Giant cells tumor: diagnosis and treatment history evolution in Instituto de Ortopedia e Traumatologia from FMUSP

ARTIGO DE REVISÃO

Giant cells tumor– diagnosis and treatment history evolution in Instituto de Ortopedia e Traumatologia from FMUSP ^*

Olavo Pires de Camargo^I; Alberto Tesconi Croci^II; Cláudia Regina Gomes Cardin Mendes de Oliveira^III; André Mathias Baptista^IV; Marcelo Tadeu Caiero^V; Marcelo Abrantes Giannotti^VI

^ILivre-Docente Professor and Chief of Orthopedic Oncology Group from IOTHCFMUSP

^IILivre-Docente Professor and Sub chief of Orthopedic Oncology Group from IOTHCFMUSP

^IIIChief of Pathologic Anatomy Service from IOTHCFMUSP

^IVAssistant Doctor from Emergency Room and Orthopedic Oncology Group from IOTHCFMUSP

^VAssistant Doctor from Emergency Room and Orthopedic Oncology Group from IOTHCFMUSP

^VIAssistant Doctor of Pathologic Anatomy Service from IOTHCFMUSP

Giant Cells Tumor (GCT) is an aggressive benign bone neoplasia, with an uncertain biological behavior. It is histologically constituted of giant multinuclear cells spread over tumoral tissue with a nucleus presenting the same features of the ovoid and fusiform cells forming its stroma.

The anatomopathological rate is given by its stroma and not by the giant cells that can also be present in other tumoral and pseudo-tumoral lesions such as the hyperparatireoidism brown tumor, the aneurismatic bone cyst, the epiphysial condroblastoma, the osteoblastoma and the non-osteogenic fibroma.

Classic radiologic features of GCT: lytic, pumping, eccentric, with thinning or erosion of cortical bone, epiphysial-metaphyseal lesion, found in young adults from 20 to 35 years old, more frequently located in distal femur or proximal tibia, can be found in other pathologies, deserving emphasis for its severity the teleangectasic osteosarcoma and malignant bone fibrohystiocitoma. Among benign lesions, aneurismatic bone cyst and epiphysial condroblastoma are differential diagnosis from GCT. Less frequently it can be located in proximal humerus, distal radius, proximal femur, dorsal spine and sacrum.

It has a clinically aggressive behavior (B3 ENNEKING staging), with a fast growth, sometimes in weeks, however has few symptoms, leading to thinning and rupture of bone cortical, invasion of adjacent soft tissues, but not however invading or ulcerating skin and subcutaneous tissue. Can be misdiagnosed as an intrinsic knee injury especially if radiography is not up to date and well performed, since clear changes can be noticed in a 10 to 15 days interval. Our own experience shows cases sent from very far away not surgically treated which after a period of fast growth stopped evolution and had bone bars formed inside and necrosis areas, but never ulceration.

From the 389 cases treated at Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da FMUSP, from 1950 to 1998, only two cases were observed under 15 years of age, with a still open epiphyses (strictly metaphyseal GCT). Only one patient had more than one bone committed (distal radius and proximal fibula) and only two cases were histologically graded III or more, that means, malignant GCT who died due to pulmonary metastasis one year after diagnosis. In two cases pulmonary metastasis histologically benign were observed, and had a more than 15 years follow-up good clinical evolution after resection of the pulmonary lesion.

Bone neoplasias are relatively rare, being 2% of all neoplasias. GCT represents 8% of all primary bone tumors. It is frequent among Asian people as in China, where it represents 20% of bone tumors.

Histologically it is known this lesion was first described by COOPER in 1818⁽⁸⁾, and considered a ''fungal medullar exostosis'' In 1845 LEBERT⁽¹⁹⁾ described a group of bone tumors with multi-nucleated giant cells presenting a trend to recur and healed by amputation.

PAGET in 1854⁽²⁸⁾ calls this lesion myeloid sarcoma and draws its first macroscopic scheme. In 1860 NELATON⁽²⁷⁾ studies 46 cases understanding them as benign lesions, being however all cases amputated. MORRIS in 1876⁽²⁵⁾, KRAUSE in 1889⁽¹⁸⁾ and VOLKMANN in 1899⁽³⁵⁾ described the first cases treated by local curettage having good functional and clinical evolution.

However BLOODGOOD⁽¹⁾ in 1912 was the first to use the name GCT, establishing its clinical features and describing the results of 52 patients who underwent curettage and the use of a local adjuvant, carbolic acid, filling the cavity with iliac grafting. He was the first to use chemical cauterization and to understand GTC as an aggressive benign tumor, so avoiding amputation.

JAFFE et al. in 1940⁽¹⁶⁾ established GCT as a clinical and pathological entity, differentiating it from the lesions considered as variants so far: non-osteogenic fibroma, epiphysial condroblastoma and osteoblastoma. Its large spectrum of clinical behavior is based on the degree of atypia of its stroma cells: Grade I – without cellular atypia, Grade II with some degree of atypia and Grade III with much cellular atypia, being considered as frankly malignant.

DAHLIN et al. (1970)⁽⁹⁾ published a classical paper from Mayo Clinic with 60% of local recidivation in patients who underwent curettage and grafting, so recommending a more aggressive resection for local control with an arthrodesis as ''Putti-Juvara'' in cases of tumors around the knee.

GOLDENBERG in 1970⁽¹⁴⁾, reports 55% of local recidivation in 218 cases of GCT and McCARTHY in 1980⁽²⁴⁾, describes in 52 patients 45% while HUTTER et al. in 1940⁽¹⁵⁾ reports 66% among 72 cases. All these works indicate for GCT segmental resection followed by arthrodesis.

Analyzing GCT cases treated at IOT from 1950 to 1972 it is observed that treatment performed followed the trends of the largest oncologic centers of the time, being at the beginning amputated or even underwent radiotherapy. Later on, in 1960, patients underwent curettage with bone grafting, also with a high degree of local recidivation (48%). Starting from 1964 it was started a more aggressive indication, with segmental resection and ''Putti-Juvara'' arthrodesis for knee tumors and acrylic endoprosthesis for cases of proximal femur and humerus.

In 1972, Professor FLÁVIO PIRES DE CAMARGO, based on personal experience of WILTSE et al. (1957)⁽³⁷⁾ is the pioneer in using mety-metacrilate along with cavity cauterization as local adjuvants of GCT getting 9% of recidivation in his first cases, so preserving joint movement. This work was published with 135 cases in 1987⁽³⁾ as Professor OLAVO PIRES DE CAMARGO Free-Teaching Thesis. In addition to methylmethacrylate used a polyethylene module based on the radiography of the lesion. In 1984 PERSSON et al. in Sweden present the same experience with 12% total recidivation, also with a minimal follow-up of two years⁽²⁹⁾. Other authors followed among them WILLERT in 1987⁽³⁶⁾ equally well succeeded.

PERSSON was the first to publish in Clinical Orthopedics in 1976 his initial results, also inciting Professor Flávio to publish his reports in the same issue, but he preferred to wait for a longer follow-up before doing it. All merits went this way to PERSSON as the creator of the method. WILLERT (1987)⁽³⁶⁾ recommended the removal of the cement two years after the surgery, for understanding that it could cause future problems to the joint.

In 1973, in New York Memorial, MARCOVE et al.⁽²³⁾ used liquid nitrogenium as an adjuvant for local controlling of GCT, getting only 5% of local recidivation, however with a high incidence of pathological fracture (25%) as a complication of this method.

At Mayo Clinic in Rochester, ROCK in 1980⁽³²⁾ used phenol in association to cement as adjuvant, getting similar results in regard to recidivation of the tumor, with few complications.

Disregarding these good results, some oncological centers still were not confident on a more conservative treatment of GCT, mainly in USA where wide resection and arthrodesis was prevalent, mostly by ENNEKING (1983) who was by that time the most important authority in orthopedic oncology.

There was still fear of malignant transformation of the GCT based on HUTTER et al. (1940)⁽¹⁵⁾ and ELLIS (1949)⁽¹¹⁾ papers. However, it is today known that or a GCT is primarily malignant, what is rare (4%), or is transformed due to radiotherapy (COMPERE – 1953)⁽⁶⁾.

Some experimental works as that performed by LINDER (1977)⁽²⁰⁾ prove the local effect of methylmethacrylate that reaches 72º C during its polymerization phase, what is enough to destroy the neoplasic cells around inner wall of the cavity, since protein denaturation takes place at 42º C. MALLAWER et al. in 1987⁽²⁰⁾ performed an experimental work in rabbits, using liquid nitrogenium and methylmethacrylate showing nitrogenium necrosis to be superior. In 1999 we performed a similar work, comparing acrylic cement, liquid nitrogenium, phenol and electron-cauterization in rabbits, getting similar degree of necrosis with all these adjuvants.

At ENNEKING's visit to Brazil in 1984, we had the opportunity to show the pioneer work of Professor Flávio, being so invited to take part in the MSTS (Musculoskeletal Tumor Society) meeting, in Orlando (1987), where we presented the results of 12 years follow-up together with PERSSON, WILLERT and CONRAD. At this round table this procedure starts to be a consensus in American, European and Asian Centers.

At Rizzoli Institute in Bologna, in 1990 776 operated GCT cases were analyzed, comparing the use of adjuvant to the single curettage and grafting. We participate with 56 cases as the only representatives from Latin America. This multicenter study made even clearer the use of two or more local adjuvants for controlling GCT, since a difference of 45% of recidivation in non-adjuvant group to 17% in the adjuvant group was observed⁽⁵⁾

In an experimental work (1986) performed at our Biomechanics Laboratory, it was compared the use of polyethylene and cement in relation to material resistance being found the isolated cement to be more resistant. We so started from this date to use only methylmethacrylate for filling the cavity, and this made the method more simple and feasible in many other centers, without the need of preparing custom-made polyethylene molds for each case.

From our experience we think that it is fundamental to get good results, whatever is re used adjuvant, a wide opening of the cavity, allowing a very careful curettage, including with electric drill, followed by an exhaustive local review. Methylmethacrylate, besides acting as an adjuvant, fills completely the tumoral cavity leaving no dead space, what is certainly one more factor contributing to avoid recidivation. Its mechanical stability, as demonstrated by few cases of pathologic fracture and absence of complications in more than 25 years of follow-up, allows a fearless use of it. When GCT reaches meta-diaphyseal region, we use a ''Ender'' kind intramedullary rod along with cement or even AO type plates, fixed over the cement (it is possible to perforate and place screws in the cement) allowing a higher mechanical resistance at this transition place, avoiding a pathological fracture.

A reevaluation of GCT cases operated with resection, cauterization plus methylmethacrylate was performed in 1999, aiming check the persistence of the good functional results observed in the first 15 years (1972 to 1985) now with 25 years follow-up. Also incidence of osteoarthrosis was evaluated in this review. It was demonstrated that knee osteoarthrosis incidence was low (12%) and the patients were oligo-symptomatic, maintaining joint range of movement, being the diagnosis rather radiological than clinical.

Even though these good results in treatment of GCT, its treatment is still far form the ideal. Not all cases are eligible for resection plus curettage and cement. According to radiographic staging as proposed by ENNEKING and CAMPANACCI in 1987 cases are divided in three degrees (Grade I – Well limited boundaries tumor, and integral cortical, Grade II – Expanded cortical with well limited borders and Grade III – Non limited borders, with soft tissue invasion). Some few cases rated as Grade II could still undergo this method. Our experience demonstrates that exactly these cases are those who have the worst functional results, because lack bone support and commitment of subcondral bone.

So, in Grade III GCT, with eccentric destruction of tumor walls, with articular cartilage commitment, we choose to perform a wide resection of the lesion (distal femur, proximal tibia, proximal humerus, proximal femur) and with endoprosthesis replacement, which keeps articular movement, even being young individuals with a benign tumor. We disagree of arthrodesis indication in these cases, even knowing they are candidates to revision of the prosthesis in 10 to 15 years. In cases of distal radius, we perform a wide resection and replacement by a free fibula, in most of the cases without arthrodesis of radio-carpal joint as a first option.

Current challenge of GCT is in dorsal spine and sacrum locations, where the use of local adjuvant is very seldom possible. We have the opportunity to follow-up these patients together with our colleagues from Spine Group form IOT, and surgical options are restricted. Radiotherapy is always a risk because besides being of doubtful result in GCT, since it is a benign tumor with few cellular atypias, literature shows that exactly these cases were those with sarcomatous degeneration observed in the past (HUTTER et al⁽¹⁵⁾. e ELLIS⁽¹¹⁾).

In sacral GCT the problems remains, even though in our experience we used also curettage plus cementation without cauterization with good results using an anterior or posterior approach with a wide exposure of the cavity and direct view of sacral plexus which is preserved. We prefer this treatment to sacrectomy that, when bilateral at S2 level or more proximal, will worsen very much life quality of these patients due to sphincter incontinency and perineal anesthesia.

In regard of surgical treatment, state of the art in GCT treatment had not large changes in the last two years except for new less morbidity local adjuvants such as H₂0₂.

In other oncology areas, works like those of RADIG et al⁽³⁰⁾. and DE SOUZA et al⁽¹⁰⁾. emphasize the study of genes related to cellular cycle regulation, the so called onco-genes. Among them the most studied are P53, c-myc and mdm2, in addition to the protein Ki67. So, genetic stability, much studied in gastrointestinal neoplasias, is now being studied in GCT through the evaluation of the micro-satellites as in SCHEINER et al⁽³³⁾ work. Cytogenetic studies performed by BRIDGE et al⁽²⁾. show GCT characteristic chromosomal changes, especially those related to telomeric regions. However, due to the small number of studied cases there is no consensus regarding its relation to prognosis.

Histo and cytomorphometric techniques (ploidia evaluation and cell quantification in cellular cycle) are much used in prognosis evaluation of GCT with conflicting results in several papers (FORNASIER et al⁽¹³⁾. e MURATA et al⁽²⁶⁾.). Another very much studied subject in this field is the role of the metalloproteases (MMP2 e MMP9) in the capacity and degree of invasion by the tumors, with some papers relating them to aggressivity and local recidivation (RAO et al⁽³¹⁾. e SCHOEDEL et al⁽³⁴⁾.). Modulating interleukins are also being studied.

A new study technique is the tumoral angiogenesis capacity. KABAN⁽¹⁷⁾ reports a case, showing good evolution of a GCT with anti-angiogenesis therapy with interferon alfa-2, stimulating the studies quantifying blood vessels as well as presence of specific receptors.

For the above exposed, giant cells tumor is an exciting subject for its challenges regarding diagnosis, that should be early, for its surgical treatment, that should be very well planned and custom-made and for the uncertainty of the local prognosis of this neoplasia. Certainly cyto-genetic studies will open new ways, making in a near future GCT more previsible in terms of biological behavior. So, some less near future perspectives of gene therapy will lead all current surgical techniques and tactics to be only history of medicine.

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Trabalho recebido em 04/01/2000. Aprovado em 12/06/2001

*

This work was performed at the Orthopedic Oncology Group from Instituto de Ortopedia e Traumatologia of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo.

Publication Dates

• Publication in this collection
  13 Oct 2005
• Date of issue
  Dec 2001