Malignant Orbital Tumors

Etiology

All anatomic structures of the orbit can give rise to malignancy. The malignant tumors of the orbit can be classified according to the site of origin and histology as follows: [3][4][5] 

Primary Tumors

Lymphoproliferative

• Ocular adnexal lymphomas: These are the most common adult malignant orbital tumors and are primarily seen in older patients with a female predominance. They can originate from the conjunctiva, eyelids, lacrimal glands, and orbital soft tissue. These are most commonly mucosal-associated, low-grade B-cell lymphomas (MALT lymphomas).[6]

Lacrimal gland

• Lacrimal gland neoplasms are often differentiated into 2 distinct categories, epithelial and nonepithelial, with nonepithelial tumors accounting for 50% to 60% of masses. Other rare tumors include mesenchymal tumors.                                                         
• Lacrimal gland lymphomas account for the majority of malignant nonepithelial gland tumors. Other tumors of nonepithelial lymphatic origin include extranodal marginal zone lymphomas, follicular lymphomas, and diffuse large B-cell lymphomas.         
• Malignant epithelial gland tumors include adenocarcinomas, adenoid cystic carcinomas, mucoepidermoid carcinomas, pleomorphic adenocarcinomas, epithelial-myoepithelial carcinomas, acinar cell carcinomas, transitional cell carcinomas, and melanomas.
• Mesenchymal tumors are rare and constitute only 10% to 15% of all lacrimal gland tumors. Examples include sarcomas, malignant peripheral nerve sheath tumors, and malignant rhabdoid tumors.

Mesenchymal: These are usually aggressive tumors seen in both pediatric and adult populations and are named according to their cell of origin. These tumors include rhabdomyosarcomas (the most common pediatric malignant orbital tumor), liposarcomas, myxofibrosarcomas, leiomyosarcomas, osteosarcomas, and chondrosarcomas.[7]

Vasculogenic: These are rare tumors of the orbit and include hemangiopericytomas, angiosarcomas, and epitheloid hemangioendotheliomas. Hemangiopericytomas constitute around 1% of all orbital tumors. The cell of origin is the pericytes of the vascular wall or pluripotent perivascular cells. Patients typically present in the fifth decade of life with no gender predilection.

Intraocular: These include tumors originating from ocular epithelium, such as retinoblastomas and orbital melanomas. Retinoblastomas are the most frequent intraocular malignancy in children, occurring before the age of 5 and with no gender predilection. Primary orbital melanomas constitute the most common primary intraocular malignancy in adults. They arise from the uveal tract, which consists of the choroid (the most common site of origin), ciliary body, and iris.

Germ cell: These tumors are of embryonic cell origin and are extremely rare malignant tumors of the orbit. Examples include teratomas, yolk sac tumors, and granulocytic sarcomas.

Secondary Tumors: Based on the site of origin, these tumors can be classified as follows:

From sinonasal malignancies

• Frontoethmoidal malignancies (like squamous cell carcinomas [SCC] and adenocarcinomas), maxillary sinus malignancies, ethmoid sinus malignancies, and rarely sphenoid sinus malignancies
• Nasopharyngeal carcinomas
• Sinonasal undifferentiated carcinomas (SNUC)
• NK/T-cell lymphomas

From the central nervous system

• Endocranial tumors of the skull base, like esthesioneuroblastomas
• Malignant meningiomas

From the globe, conjunctiva, or nasolacrimal duct

• Squamous cell carcinomas, basal cell carcinomas (BCC), adenocarcinomas, oncocytic carcinomas, mucoepidermoid carcinomas, adenoid cystic carcinomas, melanomas, Merkel cell tumors, sebaceous carcinomas

From the skin 

• Squamous cell carcinomas
• Basal cell carcinomas
• Melanomas
• Adnexal structure carcinomas (Merkel cell, apocrine, etc)

Metastatic Tumors: The orbit can be the site of metastasis (1% to 3% of all orbital tumors), and the most common types include metastases from the breast, prostate, melanoma, and lungs.[8]

Epidemiology

Primary orbital malignancies account for 82% to 87% of all orbital masses, secondary orbital malignancies represent 9% to 11%, and orbital metastasis accounts for 4% to 8% of overall orbital masses.[5] Out of all tumors of the orbit, 68% are benign, and 32% are malignant.[9] In adults older than 60 years of age, lymphoproliferative lesions are the most common primary orbital tumor, with orbital adnexal lymphomas accounting for 67% to 90% of orbital lymphoproliferative tumors and 24% to 30% of all space-occupying orbital tumors.[2][10] 

Metastases from other cancers constitute 1% to 3% of orbital tumors. Metastatic breast cancer is the most common, accounting for 48% to 53% of orbital metastases, followed by metastatic prostate carcinoma, melanoma, and lung cancer.[11] In children, neuroblastomas, Ewing sarcoma, Wilms tumor, and leukemias are the more common metastatic orbital lesions, while rhabdomyosarcoma is the most common primary malignancy.

Pathophysiology

Non-Hodgkin lymphomas, specifically the mucosa-associated lymphoid tissue (MALT) subtype of low-grade B-cell lymphoma, are the most common orbital lymphomas. Other histological subtypes include follicular lymphomas, diffuse large B-cell lymphomas, and mantle-cell lymphomas.

Various molecular and immunohistochemistry techniques can determine the oncogenes responsible for orbital tumors. For instance, BRAF mutation in orbital melanoma can be used to identify the cutaneous (metastatic) versus uveal (local) origin, and MYCN oncogene in neuroblastoma is indicative of aggressive behavior and high metastatic potential of the tumor. RAS and MET mutations are seen in epithelial lacrimal gland tumors, and the Rb gene is implicated in retinoblastoma.[5][11][12]

Histopathology

A tissue biopsy is necessary to make a pathological diagnosis. The characteristic histopathological features of some of the orbital tumors include the following:

• Orbital lymphomas: These tumors originate most commonly from B-cells. The histology shows atypical lymphocytic cells with nuclear membrane abnormalities. Immunologic markers are particularly valuable for precise diagnosis.[11][13]         
• Adenocystic carcinomas of the lacrimal gland: Tumors appear nonencapsulated and consist of generally bland-appearing epithelial cells arranged in nests or chords, thus forming a characteristic cribriform or Swiss cheese–like pattern.[11][13] 
• Hemangiopericytomas: These tumors appear histologically as dense, hypercellular tumors with spindle-shaped cells. The tumors are vascular with a variably dilated, vascular branching pattern classically described as staghorn vessels.[11][13]     
• Malignant nerve sheath tumors: The lesions are sarcomas and often lack a single tissue of origin at histologic analysis. However, the pathology can show spindle-cell neoplasms with necrotic foci, atypical mitoses, and the absence of differentiated cells that are S-100 positive on immunohistochemistry.[11][13]                       
• Squamous cell carcinomas: Nests of squamous cells with variable differentiation that may form keratin pearls. Intracellular bridges may be present.[14]                                                                                                
• Basal cell carcinomas: Basophilic cells that may display peripheral pallisading of the nuclei. The most common growth pattern is nodular, with pushing borders of aggregates of basal cells. Infiltrative growth pattern displays tendrils of cells extending deeply.[15]

History and Physical

The history focuses on orbital, ocular, and neurologic systems, but performing a complete initial history and physical examination is always important. Masses of the orbit are often slowly growing, and patients may report dull, aching eye pain, retro-orbital headache, or visual complaints like unilateral decreased vision or diplopia before any proptosis, exophthalmos, or vertical dystopia becomes evident clinically. A mnemonic known as 'the 6 Ps' (pain, progression, proptosis, pulsation, palpation, and periocular changes) has been developed to help focus a history and physical examination while ensuring completeness in evaluating for underlying orbital pathology.[16] Family history is often less relevant, as most orbital tumors are not germ-line mutations (some notable exceptions being retinoblastoma and neurofibromatosis).[17] Social history is most important to elucidate occupational exposures that may predispose to certain tumors (ie, sun exposure for cutaneous/eyelid SCC and BCC).

Physical examination will similarly focus on ocular, orbital, and neurologic symptoms but must also encompass the sinonasal cavities and neck if a malignant mass is suspected. Lesions in the intraconal space classically cause slow axial proptosis with compressive optic neuropathy, while lesions in the extraconal space are more likely to arise from periorbital structures such as the paranasal sinuses, skin, sensory nerves, or lacrimal gland tumors.[18] Symptoms such as unilateral nasal obstruction, epiphora, and recurrent unilateral epistaxis, in addition to ocular symptoms, may point towards orbital tumors secondary to sinonasal malignancy.

A complete ophthalmic examination, including visual acuity, pupillary response, extraocular muscle function, exophthalmometry, tonometry, and fundoscopy, is required. Skin, conjunctival, and corneal sensation, along with any lid lag, should also be documented. Findings such as tortuous conjunctival vessels or choroidal-retinal folds may point towards orbital pathology. For the measurement of ptosis, the margin-to-reflex distance, which is the distance in millimeters between the corneal light reflex to the upper eyelid (MRD1) or lower eyelid (MRD2), can be used to measure eyelid positioning, ptosis, lagophthalmos, ectropion, and scleral show. A complete cranial nerve examination is required, with special attention paid to V1, V2, V3, and any pain with ocular movements. Unilateral proptosis points more towards primary or secondary orbital pathology rather than a systemic disease like Graves ophthalmopathy. Asymmetry of >2 mm between the prominence of the 2 eyes is considered significant. Palpation may reveal a firm globe with restricted mobility, which is worrisome for orbital malignancy.[19][5][20]

Intranasal examination is warranted in cases of proptosis or suspicion of intraorbital mass and should include anterior rhinoscopy and nasal endoscopy. A thorough neck examination should also be undertaken to include the parotid glands and cervical lymph nodes.

Evaluation

Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are the main radiological modalities for evaluating suspected orbital malignancies. CT of the orbit, including head and paranasal sinuses, is done to see the extent of the lesion, especially as it relates to surrounding bony structures. Expansile or reactive changes to the orbit, as well as gross bony destruction, can both be seen and may hint at the aggressiveness of the underlying tumor.[21] Multiplanar thin-section MRI of the orbits with intravenous (IV) contrast is the optimal modality to delineate the soft tissue extent of the tumor. With such high-resolution imaging, it is possible to determine dural and brain involvement, as well as the extent of sinonasal involvement, by delineating tumor versus inspissated nasal secretions. Features such as diffuse lesions with irregular shapes and borders and involvement of periorbital vessels and nerves indicate malignant lesions rather than benign ones. Diffusion-weighted MRI and dynamic contrast-enhanced MRI studies help differentiate orbital lymphomas from inflammation and other low-grade malignancies. Ultrasonography of the orbit is usually reserved for pulsatile orbital masses like carotid-cavernous fistulas or cystic lesions and has less role in orbital malignancies.[22][23]

After radiological imaging, an orbital biopsy is typically required to obtain a histologic diagnosis, and an incisional biopsy is usually sufficient to make a histopathological diagnosis of a suspected malignant orbital mass. Orbital apex, optic nerve, or periocular muscles should be avoided while taking the biopsy. The lesions confined to the orbital bony walls or the ones that are encroaching less onto surrounding regions like an intracranial cavity or paranasal sinuses can be biopsied via orbital routes like upper eyelid incision or superomedial lid incision with anterior orbitotomy for superiorly and medially based lesions, lateral orbitotomy for orbital apex lesions, and transconjunctival lower anterior orbitotomy for inferiorly based lesions. For orbital malignancies that have extended into the paranasal sinuses or nasal cavity, the endoscopic trans-nasal route is often preferred to obtain a biopsy. Transcranial routes for biopsy are avoided due to the high risk of morbidity. If metastatic cervical lymphadenopathy is present, fine-needle aspiration of the metastasis is often the easiest and safest route to obtain a diagnosis.[24][25]

Treatment / Management

The treatment strategy for orbital malignancy, like any other malignancy, depends upon the extent of the tumor involvement, histopathological type, and tumor stage.

Medical treatment

Of all orbital malignancies, medical treatment (radiation therapy, chemotherapy, and/or immunotherapy) is most commonly used curatively for orbital adnexal lymphomas. For early local tumors, radiotherapy is the primary modality of treatment. Patients with advanced disease and high-grade tumors are treated with chemotherapy followed by local radiation. The standard chemotherapy regimen includes cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP). Rituximab, a monoclonal antibody directed against B-cell specific surface receptor CD20, is used in cases of non-Hodgkins B-cell lymphoma like diffuse large B-cell lymphoma. Surgery has a minimal role in orbital lymphomas.[26][27][28]                 

Surgical treatment

Surgical treatment is the primary modality of treatment in resectable orbital tumors. The extent of resection depends upon the tumor stage, histology, and primary site and can include local resection, exenteration, or radical exenteration. See StatPearls' companion reference, "Lacrimal Gland Malignancies," for more information.[29] The elective neck dissection and ipsilateral parotidectomy should be discussed in advanced-stage epithelial tumors and are indicated in solid histological subtypes or when there is high-grade malignant degeneration like in carcinoma in pleomorphic adenoma and other high-grade tumors like adenocystic carcinomas. Adjuvant radiotherapy is indicated postsurgery in most of the tumors for local control after surgery, and brachytherapy for tumors with R1 resection is also a feasible option.[26] 

See Statpearls' companion references, "Retinoblastoma" and "Ocular Melanoma," for more information.[30][31]

Differential Diagnosis

Patients presenting with decreased or double vision, ophthalmoplegia, chemosis, and proptosis should raise concerns for orbital malignancy. However, other conditions should be kept as differentials because they can mimic orbital malignancy as follows:

Nonspecific orbital inflammation

• Also known as orbital pseudotumor, it is a benign, space-occupying, and noninfectious inflammatory condition of the orbit, which may also involve periorbital structures. The exact etiology is unknown, and the histopathology consists of a pleomorphic inflammatory cellular response with a fibrovascular reaction. The commonly encountered presentation is a palpable orbital mass with ptosis and periorbital edema, which may mimic orbital malignancy. Most patients respond well to corticosteroids, but immunomodulatory therapy may be given in selected cases.[32]

IgG-4-related orbital disease

• This is a systemic disease that usually presents as lid swelling and proptosis. The proptosis may point towards an orbital mass, but patients typically have minimal signs like mild periorbital pain, unlike in orbital malignancy, in which patients may have pain due to tumor hemorrhage or inflammation. Laboratory analysis shows elevated serum levels of IgG4, IgE, and hypergammaglobulinemia. Patients respond to corticosteroids, but relapse is common. Therefore, azathioprine or rituximab are combined with steroid therapy.[33]

ANCA-related vasculitis

• ANCA-related vasculitis like granulomatosis with polyangiitis with or without eosinophilia and sarcoidosis can mimic orbital malignancy due to the involvement of orbital adnexal tissue. The symptoms can vary depending on the extent of tissue involvement. A tissue biopsy is usually required to diagnose and differentiate it from orbital malignancy.

Tolosa-Hunt syndrome

• This is idiopathic inflammation in the region of the cavernous sinus and/or superior orbital fissure, resulting in severe unilateral pain and ophthalmoplegia. The absence of a palpable orbital mass or severe proptosis can help differentiate it from an orbital malignancy. The diagnosis is usually made in retrospect after there is a dramatic response of pain and almost complete resolution of ophthalmoplegia to steroids. MRI can show inflammation in the orbital apex, which resolves after administering steroids. Tissue biopsy is rarely required.[34]

Langerhans cell histiocytosis

• Orbital involvement in Langerhans cell histiocytosis can occur in approximately 20% of the patients and can present with unilateral proptosis similar to orbital malignancy with varying degrees of ophthalmoplegia and visual loss. CT shows typical ‘punched out’ lytic lesions, and diagnosis is by excisional biopsy. Treatment varies, ranging from observation, curettage, radiation, chemotherapy, or surgical excision, depending upon the extent of involvement.[35]

Benign orbital tumors

• Hemangioma is the most common benign intraorbital tumor in adults; dermoid is the most common benign congenital mass.                                                                                                                                
• Leiomyomas, meningiomas, nerve sheath tumors, neurofibromas, and Warthin tumors have all been described intraorbitally, and all are rare.[36]

Surgical Oncology

Surgery remains the primary treatment modality for most orbital malignancies that are surgically resectable, and achieving oncologic resection frequently involves sacrifice of the globe. If the tumor has extended into structures that would render it unresectable (brain parenchyma, orbital apex, etc), radiation therapy and chemotherapy have been used in an induction protocol to be followed by surgical resection if the tumor shrinks to where it becomes resectable.[37][38]

Lateral orbitotomy is a safe approach for many extraconal lateral tumors. The extent of lateral orbitotomy depends upon the size, consistency, and nature of the lesion for easy removal and less bony resection. Medial and inferior orbitotomy are combined depending on the location of the tumor. The trans-nasal endoscopic route can be used in conjunction with an open approach for medially located tumors. An open approach for orbital malignancies involving the sinonasal cavity can be achieved by Moure incision along the lateral nasal bone with Diffenbach or Weber and Ferguson extension, depending upon the extension of the tumor. Other open approaches for extensive tumors include bitemporal coronal incision, transmaxillary, transfrontal, midfacial degloving, and facial dismasking approaches.[39][40][41]

Surgical removal of large tumors or orbital contents leads to large defects with potential exposure of the dura or brain. In smaller defects, autografts, xenografts, synthetic materials such as titanium mesh or plates, polyethylene nets, etc, have all been used to successfully reconstruct orbital walls. Suspensionplasty using the temporalis muscle offers the possibility of reducing the size of the resection cavity to facilitate care or ease in fitting a prosthesis. Goals of orbital reconstruction must be established when planning the oncologic resection. Most critical is ensuring complete tumor resection followed by coverage of all critical structures (brain). Following that, orbital reconstruction may be undertaken with the goal of creating a pocket in which to place a prosthesis or may simply involve filling in the resection cavity with tissue. Local and regional flaps such as pericranial and temporoparietal remain workhorses in re-lining reconstructed orbits in preparation for prosthesis. This is often combined with skin grafting. Larger defects, or reconstruction where the goal is simply the obliteration of cavity space, are frequently undertaken with free tissue transfer, with the anterolateral thigh, radial forearm, and latissimus dorsi, among many other flaps routinely used.[42][3][43]

Radiation Oncology

Radiation therapy is frequently used in the adjuvant management of advanced orbital malignancy, though it can be used as a primary treatment modality (both curative and palliative) in patients who are not surgical candidates.[44] Although high-dose external beam radiation therapy is a useful adjuvant treatment for orbital malignancies, it has also been linked to serious toxicity that can affect any area of the orbit, eye, or adnexa. Therefore, volumetric-modulated arc therapy, which is a type of intensity-modulated radiation therapy (IMRT), has been used to mitigate many of these adverse effects. This therapy reduces exposure to vital structures and allows for the potential of higher doses to the tumor or surgical bed. 

Over the past 10 years, proton radiation therapy (PRT) has also been utilized increasingly frequently as an option for radiation treatment of orbital malignancies. It results in lower doses immediately adjacent to the target volume and allows for total tissue sparing outside the target volume for a given beam. Like PRT, carbon-ion radiotherapy (CIRT) presents a new promising treatment option for tumors resistant to conventional radiotherapy. Radiation-induced optic neuropathy can cause visual loss or defects in visual fields depending on the area of the optic pathway affected. If the maximum dose to the optic nerve remains <54 to 55 Gy, radiation-induced optic injury is rare, but it is best to keep below 50 Gy if possible and as low as reasonably possible.[45][44]

A report by the American Academy of Ophthalmology evaluating 27 studies comprising 2009 patients demonstrated the efficacy of radiation treatment for ocular lymphoma. The report evaluated cases of extranodal marginal zone lymphoma and mucosa-associated lymphoid tissue and found that the 5-year and 10-year survival rates in patients receiving radiation therapy were 93.8% and 84.9%, respectively. They also concluded that for MALT lymphomas, local control, disease-free survival, and overall survival were good with radiation treatment, and the results of treatment of non-MALT lymphomas using radiotherapy were also good, but they were not as favorable as the treatment results of MALT lymphomas.[46]

Pertinent Studies and Ongoing Trials

Currently, most malignant orbital tumors involve the use of radiotherapy in conjunction with surgery. When the surgery involves orbital exenteration, the role of radiotherapy becomes even more important. For instance, orbital exenteration was the gold standard treatment for orbital rhabdomyosarcoma until the 1960s, and it was associated with a 70% mortality if performed alone.[47] However, radiotherapy forms a major part of the treatment of rhabdomyosarcomas currently. The Intergroup Rhabdomyosarcoma Study Group (IRSG) recommendations summarize the current protocols for rhabdomyosarcomas.[48] With regards to intraocular tumors, the treatment of choroidal melanoma, which is the second most common type of intraocular tumor, was well-studied in the Collaborative Ocular Melanoma Study.[49]

Medical Oncology

The treatment of advanced local disease and metastatic disease is often> treated with chemotherapy followed by local radiation. The regimen often follows the CHOP protocol (cyclophosphamide for 375 mg/m², hydroxydaunorubicin for 50mg/m², oncovin for 1.4mg/m², and prednisone for 40mg/m²), with rituximab (375mg/m²) often given in conjunction to the protocol. Additional treatment regimens include RICE (rituximab for 375 mg/m², ifosfamide for 5000 mg/m², carboplatin optimized for a maximum of 790mg, and etoposide for 100 mg/m²). All treatments are given as an IV infusion or IV bolus. The RICE protocol is often used in the salvage treatment of relapsed or refractory Hodgkin and non-Hogkin lymphomas.[50][51]

Staging

Historically, the most commonly used staging system for ocular adnexal lymphomas was the Ann Arbor Staging system, though the Lugano Staging has largely supplanted this to incorporate PET/CT findings. The TNM classification is the most commonly employed lymphoma staging based on the American Joint Committee on Cancer (AJCC) 8th Edition. However, regardless of staging, the recurrence and disease-free survival are more closely related to tumor histopathology and treatment modality.[52][53][54] Other orbital malignancies (sarcoma, carcinoma) are staged according to the AJCC 8th edition TNM classification.

Ann Arbor Staging of Lymphoma

• Stage I: involvement of a single lymph node region or of a single extralymphatic organ or site
• Stage II: involvement of 2 or more lymph node regions on the same side of the diaphragm or localized involvement of an extralymphatic organ or site 
• Stage III: involvement of lymph node regions or structures on both sides of the diaphragm
• Stage IV: diffuse or disseminated involvement of 1 or more extralymphatic organs, or either: 
  • isolated extralymphatic organ involvement without adjacent regional lymph node involvement, but with disease in distant sites
  • involvement of the liver, bone marrow, pleura, or cerebrospinal fluid

Additional substaging variables include the following:

• A: asymptomatic
• B: presence of B symptoms (including fever, night sweats, and weight loss of ≥10% of body weight over 6 months)
• E: involvement of a single, extranodal site, contiguous or proximal to a known nodal site (Stages I to III only; additional extranodal involvement is Stage IV)
• S: splenic involvement
• X: bulky nodal disease: nodal mass larger than one-third of intrathoracic diameter or 10 cm in dimension

Lugano Staging of Lymphoma

Limited

• Stage I: 1 node or group of adjacent nodes
• Stage IE: single extra-lymphatic site in the absence of nodal involvement                                                
• Stage II: 2 or more nodal groups, same side of the diaphragm
• Stage IIE: contiguous extra-lymphatic extension from a nodal site with or without involvement of other lymph node regions on the same side of the diaphragm.

Advanced

• Stage III: nodes on both sides of the diaphragm; nodes above the diaphragm with spleen involvement
  • Stage III(1): involvement of the spleen or splenic, hilar, celiac, or portal nodes
  • Stage III(2):  involvement of the para-aortic, iliac, inguinal, or mesenteric nodes                                    
• Stage IV: diffuse or disseminated involvement of 1 or more extranodal organs or tissue beyond that designated E, with or without associated lymph node involvement
  • all cases to indicate the absence (A) or presence (B) of systemic symptoms (fever/night sweats/unexplained weight loss)                                                                                                               
  • designation of (E) refers to extranodal contiguous extension that can still be encompassed within an irradiation field appropriate for nodal disease of the same anatomic extent (if more extensive than that, label as IV)                                   
  • designation of (bulky) if a single nodal mass >10 cm or larger than one-third of the transthoracic diameter

AJCC 8th Edition Orbital Adnexal Lymphoma Staging

Tumor (T)

• T0: No evidence of lymphoma
• T1: Lymphoma involving the conjunctiva alone without eyelid or orbital involvement
• T2: Lymphoma with orbital involvement with or without conjunctiva involvement
• T3: Lymphoma with preseptal eyelid involvement with or without orbital involvement and with or without conjunctival involvement
• T4: Orbital adnexal lymphoma and extraorbital lymphoma extending beyond the orbit to adjacent structures, such as bone, maxillofacial sinuses, and brain

Nodes (N)

• N0: No evidence of lymph node involvement
• N1: Involvement of lymph node region or regions draining the ocular adnexal structures and superior to the mediastinum
• N1a: Involvement of a single lymph node region superior to the mediastinum
• N1b: Involvement of 2 or more lymph node regions superior to the mediastinum
• N2: Involvement of lymph node regions of the mediastinum
• N3: Diffuse or disseminated involvement of peripheral and central lymph node regions

Metastasis (M)

• M0: No evidence of involvement of other extranodal sites
• M1: Involvement of other extranodal sites
• M1a: Noncontiguous involvement of tissues or organs external to the ocular adnexa (eg, parotid glands, submandibular gland, lung, liver, spleen, kidney, breast)
• M1b: Lymphomatous involvement of the bone marrow
• M1c: Both M1a and M1b involvement

AJCC 8th Edition Orbital Sarcoma Staging

Tumor (T)

• TX: primary tumor cannot be assessed
• T0: no evidence of primary tumor
• T1: tumor ≤15 mm in greatest dimension
• T2: tumor >15 mm in greatest dimension without invasion of globe or bony wall
• T3: tumor of any size with invasion of orbital tissues or bony walls
• T4: tumor invasion of globe or periorbital structure, such as eyelids, temporal fossa, nasal cavity and paranasal sinuses, or central nervous system

Nodes (N)

• NX: regional lymph nodes cannot be assessed
• N0: no regional lymph node metastasis
• N1: regional lymph node metastasis

Metastasis (M)

• M0: no distant metastasis
• M1: distant metastasis

AJCC 8th Edition Cutaneous Carcinoma of the Head and Neck Staging

Tumor (T)

• TX   Primary tumor cannot be assessed
• Tis   Carcinoma in situ
• T1   Tumor ≤2 cm in greatest dimension
• T2   Tumor > 2 cm but ≤4 cm in greatest dimension
• T3   Tumor > 4 cm in maximum dimension or minor bone erosion or perineural invasion or deep invasion*
• T4   Tumor with gross cortical bone/marrow, skull base invasion and/or skull base foramen invasion
• T4a   Tumor with gross cortical bone/marrow invasion
• T4b   Tumor with skull base invasion and/or skull base foramen involvement

* Deep invasion is defined as invasion beyond the subcutaneous fat or >6 cm (as measured from the granular layer of adjacent normal epidermis to the base of the tumor); perineural invasion for T3 classification is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression.

Nodes (N) 

Clinical N (cN)

• NX   Regional lymph nodes cannot be assessed
• N0   No regional lymph node metastasis
• N1   Metastasis in a single ipsilateral lymph node ≤3 cm in greatest dimension and no extranodal extension (ENE [-])
• N2    Metastasis in a single ipsilateral lymph node >3 cm but not more than 6 cm in greatest dimension and ENE (-); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE (-); or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE (-)
• N2a   Metastasis in a single ipsilateral lymph node >3 cm but not more than 6 cm in greatest dimension and ENE (-)
• N2b   Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE (-)
• N2c   Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE (-)
• N3   Metastasis in a lymph node >6 cm in greatest dimension and ENE (-); or metastasis in any node(s) with clinically overt ENE (+)
• N3a   Metastasis in a lymph node >6 cm in greatest dimension and ENE (-)
• N3b   Metastasis in any node(s) with clinically overt ENE (+) 

Pathological N (pN)

• NX   Regional lymph nodes cannot be assessed
• N0   No regional lymph node metastasis
• N1   Metastasis in a single ipsilateral lymph node ≤3 cm in greatest dimension and ENE (-)
• N2   Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE (+); or a single ipsilateral lymph node >3 cm but not more than 6 cm in greatest dimension and ENE (-); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE (-); or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE (-)
• N2a   Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE (+); or a single ipsilateral lymph node >3 cm but not more than 6 cm in greatest dimension and ENE (-)
• N2b   Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE (-)
• N2c   Metastasis in bilateral or contralateral lymph node(s), none >6 cm in greatest dimension and ENE (-)
• N3   Metastasis in a lymph node >6 cm in greatest dimension and ENE (-); or in a single ipsilateral node > 3 cm in greatest dimension and ENE (+); or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE (+); or a single contralateral node of any size and ENE (+)
• N3a   Metastasis in a lymph node >6 cm in greatest dimension and ENE (-)
• N3b   Metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE (+); or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE (+); or a single contralateral node of any size and ENE (+)

Metastasis (M)

• cM0   No distant metastasis
• cM1   Distant metastasis
• pM1   Distant metastasis, microscopically confirmed

Prognosis

The prognosis of orbital malignant tumors depends upon the histological type and stage. For orbital adnexal lymphomas (OALs), Rath et al proposed a scoring system for prognostication based on their laterality and node/metastatic status. They divided the patients into 3 groups: Group 1 with unilateral OALs with no nodes or metastasis, Group 2 with either bilateral or positive nodes/metastasis, and Group 3 with bilateral OALs with positive nodes/metastasis. The 10-year progression-free survival was 75%, 50%, and 0 in these groups, respectively.[54] 

Overall, 5-year survival for orbital rhabdomyosarcoma with combined surgical and medical treatment is >90%.[55] The prognosis of malignant orbital melanomas remains poor.[56]

Complications

Understanding the potential complications associated with malignant orbital tumors is essential for clinicians managing these complex conditions, as they significantly impact patient outcomes and treatment strategies. Complications include the following:

Tumor-related complications: Complete ophthalmoplegia, visual loss, superadded infection leading to periorbital cellulitis, extension into adjoining areas like the nose and paranasal sinuses leading to unilateral nasal obstruction or recurrent epistaxis, or extension to the intracranial cavity leading to meningismus.

Surgery-related complications: Patients with orbital malignancies suitable for surgery usually undergo wide local excision or orbital exenteration, leading to a non-aesthetic orbital cavity requiring reconstruction, which further leads to flap-related complications. Intraoperative complications include injury to the skull base or dura leading to a cerebrospinal fluid leak in addition to the usual risk of bleeding, compressive hematoma, vision loss, injury to the lacrimal duct leading to epiphora, cosmetic deformities, enophthalmos, and exposure keratopathy in the case of globe preservation surgeries.

Radiotherapy-related complications: Radiotherapy-related complications include damage to the radiosensitive lens, lacrimal gland, and retina located near or within the target volume.