Primary extradural tumors of the spinal column: A comprehensive treatment guide for the spine surgeon based on the 5th Edition of the World Health Organization bone and soft-tissue tumor classification.

BACKGROUND: In 2020, the World Health Organization (WHO) published the 5th version of the soft tissue and bone tumor classification. Based on this novel classification system, we reviewed the current knowledge on all tumor entities with spinal manifestations, their biologic behavior, and most importantly the appropriate treatment options as well as surgical approaches.
METHODS: All tumor entities were extracted from the WHO Soft-Tissue and Bone Tumor Classification (5th Edition). PubMed and Google Scholar were searched for the published cases of spinal tumor manifestations for each entity, and the following characteristics were extracted: Growth pattern, ability to metastasize, peak age, incidence, treatment, type of surgical resection indicated, recurrence rate, risk factors, 5-year survival rate, key molecular or genetic alterations, and possible associated tumor syndromes. Surgical treatment strategies as well as nonsurgical treatment recommendations are presented based on the biologic behavior of each lesion.
RESULTS: Out of 163 primary tumor entities of bone and soft tissue, 92 lesions have been reported along the spinal axis. Of these 92 entities, 54 have the potential to metastasize. The peak age ranges from conatal lesions to 72 years. For each tumor entity, we present recommended surgical treatment strategies based on the ability to locally destruct tissue, to grow, recur after resection, undergo malignant transformation as well as survival rates. In addition, potential systemic treatment recommendations for each tumor entity are outlined.
CONCLUSION: Based on the 5th Edition of the WHO bone and soft tumor classification, we identified 92 out of 163 tumor entities, which potentially can have spinal manifestations. Exact preoperative tissue diagnosis and interdisciplinary case discussions are crucial. Surgical resection is indicated in a significant subset of patients and has to be tailored to the specific biologic behavior of the targeted tumor entity based on the considerations outlined in detail in this article. Copyright:

INTRODUCTION

The core principles guiding surgical treatment for primary bone and soft-tissue tumors have been introduced by Enneking et al. more than 40 years ago and comprise three different types of surgical tumor resection: Intralesional, marginal en bloc, and wide en bloc resection.[1] It has been suggested that tumor location (intracompartmental versus extracompartmental) and histologic grade should be used to determine the mode of resection. Since the introduction of Enneking's system additional research regarding primary bone and soft-tissue tumors, new nonsurgical treatment modalities such as stereotactic radiosurgery or targeted molecular therapies and novel radiographic techniques together have significantly improved demarcating tumor extent and curbing tumor invasion.

This article is based on the 5th Edition of the World Health Organization (WHO) tumor classification of bone and soft-tissue tumors, published in 2020. We compiled the most recent knowledge of all tumor entities, which have been described to occur along the spinal axis and surrounding soft tissues.[2] This comprehensive overview summarizes clinical knowledge as well as imaging findings of all primary, extradural spinal tumors described in the literature.

We describe our treatment algorithms, which is individualized for each tumor entity and loosely based on Enneking's classification system, and modified by contemporary imaging protocols.

METHODS

The 5th Edition of the WHO soft tissue and bone tumors classification, published in 2020 was reviewed and individual tumor entities extracted into a spreadsheet. Medical databases (PubMed and Google Scholar) were searched for publications reporting occurrences of each entity listed in the WHO classification along the spinal axis (spinal bones or paraspinal soft tissues). If an entity has been reported to occur along the spinal axis, a case report with exemplary imaging findings was obtained. For each tumor entity, the following data were extracted from the WHO classification or other key references: Relevant differential diagnoses, growth pattern (infiltrative/destructive), potential for malignant transformation, potential to metastasize, peak age, incidence, recommended type of surgical resection (A, B, C), recurrence rate, treatment, risk factors, 5-year overall survival rate, key molecular or genetic alterations, and possible associated tumor syndromes. All primary bone and soft tissue tumor entities listed in the 5th Edition of the WHO tumor classification were listed in a spreadsheet and a note was made on entities reported to occur along the spinal axis. In a second spreadsheet, exemplary imaging findings of each entity have been listed or say: “Exemplary imaging findings of each entity are listed in a second spreadsheet.” Moreover, finally, in a third spreadsheet, the above-mentioned key characteristics for each entity have been listed.

RESULTS

A comprehensive list of all primary bone and soft-tissue tumors, as listed in the most recent WHO classification is given in Appendix 1 and comprises a total of 163 entities. Of note, the following tumors can arise in either bone or soft tissue: Hemangioma, epitheloid hemangioma, epitheloid hemangioendothelioma, angiosarcoma, desomplastic fibroma, fibrosarcoma, chondroma, and osteosarcoma.

Tumor entities are classified by the cell of tumor origin [Appendix 1]. For soft-tissue neoplasms, the following cells of origin are as follows: Adipocytic, fibroblastic and myofibroblastic, fibrohistiocytic, vascular, pericytic (perivascular), smooth muscle, skeletal muscle, gastrointestinal stromal, chondro-osseous, and peripheral nerve sheath. Two further categories exist for all soft-tissue tumors that do not fall into the above mentioned: Tumors of uncertain differentiation and undifferentiated small round cell sarcomas. In the case of bone tumors, the following subclassification based on the cell population of origin exists: Chondrogenic, osteogenic, fibrogenic, vascular, osteoclastic giant cell-rich, or notochordal. Two further subcategories are listed in the WHO classification: Other mesenchymal bone tumors and hematopoietic neoplasms of the bone.

The results of our literature search are outlined in Appendixes 2 and 3 and show that 92 out of 163 entities were reported to occur either in spinal bones or paraspinal soft tissue. We categorized 92 entities with imaging [Appendix 2] and clinical/molecular findings [Appendix 3], as well as recommended surgical and nonsurgical treatment options.

Appendix 3 shows a comprehensive characterization of each tumor by: Growth pattern (infiltrative/locally destructive or not), ability to metastasize, ability to undergo malignant transformation, mean age at diagnosis, incidence, suggested mode of resection (intralesional resection A, marginal en bloc resection B, wide, or compartmental en bloc excision C), recurrence rate, treatment strategy, tumor risk factors, 5-year overall survival (OS) rate, genetic/molecular tumor characteristics, possible associated tumor syndromes, and corresponding cross -sectional imaging findings are presented in Appendix 2.

As shown in Appendix 3, the incidence rates for primary extradural spinal bone or soft-tissue tumors range from 2% (hemangioma) to a low of only two published cases for spinal nodular fasciitis. The survival rates of malignant lesions range from 94% for 5 year OS for ossifying fibromyxoid tumor to 7% for dedifferentiated osteosarcoma. A total of 54 entities are capable of forming metastases, 1 additional entity can form so called benign pulmonary metastases (chondroblastoma). The peak age ranges from conatal lesions (lymphangioma) to 72 years (pleomorphic rhabdomyosarcoma).

DISCUSSION

The most recent edition of the WHO classification of bone and soft-tissue tumors lists a total of 163 tumor entities, out of which 92 have been previously reported in the literature to potentially occur in the spine. Surgical resection is the integral part of treatment for most of these lesions and follows the overriding principles outlined by Enneking et al. in 1980,[1] as shown in Figure 1. Type B and C resections are more complex than type A resections with higher rates of complications; however, type B/C resections are associated with superior oncologic outcome as compared to type A resections for malignant lesions.[3] It must be noted that given to the unique anatomy of the spine, when compared to long bones, in many cases, a type B resection might be indicated. While type B resections may not be technically feasible, spine surgeons may opt for type C resections with a wider excision. Figure 2 provides an overview of important growth characteristics of malignant bone and soft-tissue tumors. As indicated, the growth pattern of sarcomas is infiltrative. Even with a rim of reactive tissue, the pseudocapsule may act only as a weak barrier to prevent tumor spread. While the pseudocapsule has been shown to restrict tumor permeation after radio- or chemotherapy it is not a true barrier for tumor spread.[4] Cortical bone as well as major fascial planes, such as pleura or peritoneum are considered bone fide barriers. It is known from radiologic studies that infiltrating tumor nests, known as skip lesions, outside the primary tumor can be depicted on magnetic resonance imaging (MRI) in up to 16.5% of patients.[5] As shown in Figure 2, once the cortical bone of the vertebra is breached, the tumor cells can freely spread until they reach the next level of solid barrier [routes A-D in Figure 2]. As has been shown in previous correlating studies between preoperative imaging and intraoperative histologic analysis, the mean discrepancy between tumor margin on preoperative MRI and intraoperative histology for osteosarcomas is 5 mm.[67] Since short-tau inversion recovery and postcontrast T1 imaging overestimates the tumor extend by 1.68 cm, tumor outline is best depicted on noncontrast-enhanced T1 images.[8] Therefore, in our own experience if a malignant tumor is confined to one compartment, we perform either a type B resection with a margin of 5 mm on top of the tumor outline in the preoperative noncontrast T1 images, or we perform a type C resection, which will remove the whole tumor bearing compartment. If a malignant tumor extends into more than one compartment (e.g., cortical bone erosion in the case of vertebral osteosarcomas), we prefect to discuss either neo-adjuvant treatment to “downsize” the tumor (the more compartments the tumor extends into, the less likely a true wide en bloc resection can be achieved) or surgery to encompass an en bloc resection of the primary tumor bearing compartment plus the extension into a neighboring compartment with a safety margin of at least 5 mm.

Figure 1

Overview of the three different surgical types of resection in the treatment of spinal tumors

Figure 2

Illustration of potential routes of and barriers to spread of spinal sarcomas. Lesions, detached from the primary tumor are termed skip lesions. Barriers to skip lesions are: (A) Cortical bone, (B) pleura in cases when the lateral vertebral cortex has been breached, (C) muscle fascia in case of posterior cortical tumor breach, (D) dura in case of cortical breach of the spinal canal

How to incorporate these principles into surgical practice depends on the index level. In the case of C1 and C2, oncologic resections type B and C in most cases require a transmandibular approach [Figure 3]. When compared to the rest of the cervical spine negative margins are less likely to be obtained due to the anatomical complexity of the region.[9] For the rest of the mobile spine the WBB system has been proposed to choose the appropriate approach or combination of approach to perform a type B or C resection [Figure 4].[10] The choice of approach for oncologic resections of the sacrum is mainly determined by the anatomic level of the lesion as well as the presence of visceral tumor infiltration. Figure 5 outlines our institutional algorithm to such lesions. Only lesions located below the inferior margin of the sacroiliac joint (SIJ) without visceral invasion are resected using a posterior-only approach. All other lesions are resected using an anterior/posterior approach. Reconstruction of the pelvic ring is necessary if more than 50% of the SIJs are resected. In instances where the tumor extends by more than 3 cm beyond the SIJ, we consider them as primarily inoperable (due to the large tumor volume and complexity of reconstruction).

Figure 3

Oncologic resection (type B and C) of primary tumors of C1 and C2 are carried out in most cases utilizing a transmandibular approach

Figure 4

Choice of approach for oncologic tumor resections of the subaxial spine (excluding sacrum), based on the Weinstein-Boriani-Biagini system. The vertebra is divided in 12 zones and based on the tumor location either an anterior approach (purple), posterior approach (green) are chosen. For each scenario the osteotomy sites are indicated and in cases necessitating combined approach the suggested order is indicated (I, II)

Figure 5

Sacral resections can be performed in a posterior only approach (green) or combined anterior/posterior approach (purple and green). It is our practice to liberally perform anterior approaches to separate the tumor from the visceral structures, to ligate the bilateral internal iliac arteries, to harvest abdominal wall flaps for reconstruction

Reconstruction of large resection cavities in many cases requires the involvement of plastic surgery and is beyond the scope of this article.

En bloc resections are technically demanding and have been shown to have higher complication rates when compared to type A resections, particularly when more than 1 level is being resected (Spiessberger A, PubMed ID pending), even though lesion etiology seems to have less impact on complication rates.

Given the profile of potential complications in the case of type B and C resections, rigorous preoperative planning is of paramount importance. Neurologic deficits are particularly devastating to patients and should be avoided at all costs. Other than direct mechanical injury, ischemic spinal cord injury has been reported to occur on rare occasions.[1112] Even though spinal cord blood supply is highly collateralized, postoperative infarcts can be a complication due to segmental vessel ligation.[1113] Spinal cord blood supply is established through the anterior spinal artery, a branching vessel of the vertebral arteries, as well as from as posterior spinal arteries through branching vessels of either vertebral or posterior inferior cerebellar arteries. Collateral flow is provided through variable radiculomedullary vessels, typically 2-3 cervical (bilaterally equal), 2-3 thoracic (left more than right), and 0-1 lumbar (left more than right).[12] Three major radiculomedullary vessels are described: The artery of cervical enlargement (usually a branching vessel from the ascending cervical artery at C6), the artery “von Haller” (usually the T5 segmental vessel) as well as the artery of Adamkiewicz (usually the T10 segmental vessel).[14] Watershed areas, susceptible to ischemic infarction in cases of hypotension or hypoxia have been suggested in the mid thoracic spine as well as the posterior aspect of the conus medullaris.[15] Type B and C resections require segmental artery ligation; however, recent studies have suggested that up to three adjacent segmental vessel can be sacrificed safely.[1617] We believe, that caution should be taken when ligating one of the three major radiculomedullary vessels, as described above. Preoperative high-resolution CT angiography can help localize the level of these three vessels. Intraoperative temporary nerve root/segmental vessel clamping with cautious observation of motor evoked potential/somatosensory evoked potential is important as well. In addition, intraoperative and postoperative hypotension should be avoided at all costs when a major radiculomedullary vessel has been sacrificed. It is also worth noting that the choice of vasopressor might make a difference as well. Animal studies comparing norepinephrine and phenylephrine in their properties to increase spinal cord perfusion in the setting of hypotension have shown, that norephinephrine provides better restoration of blood flow and oxygenation.[18] One should also recognize that radiculomedullary vessel ligation may not only render the patient more susceptible to ischemic cord injury, but also surgical trauma to segmental vessels or vertebral arteries can lead to embolic cord infarcts caused by vessel dissections.[19] In the case of cervical type B and C resections, preoperative endovascular sacrifice of one vertebral artery in case high degree tumor encasement (>180°) can be safely performed following careful study of a CT angiogram of both cervical vessels and posterior circulation. Side dominance, potential stenoses, size or absence of the posterior communicating arteries (in the case of fetal posterior cerebral artery variants) must be determined. Moreover, temporary endovascular balloon occlusion can be considered to determine the safety of vessel occlusion.

CONCLUSION

Based on the 5th Edition of the WHO bone and soft tumor classification, we identified 92 out of 163 tumor entities, which potentially can have spinal manifestations. Exact preoperative tissue diagnosis and interdisciplinary case discussions are crucial. Surgical planning has to be tailored to the specific biologic behavior of the targeted tumor entity based on the considerations outlined in detail in this article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Soft tissue tumours

Adipocytic tumours

Angiolipoma

Atypical lipomatous tumour/well-differentiated liposarcoma

Atypical spindle cell/pleomorphic lipomatous tumour

Chondroid lipoma

Hibernoma

Lipoblastoma and lipoblastomatosis

Lipoma

Lipomatosis

Lipomatosis of nerve

Liposarcoma, dedifferentiated

Liposarcoma, myxoid

Liposarcoma, myxoid pleomorphic

Liposarcoma, pleomorphic

Myolipoma of soft tissue

Spindle cell lipoma and pleomorphic lipoma

Fibroblastic and myofibroblastic tumours

Acral fibromyxoma

Angiofibroma of soft tissue

Angiomyofibroblastoma

Calcifying aponeurotic fibroma

Cellular angiofibroma

Dermatofibrosarcoma protuberans

Desmoid fibromatosis

Desmoplastic fibroblastoma

Elastofibroma

EWSR1-SMAD3-positive fibroblastic tumour (emerging)

Fibroma of tendon sheath

Fibromatosis colli

Fibrosarcoma, adult

Fibrosarcoma, infantile

Fibrous hamartoma of infancy

Gardner fibroma

Giant cell fibroblastoma

Inclusion body fibromatosis

Inflammatory myofibroblastic tumour

Ischaemic fasciitis

Juvenile hyaline fibromatosis

Lipofibromatosis

Low-grade fibromyxoid sarcoma

Low-grade myofibroblastic sarcoma

Myofibroblastoma

Myositis ossificans and fibro-osseous pseudotumour of digits

Myxofibrosarcoma

Myxoinflammatory fibroblastic sarcoma

Nodular fasciitis

Nuchal-type fibroma

Palmar fibromatosis and plantar fibromatosis

Proliferative fasciitis and proliferative myositis

Sclerosing epithelioid fibrosarcoma

Solitary fibrous tumour

Superficial CD34-positive fibroblastic tumour

So-called fibrohistiocytic tumours

Deep fibrous histiocytoma

Giant cell tumour of soft tissue

Plexiform fibrohistiocytic tumour

Tenosynovial giant cell tumour

Vascular tumours

Angiosarcoma

Haemangioendothelioma, composite

Haemangioendothelioma, epitheloid

Haemangioendothelioma, pseudomyogenic

Haemangioendothelioma, retiform

Haemangioma

Haemangioma, anastomosing

Haemangioma, epitheloid

Intramuscular angioma

Kaposi sarcoma

Lymphangioma and lymphangiomatosis

Papillary intralymphatic angioendothelioma

Synovial haemangioma

Tufted angioma and kaposiform haemangioendothelioma

Venous haemangioma, venous

Pericytic (perivascular) tumours

Angioleiomyoma

Glomus tumour

Myopericytoma, including myofibroma

Smooth muscle tumours

EBV-associated smooth muscle tumour

Inflammatory leiomyosarcoma

Leiomyoma

Leiomyosarcoma

Skeletal muscle tumours

Ectomesenchymoma

Rhabdomyoma

Rhabdomyosarcoma, alveolar

Rhabdomyosarcoma, embryonal

Rhabdomyosarcoma, pleomorphic

Rhabdomyosarcoma, spindle cell

Gastrointestinal stromal tumour

Gastrointestinal stromal tumour

Chondro-osseous tumours

Soft tissue chondroma

Extraskeletal osteosarcoma

Peripheral nerve sheath tumours

Benign triton tumour/neuromuscular choristoma

Dermal nerve sheath myxoma

Ectopic meningioma and meningothelial hamartoma

Granular cell tumour

Hybrid nerve sheath tumour

Malignant melanotic nerve sheath tumour

Malignant peripheral nerve sheath tumour

Neurofibroma

Perineurioma

Schwannoma

Solitary circumscribed neuroma

Tumours of uncertain differentiation

Alveolar soft part sarcoma

Angiomatoid fibrous histiocytoma

Atypical fibroxanthoma

Clear cell sarcoma of soft tissue

Deep (aggressive) angiomyxoma

Desmoplastic small round cell tumour

Epithelioid sarcoma

Extrarenal rhabdoid tumour

Extraskeletal myxoid chondrosarcoma

Haemosiderotic fibrolipomatous tumour

Intimal sarcoma

Intramuscular myxoma

Juxta-articular myxoma

Myoepithelioma, myoepithelial carcinoma, and mixed tumour

NTRK-rearranged spindle cell neoplasm (emerging)

Ossifying fibromyxoid tumour

PEComa

Phosphaturic mesenchymal tumour

Pleomorphic hyalinizing angiectatic tumour of soft parts

Synovial sarcoma

Undifferentiated sarcoma

Undifferentiated small round cell sarcomas of bone and soft tissue

CIC-rearranged sarcoma

Ewing sarcoma

Round cell sarcoma with EWSR1-non-ETS fusions

Sarcoma with BCOR genetic alterations

Bone tumours

Chondrogenic tumours

Bizarre parosteal osteochondromatous proliferation

Central atypical cartilaginous tumour/chondrosarcoma, Grade 1

Chondroblastoma

Chondromyxoid fibroma

Chondrosarcoma, central Grades 2 and 3

Chondrosarcoma, clear cell

Chondrosarcoma, dedifferentiated

Chondrosarcoma, mesenchymal

Chondrosarcoma, periosteal

Chondrosarcoma, secondary peripheral Grades 2 and 3

Enchondroma

Osteochondroma

Osteochondromyxoma

Periosteal chondroma

Secondary peripheral atypical cartilaginous tumour/chondrosarcoma, Grade 1

Subungual exostosis

Synovial chondromatosis

Osteogenic tumours

Osteoblastoma

Osteoid osteoma

Osteoma

Osteosarcoma

Osteosarcoma, high-grade surface

Osteosarcoma, low-grade central

Osteosarcoma, parosteal

Osteosarcoma, periosteal

Osteosarcoma, secondary

Fibrogenic tumours (see soft tissue tumors)

Vascular tumours of bone (seesoft tissue tumors)

Osteoclastic giant cell-rich tumours

Aneurysmal bone cyst

Giant cell tumour of bone

Nonossifying fibroma

Notochordal tumours

Benign notochordal cell tumour

Conventional chordoma

Dedifferentiated chordoma

Poorly differentiated chordoma

Other mesenchymal tumors of bone (see soft-tissue tumors)

Haematopoietic neoplasms of bone

Erdheim-chester disease

Langerhans cell histiocytosis

Plasmacytoma of bone

Primary non-Hodgkin lymphoma of bone

Rosai-Dorfman disease

EBV - Ebstein Barr virus

Adipocytic Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/local destruction/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Angiolipoma1	-	possible/no/no	2nd-3rd decade	~1% of spinal tumors	A	<5%	resection	-	NA	PRKD2	-
Atypical lipomatous tumour/well-differentiated liposarcoma12	-	yes/yes (2-20%)/no	4th-5th decade	50% of liposarcomas	B	11%	resection; RT or Sx + RT**	-	92%	MDM2 and/or CDK4 amplification	Li Fraumeni
Hibernoma13	atypical lipomas, well-differentiated liposarcoma	no/no/no	38	1% of adipocytic tumors	A	<5%	resection if symptomatic	-	NA	Chromosome 11q13 deletion	MEN 1
Lipoblastoma14	lipoma, hibernoma, liposarcoma	no/no/no	4	?	B	13-46%*	resection	-	NA	PLAG1	-
Lipoma15	liposarcoma	no/no/no	36	14 cases	A	<5%	resection if symptomatic	obesity	NA	HMGA2 protein	PTEN hamartoma tumor syndrome
Lipomatosis16–9	-	no/no/no	68	6% of patients with spinal stenosis)	A	5%*	resection if symptomatic	steroid, alcohol	NA	-	-
Liposarcoma, myxoid110	-	yes/-/yes	childhood, 4th-5th decade	20% of liposarcomas	C	12-25%	resection; RT*, CH*	-	89%	FUS-DDIT3 or rarely EWSR1-DDIT3	-
Liposarcoma, pleomorphic11112	-	Yes/-/yes	7th decade	<5% of liposarcomas	C	45%	resection, CH	-	57%	-	-
Myolipoma1	-	no/no/no	adulthood	?	A		resection if symptomatic	-	NA	HMGA2	-
Spindle cell lipoma1	Liposarcoma	possible/no/no	45-60	?	A	<5%	resection	-	NA	Chromosome 13 and/or 16 deletion	-
Fibroblastic and Myofibroblastic Tumours
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Desmoid-type fibromatosis113	-	yes/no/no	37-39	0.4/100000	B or C**	33%	resection vs close observation; CH alone in FAP associated cases	trauma, pregnancy	52%***	CTNNB1 or APC mutations	FAP
Desmoplastic fibroblastoma1	-	yes/no/no	6th decade	?	A	<5%	resection	-	NA	t (2;11)(q31;q12)	-
Elastofibroma1	-	no/no/no	7th-8th decade	2%	A	<5%	resection if symptomatic	-	NA	gains of 6p25-q25 and Xq12-q22	-
Fibrosarcoma, adult11415	-	yes/yes/yes	50	<1% of STS	C	20%	resection + CH vs neoadjuvant CH + resection*	foreign body, previous irradiation	55%	STRN3-NTRK3 fusion	-
Fibrosarcoma, infantile1	-	yes/no/rarely (8-15%)	1	0.5/100000	B	25%-40%	resection + CH/TG	-	89%	ETV6-NTRK3 fusion	-
Inflammatory myofibroblastic tumor116–18	-	occasionally/no/yes	10	0.04%	B or C	25%-86%****	Resection vs RT, CH/TT*	-	15m*****	ALK	-
Lipofibromatosis119	-	yes/no/no	1	?	B	70%	resection	-	NA	fusions (EGF, HBEGF, TGF-α) to EGFR (HER1) or EGFR	-
Low grade fibromyxoid sarcoma120		yes/no/rarely	41	5% of STS	B or C	64%	Resection + CH*	-	83%	FUS-CREB3L2 or FUS-CREB3L1 gene fusions	-
Low grade myofibroblastic sarcoma1	-	yes/yes/rarely	42	12 cases	C	25%	resection vs RT, CH*	-	83%	-	-
Myofibrosarcoma1	-	yes/yes/yes	66	?	C	40%	resection + RT	-	-65%	gains of chromosome 5p	-
Myositis ossificans121	-	no/no/no/no	young adults	0.4%	A	<5%	resection if symptomatic	-	NA	COL1A1-USP6 fusion	-
Nodular fasciitis122	-	rarely/rarely/rarely	young adults	2 cases	A	<5%	resection	trauma	NA	USP6 rearrangement	-
Primary sclerosing epitheloid fibrosarcoma12324	-	yes/no/yes (85%)	40	89 cases	C	50%	Resection + CH*	-	66%******	EWSR1-CREB3L1 fusion	-
Solitary fibrous tumor12527	-	no/no/yes	55	0.14/100000	B or C	10-30%	resection + CH/TT*	-	49-83%	NAB2-STAT6 rearrangement	-
Fibrohistiocytic Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Deep benign fibrous histiocytoma1	-	no/no/rarely (5%)	37 years	< 1% of fibrohistiocytic tumours	A or B	20%	resection	-	NA	PRKCB or PRKCD rearrangements	-
Smooth Muscle Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
EBV associated smooth muscle tumor128	-	no/no/no	32	11 spinal cases	A	<5%	resection if symptomatic; immunreconstitution	immunodeficiency	-	-	-
Leiomyoma129	-	no/rare/no	37	<10% of leiomyoma	B	<10%	resection if symptomatic	uterine leimyomas	-	KAT6B-KANSL1 and EWSR1-PBX3 fusion genes	-
Leiomyosarcoma130		yes/NA/yes	7th decade	11% of STS	C	40%	Resection, RT and CH	radiation	57%	complex	Li-Fraumeni syndrome, hereditary retinoblastoma
Pericytic Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Myopericytoma131	-	no/no/very rare*******	52	?	A	<5%	resection if symptomatic	AIDS	-	PDGFRB gene	Infantile myofibromatosis
Skeletal Muscle Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Ectomesenchymoma132	-	yes/NA/yes	0.6	50 cases	C	50%	resection, CH/RT	-	83%	HRAS mutations	-
Rhabdomyosarcoma, pleomorphic13334	-	yes/NA/yes	72	3.5% of STS (all rhabdos)	C	54%	resection, CH/RT	-	26%	complex	-
Rhabdomyosarcoma, alveolar135	-	yes/NA/yes	10-24	25% of rhabdos	C	63%	resection, CH/RT	-	27%	PAX3-FOXO1 or a PAX7-FOXO1 fusion gene	-
Rhabdomyosarcoma, embryonal135	-	yes/NA/yes	2-20	0.45/100000	C	28%	resection, CH/RT	-	58%	complex	Costello syndrome, NF 1, Noonan syndrome, Li–Fraumeni syndrome
Rhabdomyosarcoma, spindle cell136 WHO, 26823695	-	yes/NA/yes	34	3-10% of rhabdos	C	33%	resection, CH/RT	-	18%	VGLL2/NCOA2/CITED2 or MYOD1 or TFCP2/NCOA2 rearrangements	-
Vascular Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Angiosarcoma137	-	yes/no/yes	7th decade	2% of STS	C	20%	resection + RT/CH/TT	radiation, lymph-edema, forieg bodies, AV fistulas, hemangiomas	30-40%	MYC gene amplifications	NF, Maffucci syndrome
Hemangioendothelioma, composite13839	-	yes/no/rarely	43	26 cases	B	50%	resection	radiation, lymph-edema,	62-83%	PTBP1-MAML2 and EPC1-PCH2 gene	-
Hemangioendothelioma, epitheloid140	-	yes/no/yes	adulthood	0.1/100000	C	?	resection + CH/RT	-	59%	WWTR1-CAMTA1 gene fusion	-
Hemangioendothelioma, kaposiforme141	-	yes/no/rarely (lymph nodes)	1	0.9/100000 children	B	<5%	vincristine, steroid, sirolimus vs resection	-	-	GNA14 mutations	-
Hemangioendothelioma, pseudomyogenic1	-	yes/no/rarely	30	?	A	60%	resection	-	-	SERPINE1 to FOSB or ACTB-FOSB fusion	-
Hemangioendothelioma, retiform1	-	no/no/rarely (lymph nodes)	childhood	40 cases	B or C	60%	resection	radiation, lymph-edema, lymph-angioma	-	-	-
Hemangioma, epitheloid142	-	rarely/no/rarely (lymph nodes)	4th decade	?	A or B	33%	resection	trauma	-	FOS or FOSB gene	-
Hemangioma4344	-	no/no/no	51	2%	A or B	3-50%	if symptomatic: Embo + resection (+/- kypho, +/- adjuvant RT) vs Rt alone, vs	-	-	-	-
Kaposi sarcoma14546	-	yes/no/yes	?	400-600/ 100000	-	?	immun- reconstitution, CH	immuno-suppression	74%	-	-
Lymphangioma1	-	no/no/no	congenital	?	A or B	20%	resection	-	-	PIK3CA mutations	Turner syndrome
Peripheral Nerve Sheath Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Ectopic meningioma14748	-	occasionally/no/occasionally/6%	2nd + 5th decade	1% of menigiomas	A	26%	resection if high grade, symptomatic or pogressive	-	92% (3y)	-	Cowden, Li-Fraumeni, Von Hippel-Lindau syndrome
Hybrid nerve sheath tumors149	-	no/no/no	38	?	A	< 5%	resection if high grade, symptomatic or pogressive	-	-	-	NF1, NF2, schannomatosis
Malignant periperhal Nerve sheath tumor150–52	-	yes/NA/yes	20-50 years	2-5% of STS	C	56%	Resection + CH/TT	benign nerve sheath tumor, radiation	53%	complex	NF1
Neurofibroma15354		rarely/in NF1/rarely/no	45	0.3/100000	A or B	17%	resection if symptomatic	-	-	inactivation NF1 gene	NF1
Uncertain Differentiation
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Clear cell sarcoma15556	-	yes/no/yes	3-4th decade	?	C	40%	resection + RT/CH	-	60%	reciprocal translocation t (12;22)(q13;q12)	-
Desmoplastic small round cell tumor157–61	-	yes/no/yes	19	0.1/100000	C	89%	neo CH + resection + CH/RT vs TT	-	15%	EWSR1-WT1 gene fusion	-
Epitheloid sarcoma16263	-	yes/no/yes	39	<1% STS	C	25%	resection + RT/CH	trauma	54%	loss of SMARCB1 expression	-
Extrarenal rhabdoid tumor16465	-	yes/no/yes	13	<1% of childhood STS	C	22%	resection + CH/TT	-	15%	SMARCB1 gene alterations	-
Extraskeletal myxoid chondrosarcoma166	-	yes/no/yes	50	<1% STS	C	37%	resection + RT/TT	-	82-90%	NR4A3 gene rearrangement	-
Intramuscular myxoma1	-	yes/no/no	40-70 years	?	A	<5%	resection	fibrous dysplasia	-	GNAS mutation	-
Myoepithelioma167	-	possible/no/possible	40 years	?	B	20-50%	resection	-	90%	EWSR1 gene rearrangements	-
NTRK-rearranged spindle cell neoplasm16869	-	yes/no/no	1-2nd decade	1% of STS	B	11-44%	resection + CH/TT	-	?	NTRK-rearrangements	-
Ossifying fibromyxoid tumor170	-	yes/no/possible	58 years	?	B	0-60%	resection	-	94%	PHF1 gene fusion	-
Pecoma17172	-	yes/no/yes	45	234 cases	C	0-70%	neo CH + resection + CH/RT vs TT	-	45%	LOH TSC2 locus	-
Phosphaturic mesenchymal tumour173	-	no/yes/possible	53 years	< 0.01% of all STS	B	0-13%	resection	-	100%	α-Klotho upregulation	-
Synovial sarcoma17475	-	yes/no/yes	3-4th decade	0.08/100000	C	42%	Resection + RT	radiotherapy	75-83%	SS18-SSX1/2/4 fusion gene	-
Undifferentiated Small Round Cell Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Ewing Sarcoma176–78		yes/no/yes	16	0.3/100000	-	50%	chemotherapy	-	39-69%	FET-ETS fusion genes	-
Chondrogenic Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Chondroblastoma1	chondroblastoma-like osteosarcoma	no/no/benign lung mets	2-3 decade	<1% of bone tumors	A	10-18%	resection vs RFA	-	NA	H3.3 alterations	-
Chondromyxoid fibroma179	-	no/very rare/no	2-3rd decade	?	A or B	15%	resection	-	NA	GRM1 gene recombination	-
Chondrosarcoma, clear cell1	renal cell carcinoma, chondroblastoma, osteosarcoma	yes/rare/rare	3-4th decade	2% of chondrosarcomas	C	86%	resection	-	85%	Chromosome 9, 20 aberrations	-
Chondrosarcoma, mesenchymal180	-	yes/no/yes	26	2-9% of chondrosarcomas	C	55%	resection + CH	-	60%	HEY1-NCOA2 rearrangement	-
Chondrosarcoma, central grade II, III1	chondroblastic osteosarcoma	possible/yes/no	3-6th decade	0.18/100000	C	19-26%	resection	-	31-74%	WNT/β-catenin signalling loss	-
Chondrosarcoma, dedifferentiated181	-	yes/no/yes	59	11% of chondrosarcomas	C	50%	Resection + CH	-	7-24%	IDH1 or IDH2 mutation	-
Enchondroma1	secondary peripheral atypical cartilaginous tumour/chondrosarcoma	no/very rare/no/	36	2%	A	<5%	resection if symptomatic	-	NA	IDH1 or IDH2 mutations	Enchondromatosis
Osteochondroma1	secondary peripheral atypical cartilaginous tumour/chondrosarcoma	no/possible/no	18	0.9/100000	A	<5%	resection	radiation	NA	inactivation EXT1 or EXT2 gene	multiple osteochondromas syndrome
Osteochondromyxoma182	-	possible/no/possible/no	1	?	A or B	?	resection	-	NA	PRKAR1A gene mutation	Carney complex
Secondary peripheral atypical cartilaginous tumor/chondrosarcoma grade I183	-	yes/yes/yes/	49	0.66/100000	A or B	11%	resection vs RFA	-	87-99%	IDH1 or IDH2 mutation	Enchondromatosis
Secondary peripheral atypical cartilaginous tumor/chondrosarcoma grade II, III1	periosteal osteosarcoma	yes/no/rarely	3-4th decade	5% of osteochondromas	B or C	16%	resection	-	98%	-	-
Synovial chondromatosis1r		yes/possible/possible	3-5th decade	0.18/100000	B	20%	resection	-	NA	FN1-ACVR2A and ACVR2A-FN1 fusions	-
Osteogenic Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Osteoblastoma1	-	yes/rare/no	2-3rd decade	1% of bone tumors	B	23%	resection	-	NA	FOS rearrangements	-
Osteoid osteoma1	-	no/no/no	24	10% of all bone tumors	A	<5%	resection if symptomatic vs RFA (lesion might disappear)	-	NA	FOS rearrangements	-
Osteoma1	-	no/no/no	37	6.4%	A	<5%	resection if symptomatic	-	NA	LEMD3 gene	Gardner Syndrome, Osteopoikilosis
Osteosarcoma, (chondroblastic, fibroblastic, osteoblastic, telenagiectactic)184	-	yes/no/yes	10-14 years and 65 years	0.46/100000	C	30-50%	neoadjvuant CH + resection + RT/CH	-	68%	Gains 6p, 8q	LiFraumeni, Werner, Rothmund-Thomson, Bloom syndrome
Osteosarcoma, low grade central1	fibrosarcoma	yes/rare/rare	3rd decade	1-2% of osteosarcomas	B	7%	resection	-	90%	Amplification of 12q13-q15	-
Osteosarcoma, secondary	-	yes/no/yes	6-7th decade	1-7% in Paget disease	C	?	neoadjuvant CH + resection + RT/CH	Paget diaseas, radiation, Caisson disease, Sickle cell disease, implants, chronic osteomyleitis	10-32%	?	Rothmund-Thomson syndrome
Osteoclastic giant cell-rich Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Aneurysmal bone cyst1	teleangiectactic osteosarcoma	no/no/no	1-2nd decade	0.015/100000	A or B	20-70%	resection vs denosumab vs embo vs RT	-	NA	USP6 rearrangements	-
Giant cell tumor18586	-	yes/rarely/rarely	31	0.15/100000	B	15-50%	resection vs denosumab vs embo vs RT	Paget disease, radiation	87%****	H3.3 mutation	Gorlin-Goltz syndrome, Jaffe-Campanacci syndrome
Non-ossifying fibroma1		no/no/no	2nd decade	?	A	<5%	resection if symptomatic	-	NA	KRAS and FGFR1 mutations	Jaffe-Campanacci syndrome, NF1, KRAS
Notochordal Tumors
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Benign notochordal tumor187	-	no/rarely/no	58	1.7%	A	<5%	resection if symptomatic	-	NA	expression of brachyury	-
Chordoma, conventional, dedifferentiated, poorly differentiated1	-	yes/yes/yes	6-8th decade	0.08/100000	C	35%	resection + RT/TT	-	68%	expression of brachyury	-
Haematopoietic Neoplasms of Bone
	Important differential diagnosis	Infiltrating/malignant transformation/metastasis	Peak age	Incidence	Type of surgical resection	Recurrence rate	Treatment	Risk factors	5y OS	Protein/gene	Possible associated Tumor syndroms
Plasmacytoma1 WHO	-	yes/yes/yes	55-60	6.8/100000	-	22%	RT	-	57%	-	-
Non-Hodgkin lymphoma of the bone188	-	yes/yes/yes	50-60	7% of bone tumors	-	10%	CH, RT	HIV	75%	Immunglobulin rearrangements	-

*In high risk/systemic/recurrence patients, **Depending on mutation status: CTNNB1 p.Ser45Phe, ***20 year survival rate in patients with FAP associated lesions, ****Patients with malignant variant, *****Mean survival time in aggressive variant (EIMS), ******At 46 month, *******Very rare malignant variant, „ congenital variants less aggressive, ‚ among immunospurressed, {{{ can arise secondarily in previous enchondroma, {{{{ can arise secondarily on the surface of osteochondromas. CH: Chemotherapy; TT: Targeted therapy