Primary orbital sarcoma in adults: a case series with emphasis on post-irradiation sarcoma

ABSTRACT Purpose To describe a series of eight adult patients with primary orbital sarcoma and to review the existing literature on orbital sarcoma and post-irradiation sarcoma. Methods Report of eight cases and literature review. Results We report eight cases of primary orbital sarcoma, three of which were radiation-induced. Only one patient had a history of retinoblastoma. The most common presentations were painful proptosis and reduced vision. Most tumours arose in the extraconal compartment. The overall median age at diagnosis was 50 years. The pathology comprised a diverse group of tumours. Treatment and outcome varied between patients and their clinical circumstances. Conclusions Adult primary orbital sarcomas are rare. They can comprise a variety of tumour types and are difficult to treat. Irradiation is a significant risk factor, and the incidence of post-irradiation sarcoma of the orbit may be increasing due to the widespread use of radiotherapy and improved survival of patients with cancer. Post-irradiation sarcoma should be considered in the differential diagnosis of an orbital space-occupying lesion in a patient with a history of radiotherapy.


Introduction
Primary orbital neoplasms comprise a diverse range of entities, most of which are benign.The more common entities in adults include vascular tumours and non-Hodgkin lymphomas. 1,2Primary sarcomas, however, are rare, limited to single case reports and small series, often with incomplete clinical and pathological details and without documented extended follow-up.Of those few cases that have been reported, a significant proportion are postirradiation sarcomas (PRS) arising in previously irradiated hereditary retinoblastoma survivors.By contrast, the occurrence of PRS in the orbit of nonhereditary retinoblastoma survivors or nonretinoblastoma patients is exceptional; however, with the now widespread use of radiotherapy and improved long-term survival of patients with cancer, the frequency of PRS may be increasing.Here, we report eight patients with primary orbital sarcoma, of whom three had PRS, but of whom only one had a history of retinoblastoma.We review these rare tumour types and provide an updated summary on their clinical, histopathologic, and radiological features, and discuss the need for greater awareness of the risk of PRS among practising eye specialists.

Methods
Adult patients aged over 16 years with a tissue diagnosis of orbital sarcoma were identified from our institutional pathology database between 2005 and 2020.Cases involving local invasion of the orbit by sarcoma arising in surrounding structures, such as the paranasal sinuses, were excluded.Medical data were reviewed for clinical findings, treatments, outcomes, and evidence of radiotherapy for a previous neoplasm.Histology of the newly diagnosed orbital sarcoma and, where applicable, the original neoplasm was reviewed.A diagnosis of PRS was made based on criteria defined by Murray et al.: 3 1.Radiation must have been given previously and the sarcoma that subsequently developed must have arisen in the area included within the 5% isodose line; 2. There must have been no evidence that the sarcoma was likely to have been present before the onset of irradiation; and 3.All sarcomas must have been proven histologically and must be of a different pathology than that of the primary neoplasm.

Clinical data
Results are summarised in Table 1.Eight patients were identified (4 male and 4 female), of whom three had PRS.Most patients presented with painful proptosis associated with disturbance in ocular motility and reduced vision.Most tumours arose in the extraconal compartment.The overall median age at diagnosis was 50 years.The median age of the patients at presentation with PRS was 46 (range 25-49) years, and the median latency period was 15 (range 12-45) years.The difference in age at presentation between the PRS group and the de novo group was not significant (t = 3.18; p = 0.140).The median follow-up time in survivors was 70 (range 30-144) months.No patients were lost to followup.
The original neoplasm in patient 6 was childhood bilateral retinoblastoma, treated with right enucleation and bilateral orbital radiotherapy (dose not known).The low-grade undifferentiated spindle cell sarcoma occurred 15 years after intensive chemotherapy, total body irradiation (TBI) (10-12 Gy delivered across multiple fractions) and haematopoietic stem cell transplant (HSCT) for primary pelvic alveolar rhabdomyosarcoma that had metastasised within the abdomen and to the lung.As this was treated with TBI it met our PRS criteria.Patient 8 was a long-term survivor of a left frontal lobe glioblastoma, treated with surgery, chemotherapy, and radiotherapy (60 Gy/30 fractions).

Management and outcomes
Patients 1, 2, and 5 (MPNST, MPNST, SFT) were treated with a combination of surgery and radiotherapy.To preserve ambulatory vision in his only eye, patient 6 (rhabdomyosarcoma) was treated with neoadjuvant chemoradiotherapy, which resulted in good shrinkage of the tumour, followed by globe-sparing excision of residual disease.Patients 3, 4, and 7 (ALT/WDLS, ALT/ WDLS, low-grade sarcoma) were treated by surgery alone.Surgical treatment varied between patients and their clinical circumstances.Patient 8 (ESOS) was treated palliatively as the extent of disease at presentation precluded surgery.
Complete primary resection of disease was achieved in one patient out of seven (patient 4, ALT/WDLS).Patients 1, 2, 5, 6, and 7 each had microscopic residual disease with histologically confirmed positive margins.Patient 3 had disease that extended to the orbital apex rendering primary gross total resection infeasible from the outset.
Two of the five patients with residual microscopic disease, patient 1 with MPNST and patient 7 with lowgrade undifferentiated spindle cell sarcoma, are alive and free of progressive disease long-term.Of the remaining three, patient 6 (rhabdomyosarcoma) developed a local recurrence 3 months after surgery, finally succumbing to pulmonary metastases 12 months after diagnosis.Patient 2 (MPNST) developed a recurrence in the surgical scar on the scalp 5 months after surgery that was excised with negative margins but nonetheless recurred multiple times requiring re-excision.And patient 5 (SFT), who did not have gross residual disease or develop a recurrence, died 44 months after surgery of unrelated causes.Patient 3 (ALT/WDLS) had gross residual disease following subtotal resection that has shown no definite evidence of radiological progression 28 months after surgery.Patient 4 (ALT/WDLS) had complete local clearance of disease following exenteration and is alive and free of disease long-term.Patient 8 (ESOS) died of disease 3 months after diagnosis.

Solitary fibrous tumour
The most recent edition of the World Health Organization (WHO) Classification of Tumours of Soft  tissue and Bone, published in early 2020, has classified SFT as a fibroblastic neoplasm with intermediate (rarely metastasising) behaviour.It is probably the commonest mesenchymal neoplasm of the orbit in adults, 4 and recurrent and more aggressive tumours are often managed clinically as sarcomas. 5,6FTs typically present with painless, gradual onset unilateral proptosis.The most common appearance on CT scan is of a well-demarcated mass and there is often remodelling of the bony orbit.Most cases are extraconal or involve the superomedial or superolateral orbit. 7here are fewer cases such as ours in the intraconal compartment.
SFTs are typically composed of alternating hypocellular and hypercellular areas with intervening densely hyalinised collagen.The cellular areas are composed of spindle-shaped cells with open vesicular nuclei that form a so-called patternless growth pattern.The vessels can have a staghorn-like appearance.Most show positive immunohistochemical staining for CD34, bcl2 and CD99, but staining for some, or all, of these markers can be negative in more aggressive tumours, as evidenced in our case with loss of CD34.In 2015, a NAB2-STAT6 gene fusion product derived from the inversion of chromosome 12 (q13q13) was identified as the genetic signature of SFT. 8 This results in nuclear overexpression of STAT6 that can be detected immunohistochemically and is preserved in more aggressive tumours.
0][11][12][13] Three and four variable risk stratification models have been developed that incorporate both clinical and histopathological features, including age, mitotic count, tumour size and percentage of tumour necrosis, and help to stratify SFTs into low, intermediate, and highrisk categories. 11The most significant risk score is given to the tumour's size, with tumours smaller than 5 cm given a score of zero, the lowest risk.The utility of risk stratification in orbital SFTs has not been fully investigated but given that few orbital tumours reach 5 cm it is likely to be of reduced value.Were we to apply the four variable risk stratification model, the initial resection from patient 5 would fall into the low-risk category (age <55: 0; tumour size <5 cm: 0; mitotic count ≥4: 2; and tumour necrosis <10%: 0), as would the recurrence (age ≥55: 1; tumour size <5 cm: 0; mitotic count ≥4: 2; and tumour necrosis <10%: 0).
Including our case, we identified 41 cases of recurrent orbital SFT 4,   initially with surgical excision and experienced a recurrence after a median of 36 (range 3-396) months. Not al recurrent cases showed adverse histological features and the single most important factor in predicting recurrence was incomplete resection.Recurrent tumours tend to infiltrate surrounding tissues necessitating more radical surgery.Still, obtaining negative margins is challenging.
Complete primary excision is the treatment of choice.The efficacy of adjuvant radiotherapy in cases with positive resection margins is unclear but should be considered because there is empirical evidence demonstrating improved outcomes in meningeal SFTs. 39,40Several retrospective studies have shown low or questionable response rates following treatment with chemotherapy in locally advanced and metastatic disease. 41,42Most useful, to our mind, is the identification of prognostic molecular biomarkers to augment existing risk stratification models.The ability to predict aggressive behaviour reliably and accurately would allow most patients to be reassured by potentially curative total resection, while genuinely highrisk patients could receive long-term follow-up.Although there has been some advance in this area, with a recent study showing that TERT promoter mutation and/or TP53 mutation are associated with a worse prognosis, no risk stratification model has so far incorporated these molecular factors. 43

Malignant peripheral nerve sheath tumour
Malignant peripheral nerve sheath tumours (MPNSTs) are malignant, locally aggressive neoplasms accounting for 5-10% of STS. 9,44,45A sarcoma is assumed to be an MPNST when at least one of the following criteria is met: (1) the tumour arises from a peripheral nerve and shows no aberrant or heterologous line of differentiation; (2) it arises from a pre-existing benign nerve sheath tumour (neurofibroma); or (3) the tumour demonstrates Schwann cell differentiation. 46hey generally arise de novo, but risk factors include neurofibromatosis type 1 (NF1), irradiation, and incomplete excision or a prior nerve sheath tumour. 47Most cases involve the extremities or trunk.By contrast, orbital involvement is rare, accounting for between 0% and 0.2% of all histopathologically proven orbital tumours. 480][51] The median age at diagnosis was 50 years (range 4 days to 78 years).
MPNSTs often present with pain, redness, and rapidly progressive proptosis.On CT scan they typically appear as a well-defined, homogenously enhancing mass that may show invasion of adjacent bone. 52he tumour occurs most frequently in the superior orbit because MPNSTs tend to involve the ophthalmic nerve or distal supraorbital and supratrochlear branches. 53Involvement of the infraorbital nerve, as in each of our patients, is less common. 49PNSTs are typically composed of pleomorphic spindle-shaped cells with a fascicular growth pattern and brisk mitotic activity.0][51] Fewer than 50% of MPNSTs are positive for S100 and staining is less intense and diffuse than in schwannoma.Interestingly, patient 1 showed strong and diffuse S100 staining, which prompted consideration of alternative diagnoses such as spindle cell melanoma and interdigitating dendritic cell sarcoma, but ultimately the tumour was best regarded as an MPNST.More recently, loss of H3K27me3 (H3K27 trimethylation) expression was shown to be a specific marker for MPNST that is associated with a poorer prognosis. 54omplete primary excision is the treatment of choice but by the time of initial presentation this is often impossible due to disease extent.Multiple relapses, with increased odds of metastasis, are common, and mortality is high: 11 out of the 37 patients identified in the literature died of disease within 5 years of diagnosis.Marginal efficacy has been ascribed to radiotherapy in control of local disease and this is therefore recommended in cases with positive margins.Although the role of adjuvant chemotherapy has not been established, limited by insufficient data, 52 recent research has shown reasons for optimism. 55

Liposarcoma
Liposarcoma, a malignant tumour of adipocytic tissues, is the most common soft tissue sarcoma in adulthood, comprising 20% of all sarcomas.Most present in the extremities and retroperitoneum.Despite a predominance of adipose tissue in the orbit, orbital liposarcomas are rare, accounting for less than 1% of all histopathologically proven orbital tumours. 2 The first description of orbital liposarcoma is attributed to Strauss in 1911 and since then there have been occasional case reports and a few small case series [56][57][58][59][60][61][62][63][64][65][66][67][68] resulting in around a further 60 cases (Table 2).
Presentation is indistinguishable from other orbital space-occupying lesions.The most common appearance on CT scan is of a well-defined heterogeneous mass, but they may occasionally present with muscle thickening and foci of calcification.Most reported cases are intraconal or in the superior orbit, 63 whereas both of our examples were extraconal and arose in the inferolateral orbit (patient 3) and the medial orbit (patient 4).
The current WHO classification of Tumours of Soft tissue and Bone recognises five tumour types: ALT/WDL (which includes three histopathological subtypes: adipocytic, sclerosing, and inflammatory); dedifferentiated; myxoid; pleomorphic; and myxoid pleomorphic.Most liposarcomas in the orbit are ALT/WDL, with 29 published reports including our two patients. 65The median age at diagnosis is 40 (range 14-69) years.][68] ALT and WDL are synonymous morphologically and genetically.The term ALT is used to describe tumours in the extremities that are readily resectable, while WDL is used for tumours in the retroperitoneum, paratesticular region, mediastinum, or head and neck region where more radical surgery is required, and complete resection is difficult or impossible.Lesions of the orbit can conceivably conform to either terminology.While tumours in the anterior orbit may be amenable to complete resection, even relatively small tumours located in the posterior orbit will be impossible to excise completely without sacrificing functionally important structures and without doing an orbital exenteration.Histologically, ALT/WDLs are composed of infiltrative bland spindle-shaped cells, mature adipocytes, and occasional lipoblasts.It can be difficult to distinguish, morphologically, ALT/WDL from other benign adipocytic tumours, especially if the tumour is inadequately sampled, and care should be taken to exclude mimics such as spindle cell lipoma and pleomorphic lipoma, both of which have also been described in the orbit. 69,70Cytogenetic studies can help resolve this diagnostic challenge as unlike spindle cell lipoma and pleomorphic lipoma a significant percentage of ALT/WDLs show amplification of the MDM2 gene on chromosome 12q, which can be identified with fluorescence in situ hybridisation (FISH). 71In patient 3, FISH studies demonstrated amplification of MDM2, supporting the morphological diagnosis of WDL over pleomorphic lipoma.
ATL/WDLs and myxoid liposarcomas are usually low-grade tumours but can be locally invasive and recur if incompletely excised, as in patient 4 who went on to require exenteration.In our review of the literature, we found that 6 out of 11 patients with orbital ATL/ WDL who were treated initially by local excision developed a recurrence.The median time to recurrence was 66 (range 10-204) months.ATL/WDLs do not metastasize unless they undergo dedifferentiation, which is rare.The overall prognosis is good.Supporting this, patient 3 is alive with residual but stable disease 30 months following surgery, and patient 4 is alive and free of disease 70-months after orbital exenteration.The treatment of choice is complete primary excision.The role of radiotherapy and chemotherapy is unclear, especially in welldifferentiated subtypes. 72,73

Post-irradiation sarcoma
It is noteworthy that of the eight patients who comprise our relatively small cohort, three had PRS.PRS in the orbit is, of course, well described in previously irradiated hereditary retinoblastoma survivors.The aetiology of subsequent sarcomas in these patients is attributed to a germline mutation of the RB1 tumour suppressor gene in addition to radiotherapy. 74The most common tumour in this setting is osteosarcoma, followed, in descending order, by leiomyosarcoma, fibrosarcoma, pleomorphic sarcoma, rhabdomyosarcoma and liposarcoma. 75Most patients with hereditary Rb are diagnosed in childhood, and the temporal pattern of risk for soft tissue sarcomas thus mirrors the expected age distribution for individual sarcoma subtypes in the wider population.The corollary is that the risk of rhabdomyosarcoma is highest in the first 10 years after retinoblastoma diagnosis, whereas leiomyosarcomas are more common more than 20 years after retinoblastoma diagnosis. 74,76The 45-year latency period in patient 6 is unusual because it contrasts with much shorter latency periods reported elsewhere 3,74 What is most surprising, however, is that two of our patients with PRS did not have retinoblastoma.The occurrence of PRS in the orbit of nonhereditary retinoblastoma survivors or in patients with a primary neoplasm other than retinoblastoma is exceptional, and has not, to the best of our knowledge, been detailed previously in the medical literature.
Patient 7 was 10 years old when she received chemotherapy followed by TBI and HSCT for metastatic pelvic alveolar rhabdomyosarcoma.Several large studies have demonstrated an increased risk of developing secondary neoplasms following HSCT, with TBI exposure being a major compounding factor.8][79] The occurrence of multiple osteochondromata following TBI is also well described and can occur in up to a quarter of patients. 802][83] The most common original diagnosis was acute lymphoblastic leukaemia (ALL), and the most common site was tibia, followed by femur, iliac bone, humerus, and rib.The occurrence of PRS, or any secondary neoplasm, in the orbit following TBI has not, to the best of our knowledge, been described before.
Patient 8 presented to ophthalmology with a painful left eye and blurred vision.CT imaging showed a focus of enhancement and surrounding oedema in the left inferior frontal lobe that was not visible on routine surveillance imaging 3 months previously.Subsequent MRI showed an extra-axial soft tissue mass in the left anterior cranial fossa that was contiguous with tumour in the left orbital apex via the superior orbital fissure (Figure 2).The clinical and radiological suspicion was recurrent glioblastoma, but biopsy confirmed osteosarcoma.There was no definitive skeletal attachment and thus the tumour was best regarded as an ESOS.
ESOS are rare tumours that constitute less than 4% of all osteosarcomas and are more common among PRS. 84revious trauma is also a risk factor.6][87][88][89] Three of these patients had no known risk factors.One patient, an 11-year-old boy, developed ESOS after radiotherapy for retinoblastoma, and Fan et al. report ESOS in a 78year-old man occurring 12 months after excision of a left medial canthal basal cell carcinoma that was followed by adjuvant radiotherapy.Despite the very short latency period, the authors suggest this is likely to be PRS.Our case is therefore the sixth case of orbital ESOS to be reported in the literature and the third to be classified as PRS.
1][92][93][94] The overall incidence is estimated to be less than 1%, but because of the potentially long latency period (1-50 years, with a reported mean latency of between 10 and 20 years) 3 and required long-term follow-up, it is likely cases are missed and these figures are therefore probably an underestimate.
iagnostic criteria for PRS were originally defined by Cahan et al. in 1948 95 and have since been modified by Murray et al. to allow for the inclusion of postirradiation soft tissue sarcomas and a shorter latency period. 3There is no agreed minimum latency period between irradiation and tumour development, and to stipulate an arbitrary specification of latency would probably exclude genuine PRS from being reported.Notwithstanding, it is generally considered that tumours appearing less than 2 years following irradiation are unlikely to be radiation-induced.The latency period in our small series varied from 12 to 45 years, which is comparable to that reported elsewhere.
Risk factors include genetic predisposition (e.g.germline mutations in RB1 and p53 tumour suppressor genes, in the case of retinoblastoma and Li -Fraumeni syndrome, respectively), young age at treatment, and concomitant chemotherapy.The total dose of radiation appears to influence tumour incidence and most PRS are reported to occur at doses of 50 Gy or more.There is, however, no agreed safe threshold in terms of dose below which there is zero risk of developing a secondary malignancy.Many of these risk factors contributed to the development of PRS in our patients.
PRS are less heterogeneous than spontaneously occurring sarcomas.The most common tumour type is pleomorphic undifferentiated sarcoma (previously malignant fibrous histiocytoma), which accounts for approximately 70% of cases, followed by osteosarcoma, fibrosarcoma, malignant peripheral nerve sheath tumour, chondrosarcoma, and angiosarcoma. 46ognosis is poor compared with their de novo counterparts 96 and there are several possible reasons for this.PRS are usually more aggressive and tend to be diagnosed at a more advanced stage. 97Delay in diagnosis and initial misdiagnosis are common. 97,98Unlike de novo sarcomas, most arise in central locations, precluding radical surgery.Patients with PRS of the extremities have the best survival (30% at 5 years), whereas those with lesions arising in the vertebral column, pelvis, and shoulder girdle have survival rates of less than 5% at 5 years.Several large studies have shown that obtaining negative margins is difficult and subsequent risk of a local recurrence is high, estimated at 45%. 84,99 And finally, adjuvant treatment options are limited: radiotherapy is often impossible because of the dangers of irradiating a previously irradiated field, and PRS show poor sensitivity to chemotherapy. 3Many of these factors contributed to a poor outcome in patients 6 and 8.

Conclusion
Adult primary orbital sarcomas are rare.They can comprise a variety of tumour types and are difficult to treat.Complete primary excision is the mainstay of treatment but obtaining negative histological margins is challenging and the likelihood of a local recurrence is high.Irradiation is a significant risk factor not only in hereditary retinoblastoma survivors but in all patients who receive radiotherapy, and these patients should be permanently followed up.The incidence of PRS may be increasing because of the widespread use of radiotherapy and improved survival of patients with cancer.To assist in early detection, clinicians must be aware of the risk of PRS and consider this diagnosis in any previously irradiated patient with a suspected orbital tumour.

Figure 1 .
Figure 1.Patient 2. (A) Microscopy showed a cellular malignant spindle cell tumour with a fascicular growth pattern, (B) patchy positive staining for PGP9.5, and (C) moderate Ki67 proliferative activity.Patient 3. (D) Microscopy showed a moderately cellular tumour composed of adipocytes of varying size and shape embedded in dense fibrous stroma with scattered larger atypical cells and rare lipoblasts (arrow).Patient 4. (E) Microscopy showed dense fibrous tissue infiltrated by a cellular tumour composed of pleomorphic spindle-shaped cells with occasional lipoblasts (arrow).Patient 5. (F) Microscopy showed a cellular tumour composed of pleomorphic ovoid-fusiform cells with brisk mitotic activity (>4 mitoses in 10 high power fields), a patternless growth pattern, (G) nuclear expression of STAT6, and (H) a high Ki67 proliferative activity.

Figure 2 .
Figure 2. Patient 6. (A) Microscopy showed a high-grade sarcomatoid malignancy with multinucleate giant cells (arrows), and positive staining for both (B) myogenin and (C) desmin.Patient 7. (D) Microscopy showed a cellular tumour composed of bland spindle-shaped cells with pale cytoplasm, background collagenization, mild cytological atypia, and moderate mitotic activity.Patient 8. (E) Microscopy showed a high-grade malignant neoplasm composed of polygonal cells with prominent cell borders, significant nuclear pleomorphism, brisk mitotic activity (arrows), (F) areas of lace-like osteoid formation (arrows), and (G) a high Ki67 proliferation fraction; (H) T2weighted axial MRI scan though mid-orbit showed a left intraconal soft tissue mass, causing mild proptosis, involving superior and lateral rectus muscles (arrow) but without definite skeletal attachment.

Table 1 .
Summary of key clinical and pathological details.

Table 2 .
Primary orbital liposarcoma series comprising two cases or more.