The Enduring Role and Relevance of Cytology in the Diagnosis of Orbital and Eyelid Lesions
A series of 150 fine-needle aspiration cytology (FNAC) from orbital and eyelid space- occupying lesions from years 2005 to 2015 were retrieved from records and reviewed. Corresponding histopathology was available in 112 cases, which showed concordance in 110 cases and discordance in 2 cases. Discordant cases were excluded. The male to female ratio was 1.5:1 with the mean age of 53 years. Our centre being a tertiary cancer centre had a total of only 6 benign lesions and 104 malignant lesions that were conclusively diagnosed. 73 of 104 malignant cases were of epithelial in origin; most commonly Squamous cell carcinoma followed by sebaceous carcinoma and basal cell carcinoma. Rhabdomyosarcoma was the most common non epithelial tumor followed by hematolymphoid malignancy. Four cases of orbital metastasis were identified with the primary tumor in breast, lung, prostate and thyroid. Immunocytochemistry (ICC) was performed manually on de stained wet fixed slides of 22 cases where other differential diagnosis was considered. These results confirm previous reports on the usefulness of FNA biopsy in diagnosing orbital and lid masses and emphasize the value of immunocytochemistry in tumor characterization.
Neoplastic lesions occurring within and around the eyelid and orbit, not surprisingly display entire gamut of lesions that one sees between head and foot. The complexity of the anatomy of the orbit and the situation of lesions in the deep and posterior aspect of the orbit often pose a great challenge to clinicians and surgeons.
Fine-needle aspiration cytology (FNAC) is useful when clinical examination and non-invasive techniques fail to establish the diagnosis. Early diagnosis is needed when a potentially aggressive disease warrants a prompt surgical/ therapeutic decision.[3,4] Innovations in sampling techniques using a small calibre needle, guided by the precise imaging modalities have made FNAC a safe, simple, and reliable tool for diagnosis of orbital lesions.[5,6] The diagnostic sensitivity varies from 75-88%.[7,8] Limitations of FNAC in orbital lesions include a) unfamiliarity and limited experience in orbital tumors by cytopathologists; b) insufficient cellular material due to difficulty in reaching the lesion; and c) complications such as damage to the globe, optic nerve, hematoma, and infections.[7,8]
Ancillary techniques like immunocytochemistry (ICC) are used in limited number of cases and have a great importance in typing of metastatic lesions.[9,10] Schyberg in 1975 first applied this technique for diagnosis of orbital tumors.
The aim of the present study is therefore to highlight FNAC as the diagnostic tool for various orbital and eyelid lesions presenting in tertiary cancer centres. Careful cytologic assessment is necessary to plan therapy since the therapy protocols are variable and involve surgical and non-surgical techniques.
Material and Methods :
A retrospective audit over a period of 11 years (2005-2015) was performed on all the orbital as well as eyelid lesions diagnosed on FNAC by the Department of Cytopathology. FNAC was performed under the supervision of an ophthalmologist, with or without radiological guidance depending upon the site of the lesion. Deep-seated lesions were best targeted after localization by ultrasound (US) or computed tomography (CT). No anaesthesia was generally required for this procedure, but for an anxious patient sedation can be considered.
The aspirated material was then checked for onsite adequacy with 1% toluidine blue stain. When the cellularity was adequate and representative, the smears were fixed and processed for Papanicolaou (pap) stain. Air-dried smears were stained with May-Grunwald Giemsa (MGG) stain. Pus/ necrotic aspirations were sent in a syringe for microbiological examination. Squash and imprint cytology of fresh tissue were performed for rapid intra-operative diagnosis.
Immunocytochemistry (ICC) was performed manually on de stained wet fixed slides of 22 cases where other differential diagnosis was considered. The diagnosis offered was correlated with corresponding Haematoxylin and Eosin (H&E) stained sections and radiological images.
Of a total 150 FNACs performed on orbital and lid lesions over a period of 11 years, cyto-histological correlations were available in 112 (74.7%) cases. The male to female ratio was 1.5:1 with a mean age of 53 years. Our study reported 98.2% concordant cases and 1.8% discordant cases.
Cytology smears in all the cases were reviewed and categorized under different diagnostic categories along with knowledge of corresponding histopathological diagnosis. Benign lesions were diagnosed on aspirates from six (5.5%) cases. These included two cases of infective etiology and one case each of solitary fibrous tumor (SFT), pleomorphic adenoma, odontogenic tumor (ameloblastoma) and meningioma (Table 1).
Malignant lesions comprised of total 104 (94.5%) cases. Of which 70.19% cases were epithelial (Table 2) and 19.81% cases were non-epithelial in origin (Table 3). A majority of malignant epithelial tumors in adults included squamous cell carcinoma (25%) (Figure 1A, B), sebaceous carcinoma (10.8%) (Figure 2A, B ) and basal cell carcinoma (7.6%) (Figure 3A, B).
The diagnosis of sebaceous gland carcinoma was confirmed by strong positivity for BerEP4 and negative for EMA; basal cell carcinoma showed immuno positivity for P63 and negative for EMA; squamous cell carcinoma showed positivity for EMA and P63 and negative for BerEP4.
2.8% cases of malignant melanoma were reported on scrape cytology (Figure 4A, B, C, D).
Nasopharyngeal carcinoma was reported in 0.9% cases. Adenoid cystic carcinoma (AdCC) of lacrimal gland origin was diagnosed in 5.7% cases. One of the cases showed presence of tumor cells arranged in sheets and clusters with no cribriform pattern and hyaline globules (Figure 5A, B, C).
In order to distinguish from basal cell carcinoma, immunomarkers for P63 and ckit were performed. The tumor cells showed strong positivity for ckit and focal positive for P63. Thus, confirming the diagnosis.
Other uncommon tumors like mucoepidermoid carcinoma (1.9%), salivary duct carcinoma (0.9%), ca-ex pleomorphic adenoma (0.9%) and adenocarcinoma NOS in 3.8% cases were also reported. Medulloepithelioma was reported in one case.
In contrast, a majority of non-epithelial malignant tumors in the paediatric population were hematolymphoid (8.6% cases) (Figure 6A, B,) and malignant small round cell tumor (17.3% cases).
Small round cell tumors included rhabdomyosarcoma (n=10) (Figure 7A, B, C), neuroblastoma (n=3), Ewing’s sarcoma (n=3) and primitive neuroectodermal tumor (n=2) cases. Soft tissue sarcoma was noted in 2.8% cases.
One of the cases with eyelid swelling was diagnosed as spindle cell neoplasm on cytology. The H&E sections showed presence of hypo and hypercellular areas with many giant cells. Thereby, a relatively uncommon entity of giant cell rich solitary fibrous tumor was considered and confirmed by strong immune positivity for CD34 (Figure 8A, B).
Metastatic tumors were diagnosed in 4 (3.8%) cases. Metastatic mammary carcinoma was noticed in one case (Figure 9).
1.9% cases showed metastatic adenocarcinoma, which was cytologically consistent with lung and prostatic carcinoma (Figure 10).
In neither of these cases ICC was performed, since cytopathology was conclusive.
Diagnostic difficulty was noted in two cases. An adult male with left upper lid swelling was misdiagnosed as pleomorphic adenoma on cytology which was confirmed on histology to be adenoid cystic carcinoma. Another case of an elderly male with a right upper lid swelling was diagnosed as poorly differentiated squamous cell carcinoma on cytology, which turned out to be sebaceous carcinoma on histology.
Since the first report on FNAC of orbital tumors by Schyberg in 1975, several reports have been published on orbital and eyelid lesions diagnosed on cytology as illustrated in Table 4.[12,16]
The diagnostic accuracy of orbital FNAC ranges between 23 and 100%. Similarly, in eyelid lesions, the diagnostic accuracy ranges from 85 to 100%.
In this study, the definitive diagnosis by FNAC and accuracy of this test to differentiate benign from malignant were 5.5 and 94.5% respectively, contributing to the referral centre bias. The results correlated radiologically as well as histologically. Our study reported 98.2% cases with concordance and 1.8% cases with discordance.
The eyelid is the site of several tumors that also occur elsewhere in the skin. The common lid tumors include basal cell carcinoma, squamous cell carcinoma, melanoma, sebaceous gland carcinoma and metastatic lesions.[19,20]
Epithelial tumors: Squamous cell carcinoma (SCC) typically involves the margin of lower eyelid. In the upper eyelid and outer canthus, SCC is more common in our study comprising of 25% cases as compared to basal cell carcinoma (BCC) accounting to 7.6% cases. Precursor lesions include actinic keratosis, Bowen’s disease, radiation dermatitis and xerodermapigmentosa. The tumor may arise denovo or from pre-existing lesions such as intra-epithelial carcinoma. SCC usually presents as elevated nodule or plaque with irregular borders which tends to ulcerate.
Cytology can help the decisions about planning a wide excision. FNA from an elevated margin provides diagnostic yield. Smears are often cellular and show polygonal cells with abundant acidophilic cytoplasm. Characteristic dyskeratotic cells with formation of keratin pearls are observed. The nuclei are prominent and hyperchromatic, and vary in size. Necro-inflammatory background is noted. Non-keratinizing squamous cell carcinoma is commonly misdiagnosed as sebaceous carcinoma as reported in one of our cases. In such cases, use of ancillary techniques on cytosmears for example, P40, P63, P53 and special stains like oil-red 0 can be used for confirmation of diagnosis.[19,20]
Basal cell carcinoma accounted for 7.6% cases in our study as compared to 80-90% of malignant epithelial tumors of the lid reported in literature. Patients usually present with a non-healing ulcer that often bleeds. Lesions can become pigmented and mimic melanomas. These are recognized by clinical examination and have been removed at initial biopsy, thus requiring little help from FNAC. However, when aspiration is performed smears show high cellularity with clusters and fragments of basaloid cells. Prominent spindle cell component having a fascicular pattern are noted. The nuclei show high N/C ratio, uniformly distributed coarse chromatin, and palisading. Occasionally, pigmented spindle cell fascicles result in a cytologic suspicion of Bednar tumor, but the presence of typical basaloid cells is a clue to its accurate diagnosis. Squamous, sebaceous and adenoid differentiation may be seen.[19, 21]
Sebaceous gland carcinoma (SGC) comprises of 1-3% of all the malignant eyelid tumors. We reported 10.8% cases with SGC. Common sites of origin in eyelid are meibomian glands and the sebaceous glands of the lashes. They are aggressive and lethal ocular adnexal tumours, second only to melanomas. Frequently occurs in upper eye-lid (2/3rd cases). These are common in females and elderly (>40 years). A distinctive clinical features of some SGC, which may not be fully appreciated when the patient is examined initially is chalazion, chronic blepharo-conjunctivitis, kerato-conjunctivitis, meibomianitis, papilloma, basal cell carcinoma, squamous cell carcinoma and carcinoma-in-situ that does not respond totally to therapy are called as masquerading syndromes. Early diagnosis is critical as it is associated with high mortality ranging from 22 to 41%.[22-24]
In this context, FNAC serves as a useful tool. The smears usually show clusters and occasionally discrete cells. The individual cells show moderate to abundant vacuolated cytoplasm. The nuclei show moderate pleomorphism with coarse chromatin and prominent nucleoli. These cells are often positive for Oil red O (cytoplasmic vacuoles contain lipid).[19, 25]
Differential includes chalazion which show inflammatory lipo-granuloma; pilomatrixoma which show bland sheets of basaloid cells, nucleated basophilic cells and “ghost” cells. BCC show 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 or brush) as well as in histology as squamous cell carcinoma-in-situ. SGC stain positive for EMA while BCC does not. Unlike most SGC, SCC is negative for CAM5.2. Breast cancer antigen (BRST-1) may be positive in sebaceous tumors but not in SCC. IHC detection of human milk fat globule subclasses 1 and 2 are also useful for diagnosing SGC.[23,25]
85% of all ocular melanomas are uveal with choroid being most frequent location. Other sites include conjunctiva and eyelid. We reported 2.8% cases in our study. These are rare but the most common primary intra-ocular malignancy in middle aged groups. Epithelial melanomas show large polygonal cells having eccentric nuclei with marked nuclear abnormalities, bi- and multinucleation. Nucleoli are distinct and intranuclear cytoplasmic inclusions are seen. Cytoplasm usually has abundant melanin. These cells are positive for HMB45 and S100.[26,27]
SPINDLE CELL NEOPLASM:
Orbital SFTs are largely benign tumors with few instances of recurrence. Most reported cases behave in a non aggressive fashion, similar to SFT in other sites in the head and neck region. Bernardini et al, reported 8 cases with a recurrence of 42 cases. Malignant SFT and malignant transformation of a recurrent SFT are uncommon but have been reported. Furusato et al, published a reappraisal of 41 cases of orbital tumors previously designated as hemangiopericytoma, benign fibrous histiocytoma, and giant cell angiofibroma. They, like many others, found that all these tumors have overlapping morphologic and immunohistochemical features and suggested SFT to be used as an encompassing terminology.[29,30] One of the cases with eyelid swelling was diagnosed as spindle cell neoplasm on cytology and confirmed by morphology and astrong immune positivity for CD34 as orbital SFT.
MALIGNANT ROUND CELL TUMORS:
A variety of small round cell tumors can be encountered primarily in the orbit like rhabdomyosarcoma, primitive neuroectodermal tumor/Ewing’s sarcoma; metastatic tumors like neuroblastoma and small cell carcinoma; tumors with orbital extension like medulloepithelioma and leukemic deposits.
Primary orbital lymphomas account for 10% of all orbital tumors and orbital involvement in systemic lymphomas is reported in 1.3% of the cases in literature. Lymphoid tumors and leukemias vary from 1 to 18% in their frequency. We reported 8.6% cases in our study. Lymphoid infiltrates consisting of a monomorphic, cytologically atypical, lymphoid cell population, in the absence of other inflammatory cells, is considered a lymphoma. An infiltrate featuring a heterogeneous population of cells consisting of lymphocytes, histiocytes, plasma cells, and benign lymphoid follicles with reactive germinal centers are characterized as reactive lymphoid hyperplasia or pseudolymphoma.[19,31]
Cytological smears show monomorphic population of lymphoid cells with high N/C ratio, pale basophilic cytoplasm, and slightly opened and coarse chromatin. Considering the FNAC findings of lymphoma, it appears that an increase in mast cells possibly favours a diagnosis of lymphoma rather than a reactive lymphoid lesion. In difficult situations, ICC using suitable immunomarkers (e.g.,CD 20 and CD45) is of great diagnostic value. The results are confirmed by immunophenotyping – flow cytometry (FCM) which is superior to immunostaining, as it can be performed on scanty cellular aspirate with multiple antibodies, and multiple markers can be done on the same cell by dual color FCM. Leukemic deposits commonly mimic metastatic lesion or granuloma. Patients present with orbital mass/proptosis. The cytomorphology shows presence of monomorphic round cells with loss of cohesion and vesicular nucleus. The smears are positive for myeloperoxidase.
The diagnosis and classification of lympho-proliferative lesions are the most difficult and challenging problems encountered by the pathologist. These lesions include reactive lymphoid hyperplasia and malignant lymphoma. A gray zone exists that has received names such as atypical lymphoid hyperplasia and indeterminate lymphoid lesions. Immunophenotyping and molecular techniques have established precise characterization of many of these lesions. Hodgkin’s disease and plasma cell myeloma are now recognized as lymphoid neoplasms. Orbital involvement in Hodgkin’s disease is extremely rare and usually secondary to localized involvement in other anatomic sites.[31,34] Additionally, multiple smears can be prepared simultaneously for ancillary studies such as ICC. Commonly used panel are CD20, CD3, CD45 and CD23. Staining with Mib-1 and P53 may provide additional information regarding the severity of the disease. Low grade lymphoma with Mib-1 cell count more than 20% has more aggressive biologic behaviour. P53 over expression has proven to be prognostic significance.[34,35]
Orbital rhabdomyosarcoma (RMS) comprises approximately 10% of all RMS cases which is in concordance with our study. It is the most common malignant mesenchymal neoplasms of the orbit in children. Boys are frequently affected. Embryonal RMS is seen in first decade of life whereas, alveolar type is observed in adolescents. The affected children often have fulminant and rapid development of proptosis and eyelid swelling. MRI distinguishes RMS which are extraocular from well-vascularized lesion of the orbit like retinoblastoma which are intraocular in origin.[35,36] Based on the cytomorphology alone, it is difficult to differentiate this tumor from retinoblastoma. However, the clinical history and investigative findings will help to clinch the diagnosis. Further confirmation if required is supported by radiology, ancillary techniques such as immunochemistry on cyto-smears and cell blocks, flow cytometric immunophenotyping as well as reverse transcriptase-polymerase chain reaction (RTPCR). The tumor cells of rhabdomyosarcoma show parallel bundles of thick myosin filaments and thin actin filaments on electron microscopy. Desmin positivity can be used to differentiate this tumor from retinoblastoma and neuroblastoma. In addition, MyoDl and myogenin expression are noted in majority of RMS cases. These two antibodies are highly sensitive and specific markers for RMS as compared to desmin.
About 95% of cases of Ewing’s sarcoma have t(11;22) or t(21;22) translocation. The resulting fusion of the EWS gene and FLI-1 gene results in chimeric protein that can be used for ancillary techniques. These tumor needs to be differentiated mainly from RMS, NB, lymphoma and orbital invasion from Rb. The cells stain positive for CD99 and vimentin antibodies.
Though orbital tumors are difficult to aspirate, they can be easily accessed by squash and imprint cytology which can be applied commonly for intra-operative diagnosis. Malignant epithelial tumors of lacrimal sac are generally older. The mean age of carcinoma is 58 years with age ranging from 16-89 years. The common sign and symptoms include epiphora, recurrent episodes of dacryocystitis and at times, an ulcerated mass. Bleeding from puncta or nose occurs in some cases.[19,29]
Pleomorphic adenoma is the commonest benign tumor whereas adenoid cystic carcinoma (AdCC) comprises of 25-30% malignant tumors. It is difficult to differentiate pleomorphic adenoma from AdCC as myxoid acellular material may occur in both. The globules of basement membrane like material characteristic of AdCC may also be seen in pleomorphic adenoma. The magenta coloured materials in pleomorphic adenoma are fibrillar, whereas these are homogenous in ACC. One of our cases was misdiagnosed as pleomorphic adenoma instead of adenoid cystic carcinoma due to the lack of basement membrane material. Solid variants of ACC are commonly misdiagnosed as these show round to oval cells with scanty cytoplasm. Typical pink hyaline globules or extracellular material are usually absent in the solid variant of AdCC. The cytologic picture is of small malignant epithelial tumor of lacrimal gland. In such cases, ancillary techniques and tissue diagnosis holds importance for confirmation.
The first manifestation of an occult primary could present as nodules in iris, ciliary body, or retina which mimics as an inflammatory or other neoplastic lesions. In infants and children, malignant small round cell tumor may involve the eye. In adult women, mammary carcinoma is the most common metastatic tumour. In adult men, carcinoma of lung, prostate, gastrointestinal tract and kidney may be found. A detailed clinical history and examination usually helps in identifying metastatic lesions. The cytomorphological appearance is similar to that of a primary tumour.[19,40]
In our study, there were no complications of the FNAC technique that were encountered, as the procedures were performed only for anterior, palpable, orbital and lid lesions. Selection of appropriate cases is very important with regards to FNAC as it is impossible to make an accurate diagnosis with insufficient material. In order to improve the categorization of orbital and lid lesions, an approach to cytodiagnosis is shown in Figure 11.
FNAC is an important preliminary diagnostic technique which can be applied in the field of ophthalmology and can help the ophthalmologist to provide a more focussed diagnostic and therapeutic planning. FNAC is safe, simple, and reliable for diagnosis of orbital lesions. Lack of awareness of the wide spectrum of orbital tumors and overlapping cytological features often cause difficulty in cytodiagnosis. Diagnostic accuracy can be improved when the smears are viewed with clinical and radiologic correlation.
FNAC of orbital lesions can differentiate between neoplastic and non-neoplastic lesions like inflammation, benign and malignant, and also broad lineage neoplasms. Immunocytochemistry proves to be an important tool for typing of malignant lesions, suggesting an origin of unknown primary tumors. Our study showed cytohistology correlation in 74.7% cases, of which 98.2% cases were concordant and 1.8% cases were discordant. Therefore, FNAC along with ancillary techniques can provide a very high index of accuracy, few complications, and can aid in a rapid diagnosis.
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