Хондросаркома

M. Schwab (ed.), Encyclopedia of Cancer, Springer-Verlag Berlin Heidelberg (2011)

Определение

Хондросаркома кости — злокачественная гиалиновый хрящ-формирующая опухоль (Фиг. 1). Термин «хондросаркома» описывает гетерогенную группу поражений с разнообразными морфологическими чертами и клиническим поведением. Наряду с распространенными центральной и периферической хондросаркомами, составляющей самую большую подгруппу (~85%), она включает редкие подтипы — светлоклеточную (~1%), мезенхимальную (~2%), юкстакортикальную (~2%) и недифференцированную (~10%) хондросаркомы.

Характеристики

Инцидент стандартной хондросаркомы около 1:50,000. Инцидент у мужчин и женщин почти равен, и средний возраст диагноза составляет 30-60 лет. Хондросаркомы развиваются преимущественно в костях, которые удлиняются посредством эндохондрального окостенения, с наиболее распространенными локализациями в порядке убывания – в костях таза, проксимальном отделе бедренной кости, проксимальном отделе плечевой кости, дистальном отделе бедренной кости и в ребрах.

When comparing histologically the different cartilaginous tumors to the growth plate, parallels between normal and neoplastic chondrocyte growth and differentiation become evident. Resting (primitive, mesenchymal stem-cell like) chondrocytes are found in mesenchymal chondrosarcoma, while clear cell chondrosarcoma consists mainly of hypertrophic chondrocytes. Osteochondroma, a benign cartilaginous tumor at the surface of bone, recapitulates all differentiation levels of the growth plate. In contrast, enchondroma, a benign cartilaginous tumor in the medullar cavity of bone, and conventional peripheral and central chondrosarcoma mostly contain proliferating chondrocytes, lying in small lacunae. The more rarely occurring dedifferentiated chondrosarcoma is thought to arise from conventional chondrosarcoma in which tumor cells transdifferentiate toward a more spindle-cell phenotype. In addition, the rare subtype juxtacortical chondrosarcoma is recognized, which also contains proliferating chondrocytes. This specific diagnostic term is used as a result of its typical clinicoradiological presentation and it is in general relatively favorable prognosis as compared to conventional chondrosarcoma.

There is a clinical as well as a morphological spectrum of cartilaginous tumors. Central chondrosarcoma is the most common subtype (>85%) of conventional chondrosarcoma. Malignant transformation of an enchondroma to a central chondrosarcoma is estimated to be <1%. However, since in 40% of central chondrosarcomas remnants of a preexisting enchondroma are found, there is considerable debate whether these tumors are secondary to enchondroma or arise mostly primary. The frequency of malignant transformation is significantly higher (15Ц30%) in patients with multiple enchondromas in the context of the extremely rare nonhereditary disorder Ollier disease. Conventional chondrosarcoma at the surface of bone (secondary peripheral chondrosarcoma) per definition develops within a preexisting osteochondroma. Secondary peripheral chondrosarcomas constitute up to 15% of conventional chondrosarcomas in referral centers. Multiple osteochondromas (MOs), previously known as hereditary multiple exostoses (HMEs), is an autosomal dominant disorder and malignant transformation occurs in 1Ц3% of the cases of MO. In addition, chondrosarcomas may biologically progress: up to 13% of recurrent chondrosarcomas exhibit a higher grade of malignancy than the original neoplasm, with an adverse prognosis.

Диагноз

Benign cartilaginous tumors are asymptomatic, and are often found by incidence at radiology made for other reasons. In contrast, malignant tumors almost always produce symptoms such as local swelling and pain. The distinction between enchondroma or osteochondroma and low-grade conventional chondrosarcoma is difficult, both at the radiological level (in case of central chondrosarcoma) and at the histological level (for both subtypes). Diagnosis should be made in a multidisciplinary setting, based on clinical, radiological, and histological aspects. Dynamic MRI has been proven to be informative in distinguishing benign from malignant cartilaginous tumors. Histologically, the distinction between enchondroma and low-grade conventional central chondrosarcoma is mainly based on growth patterns and cytomorphological features. Encasement (new shells of reactive bone, formed at the periphery of cartilage nodules), is a feature of benign tumors, while entrapment (permeation of tumor around preexisting lamellar bone), points to a faster growing process and thus malignancy.

Histologically, chondrosarcomas are divided in three grades of malignancy based primarily on cellularity, nuclear size and chromasia, mitoses and the composition of the matrix. Grade I tumors are moderately cellular and nuclei are uniformly sized and hyperchromatic. Grade II tumors are more cellular and nuclei are atypically shaped, hyperchromatic, and larger, and mitoses can be found (Fig. 2). At the end of the spectrum, grade III tumors are hypercellular, with nuclear pleomorphism are found, and mitoses can be frequent. In addition, the extracellular matrix of grade III tumors becomes more mucoid/myxoid compared to the abundant chondroid matrix seen in grade I tumors and their vascularity is increased. Differences in 5-year survival and the occurrence of metastases show the clinical importance of histological grading. While grade I and II tumors rarely metastasize (respectively 0% and 10%), grade III tumors do so in 71% of the cases. Five-year survival is lowest in patients with grade III tumors (29%) compared to 64% in grade II tumors and 83% in grade I chondrosarcomas.

Лечение

Корректный диагноз необходим для выбора терапевтического решения. Хирургия — единственная опция для куративного лечения, поскольку хондросаркомы очень устойчивы к стандартной химио- и лучевой терапии. Исследования механизмов, лежащих в основе резистентности, редки. Поэтому развитие таргетированной терапии для хондросаркомы означало бы значительный успех в лечении опухоли. Если для доброкачественных поражений выжидательная политика оправдана, злокачественные опухоли требуют более агрессивного лечения.

Grade I chondrosarcomas are prone to local recurrence but almost never metastasize. Therefore, there is a trend in sarcoma centers to treat them by curettage with margin improvement by phenol or cryosurgery. In contrast, high-grade tumors are usually treated by often mutilating wide en bloc resection or even amputation, since these often metastasize, being lethal in the majority of patients.

Генетика

Although histologically similar, central and peripheral chondrosarcoma have been shown to be genetically, and thereby molecularly, different entities. In Multiple Osteochondromas, germline mutations have been identified in the EXT tumor suppressor genes, located on chromosomes 8q24 (EXT1) and 11p11-12 (EXT2), respectively. These EXT genes encode glycosyltranferases involved in heparan sulfate biosynthesis. In MO germline mutations in EXT1 or EXT2 with loss of the remaining wild-type allele is found. Recently, in solitary osteochondromas somatic homozygous deletions of EXT1 have been demonstrated. In both hereditary and solitary osteochondromas, mRNA expression of EXT1 or EXT2 is decreased. This probably results in intracellular accumulation of heparan sulfate proteoglycans (HSPGs), since the Syndecan2 and the CD44v3 core proteins were shown to aberrantly localize in the Golgi apparatus in solitary and hereditary osteochondroma and peripheral chondrosarcoma. The EXT1 homologue in Drosophila (tout velu, ttv) is required for IHH diffusion to its receptor that signals to PTHLH and thereby controls chondrocyte proliferation. In contrast to the growth plate, in osteochondroma IHH signaling has become cell autonomous, probably overcoming the diffusion problems caused by defective HSPGs due to EXT inactivation. Additional genetic alterations are thought to be required for malignant transformation of osteochondroma toward low-grade secondary peripheral chondrosarcoma. These additional alterations presumably cause chromosomal instability, since peripheral chondrosarcomas are shown to be aneuploid with DNA indices ranging from 0.56 to 2.01. At the protein level, progression from osteochondroma toward low-grade peripheral chondrosarcoma is characterized by a reactivation of PTHLH signaling. Its downstream target, BCL-2, can be used as a diagnostic marker in those cases in which it is hard to distinguish between benign and malignant cases, with osteochondromas being negative in 95% (specificity) and chondrosarcomas scoring positive in 57% (sensitivity). This reactivation of PTHLH is hypothesized to be caused by increased TGF-beta signaling, since IHH signaling is downregulated in peripheral chondrosarcoma. Despite the increasing number of genetical studies including peripheral and central chondrosarcomas as separate subgroups, no specific genetic aberrations for the more common central chondrosarcoma have been identified as yet. Mutations in EXT1 and EXT2 have not been reported, and reports on IHH signaling on proliferation in central chondrosarcoma are still inconclusive. A positive relation between histological grade and the degree of karyotypic complexity and aneuploidy was found. Near-diploidy and limited loss of heterozygosity are typical of low-grade central chondrosarcomas rather than of peripheral chondrosarcomas pointing to an oncogenic mechanism with few alterations, sufficient for oncogenesis. Multiple studies report alterations at chromosomal bands 9p21 and 12q13Ц15. Genetic loss at the 9p21 locus as found by cytogenetics, loss of heterozygosity analysis and comparative genomic hybridization suggest an important role for the CDKN2A/INK4a locus. Loss of protein expression of the tumor suppressor gene p16, encoded by this locus, was found to be associated with increased histological grade in central chondrosarcoma, and thereby to be important for tumor progression. Rearrangements in the 12q13Ц14 region have been frequently reported in sarcomas. Several genes in this region have been indicated to be of importance for tumorigenesis, such as SAS (sarcoma amplified sequence), CDK4 (cyclin-dependent kinase 4), and GLI (glioma-associated oncogene homologue). Also two other often implicated genes in sarcomas, HMGA2 (high mobility group AT-hook 2) and MDM2, are located just outside the 12q13-14 region. Moreover, the progression from low-grade to high-grade central chondrosarcoma is characterized by P53 alterations. Despite the large number of studies involving central chondrosarcomas, the exact underlying molecular mechanism is still largely unknown.

Хондросаркома 1

Фиг. 1. Макроскопическая фотография грубого образца хондросаркомы дистальной бедренной кости

Хондросаркома 2

Фиг. 2. Гистология хондросаркомы

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