Dr. Bipasha Mukherjee is a fellow in Orbit & Oculoplasty from Aravind Eye Hospitals, India, and ICO fellow from University Hospital of Limoges, France, under Prof. Jean-Paul Adenis. She has undergone clinical observerships with stalwarts like Jack Rootman, Richard Collins, Geoff Rose, Mark Duffy, and Robert Goldberg.
She currently heads the department of Orbit, Oculoplasty, Aesthetic & Reconstructive services in Medical Research Foundation, Chennai. She has numerous presentations in national and international conferences and publications in peer-reviewed journals and text books. Her areas of interest include diseases of the orbit and adnexa including tumors, lacrimal surgery, socket reconstruction, traumatic lid and adnexal injuries, training residents and fellows, and photography.
Malignant transformation of an existing benign tumor is a process by which the cells acquire properties of a cancerous phenotype and starts dividing uncontrollably.
The exact reason and process by which this transformation occurs is difficult to pinpoint. Certain types of benign tumor are known to undergo malignant transformation. One of the better-known examples of this phenomenon in the orbit is the progression of a benign pleomorphic adenoma of the lacrimal gland to a pleomorphic adenocarcinoma.
Initially, malignant transformation in a benign tumor may be detected only while pathologic examination of the lesion (carcinoma in pleomorphic adenoma). Later, the clinical signs and symptoms may signal malignant change. Unexplained, unremitting pain, sudden growth, change in texture (soft to hard), or neurological deficit in an area of a preexisting lesion should raise concern for malignant transformation.
Predisposing Factors for Malignant Transformation
defective genes or genetic mutations.
Two types of genes play a major role in malignant transformation: oncogenes and tumor suppressor genes.
Oncogenes: Healthy, unmutated oncogenes (also known as proto-oncogenes) take part in stimulating normal cell growth and division, whereas a mutated oncogene continuously commands the cell to proliferate, leading to unchecked, cancerous growth.
Tumor suppressor genes: In healthy cells, tumor suppressor genes keep the cell’s growth in check. These genes stop working in a cancerous cell, allowing the cell to begin a malignant, destructive process.
Growth of normal tissues and organs is also controlled by a genetic phenomenon called programmed cell death, or apoptosis, in which a certain number of cells die and are eliminated after a finite number of divisions. Malignant transformation can impede programmed cell death, thus allowing the cells to grow uncontrollably and resulting in cancer .
viruses, chemical carcinogens, or radiation damage by free radicals and ultraviolet radiation.
Viruses of the family Polyomaviridae, a group of papovaviruses, are associated with malignancy in animals. Cancers caused by chemical or physical carcinogens in the environment probably often, if not invariably, are due to alterations in the sequences of proto-oncogenes that have converted them to oncogenes. Radiotherapy has emerged as a consistent and important risk factor for developing second malignancies due to their tumor suppressor gene defect [2, 3].
Classification of Benign Orbital Lesions with Malignant Potential
Osseous and cartilaginous
Lacrimal Gland Tumors
The incidence of epithelial tumors of the lacrimal gland ranges from 5 to 8 % of orbital neoplasia . The most common benign neoplasm of the lacrimal gland is the pleomorphic adenoma which usually presents as a unilateral painless, progressive, downward and inward displacement of the globe (Fig. 44.1).
Clinical photograph of patient with lacrimal gland pleomorphic adenoma of the right orbit
CT and MRI are invaluable in assessing lacrimal gland lesions. Radiologically benign lesions are round or oval, smooth in outline, displacing the globe and deforming the lacrimal gland fossa, but not causing any bony erosion (Fig. 44.2). Calcifications are not seen. On the contrary, malignant lacrimal gland lesions are irregular in outline, cause bony erosions and may demonstrate calcifications (Fig. 44.3).
T2-weighted coronal MRI scan showing a well-circumscribed round soft tissue lesion in the right lacrimal gland fossa (a); CT scan of the same patient showing fossa formation without bony erosion or calcification (b)
CT scan of patient with malignant lacrimal gland tumor showing bone erosion
Malignant mixed tumor, also called carcinoma ex pleomorphic adenoma, pleomorphic carcinoma or carcinoma in pleomorphic adenoma, represents a pleomorphic adenoma that has undergone malignant degeneration . These tumors can be seen in a patient who had undergone an incomplete resection of a benign mixed tumor and can present with a recurrence decades later . Malignant transformation of a long-standing, indolent lacrimal gland tumor can be heralded by sudden acute expansion of the mass with pain and swelling of the upper eyelid .
Font and Gamel reported a 10 % incidence of malignant transformation of recurrent adenomas by 20 years after treatment and 20 % by 30 years .
A high index of suspicion and knowledge of the radiologic findings and clinical behavior of the different lesions is imperative when dealing with lacrimal tumors (Table 44.1).
Clinicopathological features of benign and malignant lacrimal gland tumors
Adenoid cystic carcinoma
Malignant mixed tumor
Sudden recurrence in an incompletely removed lacrimal gland mass or sudden expansion in a long-standing benign neoplasm
4th–5th decade of life; painless
Younger age group (ave. age: 40 years); painful; rarely numbness
Older patients; painful sudden proptosis
Well-circumscribed mass lesion; expansion/remodeling of the lacrimal gland fossa; without bone invasion; no calcification
Bone invasion; calcification
May or may not show bony changes
Mixture of epithelial and mesenchymal elements (benign mixed tumor)
Five histological patterns: cribriform; solid (basaloid); sclerosing; comedocarcinomatous; tubular (ductal)
Features of benign mixed tumor with areas of malignant change
Histologically, benign and malignant components of the lesion need to be identified. A malignant mixed tumor shows features of a benign mixed tumor with areas of malignant transformation . In most cases, these elements are poorly differentiated adenocarcinomas, but squamous cell carcinoma, adenoid cystic carcinoma, or even a sarcoma can be found [10, 11].
All lacrimal gland pleomorphic adenomas should be excised completely, along with its intact pseudo-capsule, as untreated or partially excised tumors carry a significant long-term risk of recurrence and malignant transformation. Incisional biopsy of a suspected benign lesion also should be avoided as it carries the risk of cellular seeding beyond the pseudo-capsule, which forms an effective physical barrier around the intact tumor .
Management of malignant lacrimal gland tumors is still unsatisfactory and requires an aggressive approach including exenteration, en bloc craniofacial orbitectomy, lymph node dissection, and subsequent radiotherapy. A potentially promising option is intra-arterial administration of neo-adjuvant chemotherapy .
Prior to the use of immunohistochemical techniques, the diagnosis of orbital spindle cell neoplasms like solitary fibrous tumor (SFT) used to be confused with fibrous histiocytoma, giant cell angiofibroma and hemangiopericytoma. Microscopically, they all show considerable similarity, varying in degree of cellularity, stromal collagen, and the presence of giant cells. However, immunohistochemistry reveals positivity for CD34 in all cases (100 %), and these lesions are nowadays designated as solitary fibrous tumor .
Local recurrences of SFT are possible and usually follow an incomplete initial excision. Recurrent orbital SFT has the potential for malignant transformation even several years after surgery .
The treatment of choice of orbital SFT is complete surgical excision and careful follow-up .
Ocular and adnexal lymphomas (OAL) constitute 8 % of extranodal lymphomas and are the most common malignant tumors of the orbit . Lymphoid hyperplasia (LH) is a term used to describe benign lymphoproliferative lesions of the orbit. It has been hypothesized that it represents a temporary benign precursor lesion with the potential to progress to lymphoma .
The term ‘reactive’ LH (RLH) has been used for lesions with a benign morphology and immunophenotype, whereas ‘atypical’ LH (ALH) applies to borderline lesions . The association between LH and autoimmune diseases like Sjogren’s syndrome, Grave’s disease, lupus erythematosus etc suggests chronic stimulation by autoimmune antigens may play a role in the developement of polyclonal BRLH which can progress to monoclonality and lymphoma . Recent studies suggest that the risk of progression to malignant lymphoma is about 10 % .
It is at times difficult to distinguish LH from malignant lymphoma on the basis of histomorphology alone. Ancillary techniques like immunohistochemistry (IHC), flow cytometry and molecular genetic analyses based on clonality are necessary to distinguish benign from malignant lymphoproliferative processes.
RLH accounts for 10–20 % of all OALs . The majority of OAL are B-cell non-Hodgkin’s lymphoma (NHL), predominantly extranodal marginal zone lymphoma (ENMZL) of mucosa –associated lymphoid tissue (MALT). The clinical manifestations of these lesions depend on the site of involvement. Anatomic sites usually affected by BRLH and OAL are the lacrimal glands, extra ocular muscles, lacrimal sac, conjunctiva, eyelids and the entire orbit. Orbital LH is predominately extraconal and found above the horizontal midline, being most commonly centered in the lacrimal gland. Patients with conjunctival lesions may present with complaints of foreign body sensation and redness . Both LH and malignant lymphomas can present as a visible mass beneath the conjunctiva, described as a “salmon patch” (Fig. 44.4). Lymphoproliferative lesions involving the orbits and eyelids present with swelling or with painless proptosis. Imaging will demonstrate an infiltrative contrast enhancing mass lesion with molding of the globe and the adjacent structures without invasion (Fig. 44.5).
Salmon patch: Pink hyperemic infiltrative mass over bulbar conjunctiva extending from medial to lateral canthus and up to superior fornix
BRLH: well-defined homogenous soft tissue lesion extending from superior limbus to superior rectus insertion, moderately thickened SR and LPS muscle isointense on T1 W (a) and T2W (b). CT scan showing lymphoproliferative lesion involving left orbit molding the globe (c)
Reactive LH and low-grade OAL are clinically and radiologically indistinguishable from each other, requiring tissue biopsy in all cases followed by IHC and systemic workup to classify the nature of the lesion under the Revised European and American Lymphoma (REAL) classification .
Benign lesions show polymorphous array of small round lymphocytes and plasma cells whereas malignant lymphomas show anaplastic cells with nuclear pleomorphism and prominent nucleoli. Lesions beginning as polyclonal reactive processes can succumb to malignant transformation with light chain restriction. The clonality of lymphoid proliferations is assessed using immunophenotyping (immunohistochemistry or flow cytometry) to detect immunoglobulin light chain restriction and molecular genetic techniques–polymerase chain reaction (PCR) .