Two types of genes play a major role in malignant transformation: oncogenes and tumor suppressor genes.

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 [1].

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].

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 [14].

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 [15].

Ocular and adnexal lymphomas (OAL) constitute 8 % of extranodal lymphomas and are the most common malignant tumors of the orbit [17]. 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 [18].

The term ‘reactive’ LH (RLH) has been used for lesions with a benign morphology and immunophenotype, whereas ‘atypical’ LH (ALH) applies to borderline lesions [19]. 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 [20]. Recent studies suggest that the risk of progression to malignant lymphoma is about 10 % [21].

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 [22]. 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 [19]. 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).

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 [23].

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) [19].