary bone tumor histologically characterized by numerous osteoclast-like giant cells uniformly distributed amongst spindled, round, or oval mononuclear stromal cells. The stroma is often highly vascular, and areas of recent hemorrhage as well as hemosiderin deposition may be seen. GCT may rarely be associated with a high-grade malignant neoplasm at initial presentation or may undergo malignant transformation following radiation therapy. Recently, mutations in H3F3A, and less commonly H3F3B, have been identified in GCT of bone. A mutation-specific monoclonal antibody can be used to detect the most common H3F3A mutation, G34W. Immunoreactivity is seen only in the mononuclear cells and not the osteoclast-like giant cells, indicating that the mononuclear cells represent the neoplastic component while the giant cells are reactive. Detection of H3F3A mutations is useful in distinguishing GCT from other histologically similar tumors. GCT also often expresses high levels of RANKL and therefore can be treated with the anti-RANKL monoclonal antibody, denosumab.

Aneurysmal bone cyst (ABC) is most commonly seen in the metaphysis of long bones or the vertebrae but can occur in any bone, including the skull. ABC is typically well circumscribed and comprised of multiple cystic spaces filled with blood, separated by fibrous septae. The fibrous septae consist of a proliferation of fibroblasts, multinucleated osteoclast-like giant cells, and reactive woven bone rimmed by osteoblasts. Mitoses are often present, but atypical forms are not seen. The solid variant of ABC may be histologically indistinguishable from GCT of bone, giant cell reparative granuloma, and brown tumor of hyperparathyroidism. In primary ABC, which accounts for about 70% of cases, the fibroblastic proliferation is neoplastic and characterized by translocations involving the USP6 (ubiquitin specific peptidase 6/Tre-2) gene, most often resulting in fusion with the cadherin 11 (CDH11) gene. Secondary ABC changes can occur in association with other neoplasms including GCT of bone, osteoblastoma, chondroblastoma, fibrous dysplasia, and osteosarcoma. The characteristic genetic alterations involving USP6 are not seen in secondary ABC. FISH analysis for USP6 rearrangements can also be useful in distinguishing the solid variant of ABC from its histologic mimickers. The H3F3A and H3F3B mutations seen in GCT of bone are considered mutually exclusive with USP6 rearrangements.

*Although generally benign, some cases may display malignant behavior.

*Although generally benign, some cases may display malignant behavior.

• The differential diagnosis of skull lesions is broad and can include both nonneoplastic and neoplastic entities. Clinical and radiographic information can assist in narrowing the differential.
• Chordoma is characterized by immunoreactivity for cytokeratin, EMA, S100, and brachyury, while chondrosarcoma is characterized by IDH1/2 mutations.
• Diffuse large B-cell lymphoma is the most common primary bone lymphoma and should be stratified into germinal center versus nongerminal center subtype, as well as examined for “double expressor” status.
• Ewing sarcoma is characterized by diffuse membranous CD99 immunoreactivity, but this same staining pattern can be seen in lymphoblastic leukemia/lymphoma and myeloid sarcoma.
• Approximately half of cases of Langerhans cell histiocytosis and Erdheim-Chester disease harbor BRAF V600E mutations, leading to speculation that the two entities may be related.
• Giant cell tumor of bone is characterized by H3F3A mutations, while aneurysmal bone cyst (including the solid variant, which can be histologically indistinguishable from giant cell tumor of bone) is characterized by USP6 rearrangements.

1. Di Carlo FS, Divisato G, Iacoangeli M, et al. The identification of H3F3A mutation in giant cell tumour of the clivus and the histological diagnostic algorithm of other clival lesions permit the differential diagnosis in this location. BMC Cancer. 2018;18:358.
2. Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127(22):2672-81.
3. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: International Agency for Research on Cancer; 2013.
4. Garfinkle J, Melancon D, Cortes M , Tampieri D. Imaging pattern of calvarial lesions in adults. Skeletal Radiol. 2011;40:1261-73.
5. Haroche J, Cohen-Aubart F, Rollins BJ, et al. Histiocytoses: emerging neoplasia behind the inflammation. Lancet Oncol. 2017;18:e113-25.
6. Kakkar A, Nambirajan A, Suri V, et al. Primary bone tumors of the skull: spectrum of 125 cases, with review of literature. J Neurol Surg B. 2016;77:319-25.
7. Kitamura Y, Sasaki H, Yoshida K. Genetic aberrations and molecular biology of skull base chordoma and chondrosarcoma. Brain Tumor Pathol. 2017;34:78-90.
8. Li HR, Tai CF, Huant HY, et al. USP6 gene rearrangement differentiate primary paranasal sinus solid aneurysmal bone cyst from other giant cell-rich lesions, report of a rare case [Epub ahead of print]. Hum Pathol. 2017.
9. Miettinen M, Wang Z, Lasota J, Heery C, Schlom J, Palena C. Nuclear brachyury expression is consistent in chordoma, common in germ cell tumors and small cell carcinomas and rare in other carcinomas and sarcomas. An immunohistochemical study of 5229 cases. Am J Surg Pathol. 2015;39(10):1305-12.
10. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90.
11. Wilberger AC, Prayson RA. Intracranial involvement by plasma cell neoplasms. Am J Clin Pathol. 2016;146:156-62.