Journal of Cytology
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Year : 2007  |  Volume : 24  |  Issue : 1  |  Page : 30-36
Neoplastic lesions of eyelids, eyeball and orbit

1 Ophthalmic Pathology Service, LV Prasad Eye Institute, Hyderabad, India
2 Department of Pathology, Kota Medical College, Rajasthan, India

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Keywords: Neoplastic lesions, eye

How to cite this article:
Vemuganti G K, Rai N N. Neoplastic lesions of eyelids, eyeball and orbit. J Cytol 2007;24:30-6

How to cite this URL:
Vemuganti G K, Rai N N. Neoplastic lesions of eyelids, eyeball and orbit. J Cytol [serial online] 2007 [cited 2021 Sep 21];24:30-6. Available from:

   Introduction Top

Neoplastic lesions occurring within and around eyelid, eyeball and orbit spanning an area of about 4­5 cm, not surprisingly could display the entire gamut of lesions that one sees between head and foot! The soft tissues of the lid, conjunctiva, ocular surface, various layers of the eyeball and the orbital soft tissues are unique in many ways. Many of the tissues are neuroectodermal in derivatives hence the neoplastic lesions of these tissues display much more variation than similar tumours in other parts of the body.[1] It is not the scope of this symposium to describe each and every lesion of this region, however we intend to describe in brief the cytologic appearance of the lesions that are most commonly seen in clinical practice and which influence the surgical management in patients.

   Cytology of Eye-lid Tumours Top

The common lid tumours include basal cell carcinoma, squamous cell carcinoma, melanoma, sebaceous gland carcinoma, Merkel cell tumour and metastatic lesions.[1] The cytology specimens could be either from FNAC, scrape, squash or imprint cytology.

Sebaceous Gland Carcinoma: Sebaceous gland carcinoma (SGC) of eyelid arises from  Meibomian gland More Detailss located in tarsal plate; glands of Zeiss associated with eyelashes, sebaceous glands found in caruncle and eye brow skin. They are more common and more aggressive than their cutaneous counterpart, and are most lethal ocular adnexal tumour, second only to melanoma. SGC frequently masquerades as other less aggressive eye lid lesions like chalazion, chronic blepharo-conjunctivitis, kerato-conjunctivitis, meibomianitis, papilloma, basal cell carcinoma, squamous cell carcinoma and carcinoma-in-situ. [2] Early diagnosis is thus of extreme importance to avoid high morbidity and mortality (23%). SGC is more frequent in upper eye-lid (2/3rd cases), in females, Asians and elderly (>40 years). Sometimes a proven case of sebaceous gland carcinoma can present with lymph node enlargement and may require a cytologic confirmation of metastasis for further management. [7] SGC can also be scraped, but more often a nodular swelling or a recurrent chalazion is target for FNAC. The smears are highly cellular and demonstrate sheets, three-dimensional clusters, and singly scattered polygonal tumour cells having centrally located hyperchromatic and pleomorphic nuclei and cytoplasmic microvacuolations. Oil red-O stain performed on air-dried smears showed orange intracytoplasmic globules, confirming the presence of intracellular and extracellular lipid globules. Two types of tumour cells can be seen: large pale cells and vacuolated cytoplasm- differentiating toward sebaceous gland; the other demonstrated poorly­differentiated cell with dark and irregular nuclei. [3] Sometimes the tumour cells may demonstrate basaloid, fusiform or squamous features, corresponding to various histopathological types. Many mitoses can be seen in these cells. The differential diagnosis include Chalazion which show inflammatory lipo-granuloma; pilomatrixoma which show bland sheets of basaloid cells, nucleated basophilic cells and "ghost" cells. Basal Cell Carcinoma show less cellular smears and tightly cohesive small clusters of monomorphic basaloid cells without vacuolation. An important histologic feature of sebaceous gland carcinoma is the tendency for pagetoid spread, involving the overlying skin and mucosa. This could erroneously be reported on cytology (impression of brush) as well as in histology as squamous cell carcinoma-in-situ. [5]

Basal Cell Carcinoma: Most common malignancy of eye-lid (80-90%). Most frequently occur in lower eye-lid, followed by medial canthus, upper eye-lid and lateral canthus. BCC is common in males, Caucasians and older individuals (>60 years). Usually present with a non-healing ulcer that often bleeds with mild trauma. Nodular type presents as pearly white nodule with small telangiectatic vessels- it ulcerates as it enlarges. Scalloping (morphea) type presents as pale, well-defined indurated plaque. Lesion can become pigmented (melanin or haemosiderin) and mimic melanoma, become cystic mimicking benign inclusion cyst. Neglected tumours invade orbital and facial structures ("rodent ulcer"). Pre-operative and pre­radiotherapy diagnoses are indications for cytology. Cytology is sufficiently accurate, but its sensitivity is said to be limited when planning surgical management. [6] FNAC from nodular lesions and scrape from ulcerated lesions are effective sampling techniques. Cytology smears are less cellular than SGC; show tightly cohesive small clusters of uniform hyper­chromatic basaloid cells with high Nuclear-cytoplasmic ratio and absence of cytoplasmic vacuolation. Peripheral palisading of nuclei may be evident in some clusters. Squamous, sebaceous and adenoid differentiation may be seen and pigmented variant may be seen.

Squamous Cell Carcinoma: Usually involve the lower lid margin in elderly fair-skinned persons. In upper eye-lid and lateral canthus, it is more common than BCC. Most commonly arises from actinic keratosis. Bowen's Disease, radiation dermatitis and xeroderma pigmentosa are other precursor lesions. It present as single elevated nodule or plaque with irregular borders. Cytology can help surgeon in planning wide excision. Scrape smears are rich in inflammatory exudates. FNA from elevated margin provide diagnostic yield. Smears show markedly enlarged hyper-chromatic nuclei of variable size and keratinization.

   Cytology of Intra-ocular Tumours Top

Cytology specimens of intraocular lesions though rare, are of utmost importance. These could be obtained either by trans-ocular fine needle aspiration cytology, from imprint or squash smears of eviscerated specimens. Transocular fine needle aspiration cytology is a safe and reliable diagnostic method for suspected intraocular tumours and inflammatory conditions in which noninvasive diagnostic modalities have failed to establish the diagnosis and in which cytologic verification of the diagnosis is necessary to institute appropriate treatment. [7] FNAC of Intra-ocular tumours has also been used to confirm the clinical diagnosis when the patient or their parents requested pathological confirmation prior to consenting to planned treatment. [8]

   Cytology of Intraocular Space Occupying Lesions Top

Melanoma: Ocular melanomas include lesions of uvea, conjunctivae and eyelids. More than 85% of all ocular melanomas are uveal. Choroid is the most frequent location (80%) of uveal melanoma, followed by ciliary body (10-15%) and iris (5-8%). Uveal melanomas are rare tumours (6-7 cases per million people per year), but remain the most common primary intra-ocular malignancy in adults, most commonly occur in middle aged and older whites. [9] They arise from melanocytes of uveal stroma and initially oval in configuration, but many (63%) extend through Bruch's membrane and proliferate in the sub­retinal space giving mushroom or collar button configuration.

Histologically tumours are classified into spindle cell type A and B and epithelial type. [10] Cytologically Type A spindle melanomas are difficult to recognize. Aspirates contain a monotonous population of small spindle cells with slender cytoplasmic extensions, resembling smooth muscle cells. Nuclei are oval and granular with prominent nuclear crease (fold) along the long axis and have small nucleoli. Pigmented cells are few. In Type B spindle cell melanomas the aspirate contains abundant cancer cells forming bundles. The cells are larger than in type A and have long fragile bipolar cytoplasmic processes. The nuclei are hyperchromatic, coarsely granular with large nucleoli. Intranuclear cytoplasmic inclusions can be seen.

Epithelial melanomas are easiest to recognize and show large polygonal cells having eccentric nuclei with marked nuclear abnormalities, binucleation and multinucleation. Nucleoli are distinct and intranuclear cytoplasmic inclusions are seen. Cytoplasm usually has abundant melanin. Bipolar pigmented cells and cells resembling dendrites with multiple cytoplasmic extensions also seen. [11]

Smears may have a pure spindle cell pattern, pure epithelial pattern or a mixed pattern. Tumours composed of pure spindle cell A are rare and now classified as benign spindle cell nevi. Tumours with pure epithelial cell pattern are also rare. Most cases show a variable number of spindle A, spindle B and epithelial cells.

Metastatic lesions: These could present as nodules in iris, ciliary body, retina with vitreous hemorrhage and mimic inflammatory and other neoplastic lesions and could be the first manifestation of an occult primary. Uveal tract being the vascular tissue of the eye is the common site to harbor metastatic lesions. In infants and children, neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma may involve the eye. In adult women mammary carcinoma is most common metastatic tumour. In adult men, carcinoma of lung, prostate, gastrointestinal tract and kidney may be found. The clinical appearance, multiplicity of the lesions, and detailed clinical history and examination usually helps in identifying a metastatic lesion. [2] The morphological appearance is similar to that of the primary tumour. In our experience, carcinoma from breast, lung and renal cell carcinoma were common. We also reported rare cases of metastatic hepatocellular carcinoma. [12]

Leukemic deposits: These deposits could be seen in iris, ciliary body and mimic a metastatic lesion or a granuloma. The presence of monomorphic round cells with loss of cohesion, vesicular nucleus should raise a suspicion of leukemic deposits.

Retinoblastoma: Retinoblastoma is the most common intra-ocular tumour of childhood (<2 years) and most common tumour of retina; though overall a rare malignancy. Retinoblastoma is a neuroblastic tumour arising from any of the nucleated retinal layer. Clinically presents as white eye (leukocoria), strabismus or diminished vision. About 10% cases masquerades as orbital inflammation. [2] It frequently spread intra-ocularly producing macroscopic retinal and vitreous seeding, occasionally reaching anterior segment. It also invades optic nerve and brain, seeding malignant cells in cerebrospinal fluid (CSF). Invasion into choroids, metastasis in bone marrow, cervical and pre-auricular lymph nodes usually occur. [13]

Cytodiagnosis of retinoblastoma can be done in CSF, vitreous and anterior chamber aspirates and bone marrow aspirate. FNAC of primary tumour or cervical lymph node can be done. Intra-ocular FNAC however is rarely needed as majority of cases can be diagnosed and treated without invasive procedures [14] However from the experience of a few cases and the squash smears made from the freshly enucleated eyeball serves as a teaching material to identify this lesion. Akhtar et al [15],[16] described FNA smears revealing small markedly undifferentiated cells with frequent mitoses and apoptosis. Nuclei are hyperchromatic without nucleoli. Cells are found singly or in molded aggregates. Evidence of tumour cell phagocytosis is seen (Type I cells). Differentiated tumours show cells having cytoplasmic processes and forming well-defined structures in variable number- corresponding to Flexner-Wintersteiner rosettes or fleurettes (Type II cells). Calcification could be seen in the background and with the aid with B scan findings clinches the diagnosis of retinoblastoma. We had one case of tumour seedlings in the silicone oil, which was introduced as tamponade for retinal detachment, which occurred after local treatment for retinoblastoma. The direct smears made from emulsified silicone oil removed during the re-surgery showed clumps of tumour cells.

Medulloepithelioma: Medulloepithelioma is a tumour of ciliary body and is usually seen in children. [17] Though most lesions present with classical features that can be diagnosed by clinical findings, ultrasound and bio-microscopy, the type of lesion can be commented upon by histopathology. The lesion could be benign, malignant, teratoid or non-teratoid. Though in most of the cases, it remains an intraocular lesion, there are case reports of medulloepithelioma with extra ocular spread and with local or distant metastasis. These lesions are either left alone, or in rapidly growing lesions, it is excised. Sometimes, it is required to confirm the diagnosis before the child is taken for enulceation hence it is important to know the cytologic features. The smears are cellular and show variable cells consisting of round undifferentiated cells seen singly or in clumps. Rosettes or tubular structures can also be identified. Cytologic features of malignancy if found, can be useful, however extra ocular extension and infiltration is the final diagnosis of malignancy, which can be provided, only by histologic diagnosis.

   Vitreous Cytology Top

Vitreous is the natural medium of the posterior segment. The common indications of vitreous biopsy include endoophthalmitis, lymphoma, and masquerading syndromes. [18] All samples can be subjected to conventional cytologic procedures, and based on the availability of techniques and expertise, it could be subjected to immunocytochemistry and clonality analysis using polymerase chain reaction. Compared to the unfixed vitreal specimens, the quality of the cytomorphology and immunohistochemistry improves in the HOPE-fixed specimens. IgH-PCR and GeneScan analysis demonstrates polyclonal amplification products in the reactive cases, and monoclonal B-cell populations in the B-PIOL. [19] The specimens can be evaluated for cellularity, cellular appearance, cytoplasmic and nuclear features as well as quality of the immunostains.

Lymphoma: Primary intraocular lymphoma (PIOL) is a rare non-Hodgkin lymphoma, which arises in the retina or the vitreous. Though the diagnosis of intraocular lymphoma with immunostaining was reported in 80's, there have been many advances in terms of obtaining the specimen, diagnosis, classification and use of newer modalities. [20],[21],[22] It can occur either together with or independently of primary cerebral nervous system lymphoma (PCNSL); the incidence of the latter has significantly increased over the past three decades. PIOL remains one of the most difficult diagnoses to establish, particularly due to its ability to mimic other diseases in the eye and to the limited material, which is often available for examination. The differential diagnoses, including other lymphomatous manifestations in the eye, e.g. primary uveal lymphoma, as well as non-neoplastic uveal diseases. B-cell lymphoma of retina and central nervous system is a large B cell lymphoma with extensive necrosis. Its incidence is rising because of, and also independent of rising incidence of AIDS and transplant recipient. It is seen in elderly persons (5th to 7th decade). It clinically presents as refractory uveitis and vitritis and because of masquerading as orbital inflammation, poses a diagnostic challenge. [2] Early diagnosis is essential because of its aggressive course. Cytodiagnostic modalities include examination of cerebrospinal fluid; vitreous, anterior chamber aspirate and intra-ocular fine needle aspiration of retina or uveal lesions. The abnormal lymphoid cells are large (2-4 times the size of a lymphocyte) and have a high nuclear/cytoplasmic ratio, prominent nucleoli, irregular nuclear contours and a fine to coarse chromatin pattern. The cells may be admixed with degenerating inflammatory cells.

   Cytology of Orbital Tumours Top

Orbit is a bony cage giving support to the eye and the surrounding orbital tissues. [1] The lesions that can occur in orbit are innumerable and similar to those seen in all the soft tissues of the body. Compared to the other lesions of the eye, orbital lesions are most commonly accessed tumours. [22],[23] we have also reported the utility and ease with which squash and imprint cytology can be applied to orbital lesions for intra-operative diagnosis. [24] The common neoplastic lesions encountered are mentioned here.

Lacrimal Gland Tumours: Lacrimal gland tumours pose common diagnostic problems in clinical practice and have been well documented in literature. [26],[27] Similar to the salivary gland lesions, fortunately most of the lesions can be well recognized on cytology.

Adenoid cystic carcinoma: The most common malignant tumour of lacrimal gland. The smears show the characteristic features of basaloid cells in sheets, finger like processes, lacy pattern and the classical 3­dimensional cell balls with minimal nuclear pleomorphism. Basement membrane globules are seen between the cell groups- stained bright magenta

by MGG. [27]

Pleomorphic adenoma: The common benign tumour is pleomorphic tumour, which usually is excised in toto and rarely comes in for a cytologic diagnosis. [28] However some times atypical presentations like rupture of capsule and infiltrative lesions with osseous metaplasia can mimic an infiltrating tumour with bone involvement. The characteristic biphasic pattern with myxoid fibrillar stromal fragments specially in MGG stained smears clinches the diagnosis in most cases.

Adenocarcinoma: of lacrimal glands situated in the peri-ocular orbital space behaves as space occupying lesion exerting significant pressure on globe, alter vision and cause proptosis. FNAC as a minimally invasive procedure is an efficient, reliable, timely, safe and cost-effective mode of pre-operative diagnosis. [25] Eccrine Adenocarcinoma arising from eccrine sweat glands of lid skin and apocrine carcinoma arising from glands of Moll are rare tumours.

Rhabdomyosarcoma: Rhabdomyosarcoma is most common orbital malignancy of childhood, usually seen in 1 st decade. RMS develops from pleuripotential mesenchymal stem cells. Embryonal RMS is most common subtype and has better survival than alveolar RMS. Rarely Botryoid and Pleomorphic subtypes also seen. Majority of ophthalmic RMS are located in orbit (76%), followed by conjunctiva (12%), eye-lids (3%) and uveal tract (9%). RMS clinically present as rapidly progressing proptosis and displacement of globe, swelling and edema of eye-lid, blepharoptosis and palpable sub-conjunctival nodule with chemosis. Most common orbital location is superior quadrant. [29] The cytology smears show cells of varying size and shape containing moderate to abundant amount of cytoplasm staining deep blue and containing occasional small glycogen vacuoles. Few cells show ill-defined relatively dense cytoplasmic inclusion. Tumour cells are found singly, but loose clusters also seen. Based on degree of myogenic differentiation Akhtar et al [30] divided Rhabdomyoblasts into 3 categories- Early Rhabdomyoblasts are round undifferentiated cells with high Nuclear: Cytoplasmic ratio. Intermediate Rhabdomyoblasts have relatively abundant pale staining cytoplasm and one or more irregular nuclei with occasional nucleoli. Late Rhabdomyoblasts contain abundant cytoplasm staining grayish blue and opaque. These cells vary from round to markedly elongated. Some cells show localized inclusion like grayish blue area within cytoplasm. Some intermediate and Late Rhabdomyoblasts show extremely large and pleomorphic nuclei. Embryonal RMS shows many intermediate and late Rhabdomyoblasts, whereas Alveolar RMS shows monomorphic early Rhabdomyoblasts with scanty late Rhabdomyoblasts and only rare late Rhabdomyoblasts. Akhtar et al also studied and correlated pediatric small blue round cell tumours by cytology, histology and electron microscopy (using material obtained by FNA). [15] Beside Retinoblastoma, the differential diagnosis also includes Burkitt's lymphoma, metastatic Neuroblastoma, PNET/Ewing's sarcoma and myeloid leukemia, which can all present as ocular tumours.

Lympho-Proliferative Lesions: Ocular and periocular hematolymphoid diseases are a diverse group of lesions affecting various soft tissue structures within the orbital cavity. Lymphoid proliferations in particular are among the most commonly diagnosed entities in orbital pathology. When noninvasive techniques fail to confirm or rule out the suspicion of orbital neoplasia, fine-needle aspiration (FNA) may be of use in establishing a diagnosis in a reliable, timely, cost-effective and safe manner. [31],[32] Lymphoid tumours of the orbit are constituted by Idiopathic Inflammatory psuedo-tumours/reactive lymphoid hyperplasias and lymphomas. Lymphomas can occur in the conjunctiva as well as primarily in the orbit. Lymphocytes are normal constituents of conjunctiva and are termed as mucosa-associated lymphoid tissue (MALT). The conjunctival lymphomas are therefore localized and not part of systemic disease in 80-90% of cases. On the other hand orbit has neither lymphocytes nor lymph nodes and therefore any lymphoid mass within the orbital soft tissues is extremely abnormal and therefore extra-orbital manifestations of lympho-proliferative disease are found in approximately 35-50% of orbital cases. The orbital lymphoid tumours constitute 10 % of all orbital lesions and usually pose diagnostic and therapeutic challenges. Clinically they present as slow growing lesions with proptosis and the lesions usually mold to the orbital septum. As per the WHO classification, primary orbital non-Hodgkin lymphoma is a mucosa­associated lymphoid tissue (MALT)-type extranodal marginal zone lymphoma. It is not always easy to differentiate lymphomas from reactive lymphoid hyperplasias on the basis of cytology and for that matter morphology alone. With increasing knowledge of clonal nature of the lesions and the genetic rearrangements, the morphological diagnosis can now be complemented by immunohistochemistry, flow cytometry, in-situ hybridization and PCR studies. B cell clonality has been reported in 55-57% of primary and MALT lymphomas as against 0% of reactive lymphoid hyperplasia.

Langerhans Cell Histiocytosis: The lesion shows cellular infiltrates consisting of neutrophils, eosinophils, plasma cells and giant cells. In addition there are large cells with moderate amount of cytoplasm and large vesicular nucleus with prominent grooves and folds. [33] Frequent multinucleated giant cells are seen. Tingible body macrophages and histiocytes with phagocytic activity are noted.

Granulocytic sarcoma and other Leukemic Infiltrate: The cytologic appearance is that of a malignant round cell tumour. However the characteristic feature of myeloid tumours is the pale staining nucleus, irregular nuclear membrane, pinkish cytoplasm. [35] The Giemsa stained smears of imprint smears are of great importance in confirming the blast like morphology with cytoplasmic granules and sometime  Auer rods More Details can also be identified. Leder's esterase stain must be done in a suspected orbital lymphoma.22, [24] Rarely CLL in adults and ALL (of T­cell phenotype) can produce orbital deposits. [2]

Alveolar Soft Part Sarcoma (ASPS): We had one case of ASPS, which showed granular debris in the background mimicking a glial or fibrillary background. A few polygonal cells with abundant granular cytoplasm can be identified, but may be mistaken for a histiocyte. The fragile cytoplasm of these cells possibly results in the dusty or granular pattern, which needs to be kept in mind when reporting a tumour around the extraocular muscle in a child. Histopathology is required to confirm the diagnosis, which in our case turned out to be a case of solid variant of ASPS with classic histologic features and vascular emboli.

Optic Nerve Tumours: Meningioma: Some times atypical presentation of meningioma may warrant a need for intra operative cytology. The meningothelial cells are seen as whorls and in sheets. The cells contain moderate amount of pale cytoplasm and a pale staining vesicular nucleus with prominent intranuclear inclusions. Astrocytoma: the neuropils are the characteristic of an astrocytoma. The cellularity and pleomorphism needs to be looked for. Most of the Optic nerve gliomas are the juvenile pilocytic astrocytomas.

Plasma Cell Tumours: The cytologic appearance of plasma cell tumour is similar to that seen elsewhere. The plasma cells show abundant amphophilic cytoplasm and an eccentric nucleus with a perinuclear halo. [33] Plasmablasts, binucleated and multinucleated cells may be noted. Some cells with prominent nucleoli may mimic the cytoplasmic appearance of a melanoma. The Giemsa stained smears of melanoma however lack the amphophilic cytoplasm and the perinuclear vacuole, that is seen in the plasma cell lineage

Metastasis: Metastatic deposits from breast, lung, thyroid, hepatocellular carcinoma may be seen in the orbit and show similar appearance as seen in the primary location. This is one of the important indications of fine needle aspiration cytology of orbital lesions, which influences the surgical management of the case.

Ewing's Sarcoma: One of the malignant round cell tumours that can be seen in the orbit is Ewing's sarcoma, which could involve either the bone, orbital soft tissues or both. Immunohistochemistry and histopathology to differentiate it from other malignant round cell tumours of the orbit.

In summary, we emphasize the need for awareness of lesions occurring in eye and orbit so that the cytologist is prepared to diagnose these lesions. Though some of the lesions are peculiar to these sites, most of the lesions are seen elsewhere in the body hence it's important for the general pathologists, cytologists to be aware of these lesions

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Correspondence Address:
G K Vemuganti
Ophthalmic Pathology Service, LV Prasad Eye Institute, LV Prasad Marg, Banjara Hills, Hyderabad - 500 003
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-9371.42088

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