Bone pathology--small cells, large cells, and what's in between.

This edition of the ARCHIVES contains a special section on bone pathology. Two of the articles review bone neoplasms, one describing the gamut of bone tumors with epithelial differentiation or epithelioid morphology and the other describing the spectrum of small, round cell neoplasms. The third article reviews the morphology of skeletal substitute materials, which all pathologists will encounter with increasing frequency in the future.

The accurate diagnosis of "small, round, blue cell tumors" of bone requires careful correlation of clinical, radiographic, histologic, and immunohistochemical data, and the utilization of flow cytometry, cytogenetics, and molecular diagnostic testing. Given the significant differences in treatment between the various entities included in this general category of tumors, accurate pathologic diagnosis is absolutely essential, and familiarity with the various techniques that aid in the diagnosis is imperative. As Dr Meera Hameed discusses in her article on small round cell tumors of bone, this heterogeneous family of tumors shares many radiographic and morphologic similarities, but the exploitation of their unique biologic and genetic features allows for accurate classification. The prototypic small round cell tumor of bone is the Ewing sarcoma family of tumors (EFT), and this review details the pathologic features of not only the "classic" EFT but of several unusual variants, including the adamantinoma-like Ewing sarcoma, sclerosing EFT, and spindle cell sarcoma-like EFT. The morphologic descriptions are accompanied by an in-depth examination of the immunohistochemical and molecular diagnostic features that not only allow accurate classification of this tumor, but potentially offer prognostic information as well. The distinction between EFT and non-Hodgkin lymphoma, particularly lymphoblastic lymphoma/leukemia, is always challenging, and Dr Hameed provides a succinct overview of the most common variants of non-Hodgkin lymphoma of bone, emphasizing the need for an algorithmic approach to diagnosis that includes immunohistochemistry and flow cytometry. Finally, the clinical, radiographic, and pathologic aspects of two relatively distinctive bone tumors, mesenchymal chondrosarcoma and small cell osteosarcoma, are presented. The importance of ancillary diagnostic techniques, including molecular diagnostics, cytogenetics, and flow cytometry, cannot be stressed enough should one encounter a small round cell tumor of bone in practice.

The most common tumor encountered in bone is metastatic carcinoma. However, a variety of primary skeletal neoplasms, both benign and malignant, can display either true epithelial differentiation or epithelioid morphology. Drs Deyrup and Montag tackle several controversial issues in their article entitled "Epithelioid and Epithelial Neoplasms of Bone." The classification of epithelioid vascular neoplasms of bone has been a controversial subject for many years, and this article nicely summarizes the literature on the pathology and biologic behavior of these rare entities, offering criteria by which epithelioid hemangioma, epithelioid hemangioendothelioma, and epithelioid angiosarcoma can be reliably distinguished in most instances. The article also briefly addresses the emerging entity "hemorrhagic epithelioid and spindle cell hemangioma." Next, the article addresses adamantinoma, a primary bone tumor with true epithelial differentiation. Although the relationship between classic adamantinoma, differentiated adamantinoma, and osteofibrous dysplasia remains controversial, Drs Deyrup and Montag succinctly summarize the nosology of these lesions. Finally, epithelioid bone-forming neoplasms are addressed. Perhaps the most challenging aspect of these tumors is separating the epithelioid (aggressive) osteoblastoma from osteoblastoma-like osteosarcoma. Drs Deyrup and Montag provide the necessary radiographic and histologic data to make this vitally important distinction, and also discuss the significance of rosette formation in epithelioid osteosarcoma, a finding recently associated with poor prognosis.

The final article in this special section should provide most readers with a wealth of new information. In "An Overview of the Histology of Skeletal Substitute Materials," Dr Thomas Bauer provides clues to the recognition of a wide variety of bone defect fillers. Many of these are currently utilized by orthopedic surgeons, neurosurgeons, and maxillofacial surgeons in spinal fusions; in voids created by the excision of tumors, fixation of fractures, or in arthroplasty surgery; and in defects created in maxillofacial surgeries. As Dr Bauer discusses in the introduction, the histologic recognition of these materials, and the reactions that they elicit, are important (1) to avoid mistinterpretation of the materials as evidence of recurrent tumor, (2) to help define the biocompatibility of the material, and (3) to further define the best clinical applications of the various materials. It is also important to understand the type of inflammatory response that these materials induce in order to raise the possibility of infection in certain clinical scenarios. Any pathologist who routinely deals with specimens from orthopedic surgeons, neurosurgeons, or maxillofacial surgeons will benefit tremendously from Dr Bauer's review of this fascinating topic.

Whether you deal routinely with bone tumors in a large center or encounter only an occasional bone tumor in a smaller practice, we hope that these reviews, which include both controversial topics and emerging entities, will be of both interest and value to you. The review of skeletal substitute materials should provide novel and useful information to most surgical pathologists.

Accepted for publication October 12, 2006.

John D. Reith, MD

From the Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: John D. Reith, MD, Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, College of Medicine, JHMHSC Room 3105, 1600 SW Archer Rd, Gainesville, FL 32610-0275 (e-mail: [e-mail]).

John D. Reith, MD, earned his medical degree from the Northeastern Ohio Universities College of Medicine in 1991. Following residency in anatomic and clinical pathology at the Cleveland Clinic Foundation, he completed fellowships in surgical pathology at the University of Michigan and orthopaedic pathology at Albert Einstein College of Medicine. He subsequently served as an attending pathologist and assistant professor at the University of Miami School of Medicine until 1998. Dr Reith is currently an associate professor in the Departments of Pathology, Immunology, and Laboratory Medicine and Orthopaedics and Rehabilitation at the University of Florida College of Medicine in Gainesville, and is the director of Bone and Soft Tissue Pathology and the pathology residency director.