A Reassessment of the Barrier Effect of the Physis against Metaphyseal Osteosarcoma: A Comprehensive Pathological Study with Its Radiological and Clinical Follow-Up Correlations

Abstract

Osteosarcoma is a primary malignant bone tumor usually arising at the metaphysis of long bones, particularly around the knee. The physis has been regarded as a barrier capable of blocking tumor extension, thus allowing it to preserve their epiphysis and therefore improve functional results. With the objective of clarifying how effective the physis is as a barrier to tumor spread, a large series of skeletally immature patients with osteosarcoma were reviewed. From 452 metaphyseal osteosarcomas a selection of 282 cases in which the tumor was close or crossing the physis were carried out. This sub-sample was split into two groups according to the surgical treatment (epiphyseal preservation or not). The specimens obtained by resection were studied, and the physeal and metaphyseal areas were studied by multiple sections. Immunostaining against VEGF of physis was obtained in selected cases. In about half of the patients affected by metaphyseal malignant bone tumors, the growth plate and epiphysis were not compromised by the tumor. Three sequential invasive growth patterns of an osteosarcoma in its relationship with the physis could be distinguished. An intense angiogenesis and osteoclastic reaction could be observed in the growth plate in the free zone between the tumor and the physis. The local recurrence incidence was lower in the epiphyseal preservation treated patients than it was in the conventional treatment (8% vs. 12%). Most local recurrences appeared in the first 2 years. The overall survival of patients treated with epiphyseal preservation was better than that of the patients treated without preserving the epiphysis (73% vs. 59%; p = 0.03) at a mean follow-up of 18 years. We have described an angiogenic and osteoclastic reaction in the base of the growth plate in the proximity of the advance front of the tumor, which could facilitate the osteosarcoma invasion. It is also shown that the preoperative imaging method for examination is a valid approach for the decision to carry out epiphyseal preservation. Finally, we concluded that epiphyseal preservation combined with protective chemotherapy is an excellent clinical approach for selected patients with metaphyseal osteosarcoma.

Keywords: growth plate; immunohistochemistry; neoplasm invasiveness; neovascularization; osteosarcoma; radiology; survival analysis.

Figure 1

Flow chart that represents stepwise procedures for clinical decision making about the evaluation and management of metaphyseal pediatric osteosarcoma.

Figure 2

(A) MRI of an osteosarcoma that is separated from the cartilage growth. (B) The same osteosarcoma is studied macroscopically. The tumor is located away from the physis. In addition, the procedure of sampling the tumor is shown. (C) Normal physis without vascular angiogenesis and osteoblastic/osteoclastic activation when the tumor is far enough away from the physis (H&E, ×100).

Figure 3

(A) MRI showing tumor is in proximity of the physis. (B) The corresponding macroscopy is shown. A good correlation can be observed between the radiology and the macroscopy of the osteosarcoma. (C) The physis is altered because of the vascular and cell proliferation in zones of the physis in proximity of osteosarcoma (H&E, ×100). (D). Intense angiogenesis in the physis is observed. (H&E, ×200). (E). A few osteoclasts and osteoblasts are seen in the bone trabeculae in the growth plate. The osteoblasts have a hypertrophic aspect (H&E, ×200).

Figure 4

A strong immunoreactivity against VEGF can be observed in the osteoclasts and osteoblasts in the physis. A high density of vessels can be distinguished (Immunohistochemistry, (A) ×100, (B) ×200).

Figure 5

(A) MRI of an osteosarcoma in contact with the growth plate. (B) The corresponding macroscopy of the osteosarcoma is shown. It is observed that the tumor is placed in contact with the cartilage growth. (C) A vascular communication that passes through the physeal cartilage as finger-like growths permeating the calcification and hypertrophic zones is observed. This vascular channel is not composed of tumor cells (H&E, ×200).

Figure 6

(A). MRI of a telangiectatic osteosarcoma crossing the growth plate. (B) The corresponding tumor can be observed. The arrows indicate where the tumor disrupts the physis. (C) Histological illustration of the finger-like projections of the osteosarcoma crossing the growth plate (×40).

Figure 7

Kaplan–Meier analysis showing that patients treated with epiphyseal preservation had a significantly better overall survival rate than patients treated without physis preservation.