1. Uniformity of classification principles
The major difference between the third edition of WHO tumor classification and the first two editions is that all tumors are considered as independent diseases, not just morphologically described histological subtypes. As with other fascicles, all bone tumors and their variants are described strictly by disease in terms of diagnostic criteria, pathological features and associated genetic alterations, including new ICO-10 codes, incidence, age, sex distribution, lesion location, clinical symptoms and signs, pathology, genetics, and prognostic factors.
In the second edition, bone marrow tumors (round cell tumors) are divided into four categories: Ewing sarcoma, primitive neuroectodermal tumor of bone (ES/PNET), malignant lymphoma of bone, and myeloma. The histogenesis of Ewing sarcoma has been controversial, and PENT was previously considered to be a small cell malignancy similar in some respects to, but distinct from, Ewing sarcoma. malignant tumors. Recent immunohistochemical studies have shown that both express CD99 and NSE, and cytogenetic studies have confirmed the presence of frequent, nonrandom chromosomal translocations t(11;12) in both (q24; q12). Therefore, the new classification treats Ewing sarcoma/primitive neuroectodermal tumor as the same tumor showing different degrees of neuroectodermal differentiation. The term Ewing sarcoma is used for tumors lacking evidence of neuroectodermal differentiation by light microscopy, immunohistochemistry, and electron microscopy, whereas PENT can be characterized by neuroectodermal differentiation confirmed by one or more of these methods.
2. Slight addition and deletion of tumor types
Compared with the second edition, the categories of tumors have been slightly changed, and the types of tumors have been slightly added and deleted. The tumor categories are divided into ES/PENT and hematopoietic tumors, except for “bone marrow tumors” which are divided into ES/PENT and hematopoietic tumors, and “other connective tissue tumors” which are divided into various categories according to fibrous origin, fibrous histiocytic, smooth muscle, adipose origin and neurological tumors. There were no changes in the other tumor categories. Although there are not many additions and deletions of tumor categories, we should understand the reasons for them, which are introduced below.
(1) Cartilaginous tumors
Multiple osteochondromas and chondromatosis can occur on the basis of genetic diseases and have special clinicopathological and genetic characteristics. The existence of true “malignant” chondroblastoma is still controversial, and most scholars believe that this tumor is actually a post-irradiation sarcoma or a pure misdiagnosis, so it has been removed from the new classification. Although synovial chondromatosis does not originate from bone, it is a primary lesion with cartilaginous nature and local destructive behavior of tumor, so it is included in the classification.
(2) Osteogenic tumor
Osteoma is now considered not to be a tumor and is deleted. Aggressive (malignant) osteoblastoma has a local invasive behavior clinically, but the morphology and genetics are not fundamentally different from typical osteoblastoma, so it is described under osteoblastoma. Secondary osteosarcomas are often secondary to Paget’s disease, post-irradiation and other pre-existing abnormalities. Patients are older and about 1/3 of cases are located in flat bones. Comparative genomic hybridization (CGH) studies show that DNA copy number loss is higher in irradiated osteosarcoma
The former often shows 3p loss. In addition, the rate of TP53 mutation in irradiated osteosarcoma was significantly higher than that in sporadic osteosarcoma, and therefore secondary osteosarcoma is listed separately.
(3) Giant cell tumor
Almost all bone lesions can contain giant cells, sometimes in large numbers. The importance of clinical and pathological features in the diagnosis of giant cell tumors is particularly emphasized in the classification. Microscopically, the tumor must have a combination of round or ovoid mononuclear mesenchymal cells and more or less uniformly distributed giant cells, with the giant cell nuclei closely resembling those of mononuclear mesenchymal cells. Occasionally, giant cell tumors can become malignant, and the new classification, named malignancy in giant cell tumour, is listed separately as a highly malignant sarcoma arising from a giant cell tumor (primary) or from a site previously diagnosed as a giant cell tumor (secondary).
(4) Vascular tumors
Intermediate vascular tumors have been removed from the new classification, in which hemangioendothelioma is included in hemangiosarcoma, which is considered a low-grade malignant hemangiosarcoma. Angioepithelioma and malignant angioepithelioma known not to be tumors of true perivascular cell origin have been removed.
(5) Others
Smooth muscle tumors and lipomas of bone were added to the new classification, and neurofibromas of bone were deleted. Among other lesions, proximal articular bone cysts, fibrous defects of the epiphysis (non-ossifying fibromas), ossifying myositis, hyperparathyroid brown tumors, intraosseous epidermoid cysts, and giant cell (reparative) sarcoidosis were deleted. The deletion of fibrous defects of the epiphysis, a common lesion occurring in the long bone epiphysis of children, does not seem reasonable. Two lesions have been added to the new classification.
Erdheim-Dhester disease, a rare histiocytic proliferative disease in which lipid-laden histiocytes infiltrate the bones and viscera, leading to fibrosis and osteosclerosis, and chest wall malformation tumor. Chest
wall hamartoma is a non-neoplastic proliferation of mesenchymal tissue consisting mainly of cartilage mixed with aneurysmal bone cysts that occurs in the ribs of infants and children.
3. Prominent genetic typing
The most significant feature of the new classification is that the histological typing and genetic typing of tumors are equally important. Some disease types (types) of bone tumors have frequent and non-random genetic alterations, and these characteristic genetic alterations are of great importance for the occurrence, diagnosis and classification of tumors as well as prognosis. However, the genetic alterations of some other bone tumors are not well understood and need to be further investigated. Examples are given below.
(1) Osteochondroma and secondary chondrosarcoma
Whether osteochondroma is a developmental abnormality or a true tumor has been controversial. Cytogenetic studies confirmed the presence of abnormalities involving 8q22-24.1, the EXT1 locus, in this tumor, and almost all of the LDH detected by microsatellite analysis of DNA isolated from the cartilage cap was at the EXT1 locus; loss of the 8q24.1 locus was also detected by FISH; DNA flow cytometry analysis confirmed the presence of heteroploidy in the cartilage cap (DNA index 0.88-1.17). The above findings suggest that either sporadic or hereditary osteochondroma is a true tumor.
Inactivation of the EXT1 gene in growth plate chondrocytes resulted in downregulation of IHh/PTHrP and FGF/FGFR signaling, contributing to osteochondroma formation. Involvement of Rb,TP53, and EXT(L) genes leads to genetic instability, manifested by a high incidence of LDH, heteroploidy and nonspecific chromosomal abnormalities, and upregulation of PTHrP and bcl-2 expression at the protein level, contributing to the transformation of osteochondroma into a secondary low-grade malignant peripheral chondrosarcoma. The combination of chromosomal polyploidization and TP53 overexpression eventually progresses to highly malignant chondrosarcoma.
(2) Osteosarcoma
Most osteosarcomas have complex clonal chromosome number and structural abnormalities, DNA copy number acquisition, high incidence of LDH, molecular genetic alterations, and gene product overexpression. Although these genetic abnormalities are nonspecific, they most often involve 1p21-23, 3q26, 8121-23, 12q13-15, and 17p11-12, and involve genes such as MYC, MDM2, and CDK4, as well as overexpression of MET, FOS, and MYC. increased MYC copy number, CDK4, and MDM2 amplification suggest a poor prognosis for bone tumors.
(3) Giant cell tumor
The most common chromosomal abnormality is related to telomeres, with telomeres at 11p, 13p, 14p, 15p, 19q, 20q and 21q being most frequently involved. Giant cell tumors with fibrous histiocytic reactions are not karyotypically distinct from typical giant cell tumors, suggesting that these lesions are true giant cell tumors rather than fibrous yellow tumors.
(4) Ewing sarcoma/primitive neuroectodermal tumor (ES/PENT)
About 85% of ES/PENT have frequent sex chromosome t(11;22)(q24;q12) translocations involving EWS/FLI1 gene fusion; about 10%-15% of cases have t(21;22)(q22;q12) involving EWS/ERG gene fusion; in addition, there are t(7;22), t(17;22) and t(2;22) translocations, and inv(22) and other abnormalities. These frequent, non-random chromosomal translocations not only confirm that ES and PENT are the same tumor, but also allow the diagnosis of ES/PENT by detecting the presence of t(11;22) and differentiating it from other small round cell malignancies.
(5) Others
Fibrous tissue proliferative fibroma of bone has non-random chromosomal abnormalities +8 and +12, similar to ligament-like tumors in soft tissue. Enameloblastoma of long bone shows non-random chromosome number abnormalities, mainly the acquisition of chromosomes 7, 8, 12 and 19, and these alterations are also present in fibrous dyskeratosis-like enameloblastoma of bone. The chromosome number abnormalities in dyskeratosis often involve +7 and +8, suggesting that the lesion is associated with enameloblastoma. An “atypical” or “Ewing-like” enameloblastoma has been reported in the literature, and the combination of cytogenetic, FISH and RT-PCR assays confirmed the presence of this tumor t (11; 22), so it should be referred to as “Ewing sarcoma with enamel cell tumor”. Genetic studies in Langerhans histiocytic hyperplasia (LCH) confirmed the presence of X chromosome inactivation, suggesting that LCH is a clonal proliferative neoplastic lesion.
4. New congenital and hereditary syndromes associated with bone and soft tissue tumors
In recent years, there has been rapid progress in understanding how genetic abnormalities affect tumorigenesis. The following is a brief description of the clinical, histopathological and genetic features of several syndromes associated with bone tumors.
(1) Hereditary multiple osteochondromas (HMOs)
It is an autosomal dominant disorder that occurs in children and adolescents, with a male to female ratio of 1.5:1, and approximately 62% of patients have a positive family history. Clinically, it presents as multiple tipped/untipped masses, mostly located in the long bones of the extremities, especially around the knee joint. Histologically, it is a typical osteochondroma, with approximately 0.5%-3% developing malignant transformation, the majority of malignant transformation being secondary to peripheral chondrosarcoma. Genetically, multiple osteochondromas are heterogeneous and involve mutations in one of the EXT genes. The two most common genes are EXT1 at 8q24 and EXT2 at 11p11-12, with mutation rates of 44%-66% and 27% in the EXT1 and EXT2 genes, respectively, in multiple osteochondroma families. The EXT3 gene at 19q was also identified, as well as novel mutations in EXTL1, EXTL2 and EXTLT3 similar to the above genes.
(2) Endogenous chondromatosis (Ollier’s disease and Maffucci’s syndrome)
Ollier disease is a developmental abnormality characterized by multiple chondroid masses involving bone, especially short and long tubular bones of the extremities. When skin, soft tissue and visceral hemangiomas are also present, it is called Maffucci syndrome. Both lesions have not been shown to have specific genetic or biochemical markers, however, the involvement of multiple members in a family suggests a possible autosomal dominant disorder with reduced ectodominance. ollier’s disease occurs in young children without sex differences and often presents as swelling of the fingers and toes. Endogenous chondrosarcomas are mainly located in the tubular bones of the extremities, but tend to be more prevalent in one limb, sometimes involving the pelvis and ribs, and can become malignant in about 15-30% of patients, the majority being chondrosarcoma. maffucci syndrome occurs in infants and young children, and the bone lesions are indistinguishable from Ollier disease, but the malignancy rate is higher, about 20-30%. In addition, dermal and subcutaneous tissues and viscera are associated with hemangiomas, mostly cavernous and sometimes spindle cell hemangiomas, and the vascular component can malign into angiosarcoma. Molecular genetic analysis has shown that chondrosarcomas arising from Ollier disease have overexpression of LDH and TP53 on chromosomal bands of the RB1 and CDKN2A tumor suppressor genes. Mutations in the PTHR1 gene encoding parathyroid hormone and parathyroid hormone-releasing protein (PTH/PTHrP) have also been recently demonstrated in Ollier’s disease.
(3) McCune-Albringht syndrome (MAS)
MAS is a sporadic disorder characterized by polyostotic fibrous dysplasia, café-au-lait discoloration and hyperfunctional endocrinopathy, caused by mutations in the GNAS1 gene, which is more common in children, slightly more common in women, and often associated with precocious puberty. Mucinous cysts, simple bone cysts and aneurysmal bone cysts. Fibrous dysplasia can malign into osteosarcoma, occasionally chondrosarcoma, fibrosarcoma, and malignant fibrous histiocytoma. Genetically, the mutated GNAS1 gene is located on 20q13. GNAS1 (guanine nucleotide-binding protein, 2-stimulant active polypeptide 1) encodes the G protein 2-stimulant subunit (Gsα). mutations in the GNAS1 gene can lead to disruption of GTP. hydrolysis to GDP and increased cAMP. activity, resulting in a series of pathological changes.
(4) Other retinoblastoma syndrome (retinoblastomasyndrome)
Caused by a germline mutation in the RB1 gene located at 13q14.1. Causes bilateral familial retinoblastoma, often with the development of a second site of primary tumor, including osteosarcoma, fibrosarcoma, chondrosarcoma, Ewing sarcoma, and pineal tumor, etc. Rothmund-Thomson syndrome is caused by a mutation in the RECQL4 gene located at 8q24.3, resulting in various skin abnormalities, bone defects, juvenile cataracts, and premature aging, predisposing to Wemer syndrome is an autosomal recessive disorder caused by mutations in the WRN gene at 8p11-12, which can lead to a variety of neoplastic and non-neoplastic diseases, including osteosarcoma.