Bone and Soft Tissue Pathology

Bone and Soft Tissue Pathology

The Division of Bone and Soft Tissue Pathology provides diagnostic services to Massachusetts General Hospital and pathologists throughout the United States and many foreign countries. Fellows trained by this group have generally become academic pathologists, or specialists in large community hospitals that have active orthopaedic and oncology services. The major research efforts of the group since 1986 have focused on the clinicopathologic features of a variety neoplastic processes that affect the skeleton and soft tissues. Some of this work has been in collaboration with the Mass General Departments of Orthopaedics, Radiation Oncology, Medical Oncology and Radiology. Currently, the group is expanding its research effort into include the molecular genetics of bone and soft tissue tumors.

Within the Mass General, the division is a key member of the Connective Tissue Oncology Group, which is a multidisciplinary collection of physicians dedicated to the treatment of patients at the Mass General with tumors of the soft tissue and skeleton. We are also members of the Mass General Brigham Connective Tissue Oncology Group, which includes our counterparts at the Brigham and Woman's Hospital.

Faculty

• G. Petur Nielsen, MD - Subspecialty Head, Bone and Soft Tissue Pathology
• Ivan A. Chebib, MD
• Yin Rex Hung, MD, PhD

Clinical Program

The service volume is approximately 4700 surgical specimens per year. Of these cases, approximately 20% are from benign and malignant neoplasms with the remainder representing a variety of diseases including arthritis, infection, metabolic disorders, mechanical problems, circulatory dysfunction, and trauma. Many of the neoplasms require a complex evaluation in addition to conventional light microscopy, including immunohistochemistry, electron microscopy, cytogenetics, FISH, and PCR.

The service is one of the most active users of the immunohistochemistry, electron microscopy and molecular genetics. Not included in the Mass General volume of cases are many private consult cases that are requested from pathologists and surgeons from throughout the United States and many foreign countries.

Academic and Research Accomplishments

Skull Base Tumors
The division reviews more surgical specimens from skull base tumors than any other center. This large number of referral is based on the availability of proton beam radiation in the Department of Radiation Oncology, and it attracts patients from around the world.

The majority of skull base tumors are chondrosarcomas and chordomas. The division has published a series of papers strictly defining the morphology of these tumors in relation to their immunoprofile and prognosis. Importantly, these studies have shown that 37% of chordomas and chondrosarcomas are misdiagnosed at outside institutions. The majority of errors involve the misclassification of myxoid chondrosarcoma as chordoma, and performing immunohistochemistry could prevent most of these mistakes. The relevance of this error is that chondrosarcomas do not require aggressive surgical resection, and the five year local control rate of chondrosarcoma is 99% in comparison to 50-60% for chordoma.

Other important morphologic studies related to treatment and prognosis have included the documentation that certain benign bone tumors that can be confused pathologically with chondrosarcoma, chordoma, arise in the skull base and the description of variants of chordomas that can be confused with benign processes.

We have recently published a large series of chordoma in children and are now studying a subgroup of children with aggressive skull base chordomas.

Currently we are studying chordomas and precursor lesions in ferrets and have recently completed a comparative genomic hybridization study on chordomas.

Suppressor Genes and Cell Cycle Regulators

The division has also studied the mechanisms underlying the pathogenesis, diagnosis and treatment of bone and soft tissue tumors, in relation to tumor suppressor genes and cell cycle regulators. In an animal model NF2 gene knockout mice showed an increased risk for developing osteosarcoma, suggesting a possible role for the NF2 gene in osteosarcomas.

However, our study did not demonstrate NF2 mutations in human osteosarcoma. Another study investigated the expression of p16, RB and CDk4 in osteosarcomas. This investigation showed that a large number of osteosarcomas that lack RB abnormalities do have p16 abnormalities implicating this important cell cycle regulatory pathway in the genesis of osteosarcoma.

Additionally, we have shown that malignant transformation of neurofibromas in patients with neurofibromatosis type 1 is associated with CDKN2/p16 inactivation. This finding has the potential to be applied in the clinical setting to help distinguish neurofibroma from malignant peripheral nerve sheath tumors. We have also studied the immunohistochemical expression of p16 in normal adult and infant tissue, which has increased our understanding of the normal function of this protein, and the significance of altered p16 expression in human tumors.

Additionally, the division has collaborated in a study that is trying to determine whether or not tolerance to transplanted allogenic vascularized skeletal tissue can be achieved with short-term cyclosporine therapy in miniature swine.

Epithelioid Vascular Tumors of Bone

Epithelioid vascular tumors of bone are uncommon tumors, are morphologically diverse, and have a broad spectrum of biological behavior. The division has published several articles showing that the previously accepted morphologic features used to distinguish benign from malignant epithelioid vascular tumors are erroneous and this has resulted in the misdiagnosis and over treatment of many benign tumors as endothelial sarcomas. These studies define the morphologic features that allow the accurate distinction of these tumors. Additionally, another study identified a previously unrecognized benign variant that was frequently confused with sarcoma.

Mesenchymal Tumors of the Gynecologic Tract

A variety of mesenchymal tumors arise in the female genital tract. Many of them have unique morphologic features making their recognition difficult and predisposing them to misdiagnosis. The division has published several papers describing the morphologic features and prognosis of different types of tumors arising in this anatomic region.

Other Studies

The division has published many clinicopathologic studies of a variety of different neoplasms that have focused on their incidence, morphology, ultrastructural characteristics, immunoprofile and biologic behavior. Some of these provided the first detailed description of these entities.

Teaching and Educational Activities

Clinical Service
The division runs, or participates in, a variety of departmental and interdepartmental conferences. For the Department of Pathology, the division offers cases for discussion by the residents at the surgical pathology ‘outs’ conference. The division presents an hour-long conference to the residents on a regular basis. The division also participates in the weekly, hour long, skeletal radiology conference and the weekly, hour-long, Connective Tissue Oncology Group working conference.

The division gives one hour long conferences to the pathology and orthopaedic residents at Boston University School of Medicine three times a month and a monthly hour long conference to the pathology residents at the Brigham and Woman’s Hospital. The division also gives regular lectures to pathology residents at the Mallory Institute of Pathology and participates in the teaching of medical students at the Boston University School of Medicine.

Residents
Every resident training in anatomic pathology rotates on the Bone and Soft Tissue Pathology Service for one week long rotations for a total of four to ten weeks for each resident. During that time period the residents acquire the skills to diagnose many of the diseases that affect the musculoskeletal system.

Each year the division participates in the Boston Orthopaedic Pathology Course. These courses are offered for orthopaedic surgery residents in the New England and New York areas.