Malignant Lymphoma of the Conjunctiva

The most common lymphoma of the conjunctiva is the low grade mucosal associated lymphoid tumor also called MALT. In some recent series this accounts for up to 55% of the lymphomas. MALT is described in detail under orbital lymphomas.

What is Molluscum Contagiosum?

Molluscum Contagiosum
Definition: a viral infection, poxvirus, that produces one or multiple eyelid nodules
Incidence/Prevalence: comprises about 0.3% of eyelid biopsies at UCLA.
Etiology: The virus belongs to the poxvirus group and is somewhat rectangular or brick-shaped and measures 300 nm by 240 nm.
Clinical Findings: Patients present with a variable number of waxy, dome-shaped papules that have umbilicated centers and measure 1-4 mm in diameter. The fully developed lesions may have cheesy or curd-like material which can be expressed from the center. The lesions are frequently located near the lid margin and conjunctiva and may be associated with a follicular conjunctivitis. The lesions may spontaneously involute and in this phase may be accompanied by inflammation, pain and tenderness.
Histopathology: At low magnification the "domed papule" is divided into pear shaped nodules of proliferating epidermis which on the surface appear as volcanic micro craters (arrow 2) separated by the epidermal lips of the crater (arrow 1). The characteristic and key feature is the presence of molluscum bodies also known as Henderson-Patterson bodies in the depths of the "volcanos". These bodies appear about 1-2 layers above the basal cell layer (arrow 5) of the epidermis as pink to red inclusions (arrow 3) and progress to become large bright red inclusions in the upper layers of the epidermis. Finally, they may exceed the size of the original cell (arrows 3 in high mag images). The inclusions displace the nucleus and leave only a thin crescent of basophilic material. In the granular layer the inclusions at first are surrounded by blue granules (arrow 4) and eventually may even appear slightly basophilic in the upper layers. The stratum corneum or cornified layer is often disintegrated as the inclusions enlarge (arrow 2). At the peak the molluscum bodies may reach a diameter of 35 microns. Ultrastructure shows each inclusion is composed of brick shaped viruses with dumbbell shaped nucleoids surrounded by the amorphous layer of capsids.
Treatment: With a nodular shape and umbilicated center, a single Molluscum lesion may mimic and frequently can be misdiagnosed clinically as a basal cell carcinoma. Single lesions are frequently removed. Spontaneous involution also occurs.

What is an oncocytoma of the caruncle?

Oncocytoma
Definition: Oncocytomas are benign tumors that arise most commonly in the caruncle or canthal conjunctiva but may also occur in the lacrimal glands (including accessory glands) and lacrimal sac.
Incidence/Prevalence: Oncocytomas are considered rare tumors.
Etiology: Oncocytoma are believed to arise from oncocytic metaplasia of ductal and acinar cells of lacrimal epithelium or perhaps conjunctival epithelium.
Clinical Findings: Oncocytomas most commonly present in women of middle age or older (>50 years) as a red-yellow mass (arrow 1 in the clinical photograph). In this case the mass is red to pink in color, located in the caruncle and has a cystic appearance. Note the yellow lesion, a pingueculum near the limbus (arrow 2).

Histopathology: Oncocytomas are characterized by large eosinophilic cells that form glandular or ductular spaces (number 1 in the low mag photomicrograph). Between the ducts there are solid trabeculae of cells. The abundant eosinophilic cytoplasm and the relatively small round to oval nuclei that are located in the middle of the epithelial cell (arrow 2) are key features. The cells may contain small nucleolar organizer regions (nucleoli) and their may be clearing of the nuclear material in some cells. Electron microscopy shows numerous mitochondria.
Treatment: Excision is usually curative.
Prognosis: It is believed by some that malignant transformation may occur to produce oncocytic adenocarcinoma, although this mode of transition has not been proven.

What is squamous carcinoma of the conjunctiva?

Squamous carcinoma of conjunctiva (cornea)
Definition: malignant neoplasm of conjunctiva characterized by invasion of the substantia propria and squamous differentiation
Incidence/Prevalence: squamous carcinoma is the most common conjunctival malignancy in adults. The conjoined incidence of dysplasia, carcinoma in situ, and invasive carcinoma of the cornea and conjunctiva was estimated to be 1.9 per 100,000 per year averaged for 10 years in a study from Brisbane, Australia. In a study from Queensland, Australia, 288 cases were identified : 155 dysplasia, 71 carcinoma in situ, and 62 squamous cell carcinoma. 78.5% of the cases occurred in males with an average age of 60.1 years.
Etiology: Squamous carcinoma is strongly correlated to overexposure of the conjunctiva to ultraviolet light. The appearance of dysplasia has also been found to result from human papillomavirus type 16 (HPV 16).
Clinical Findings: Most present in elderly people as a white vascularized lesion in the limbal and perilimbal areas of the interpalpebral fissure. Squamous carcinomas usually invade superficially. The lesions may be papillary and elevated and even protrude from the interpalpebral fissue in neglected cases. Squamous carcinomas often mimic pterygium, the most frequent misdiagnosis. If dendritic melanocytes are present, squamous carcinoma in situ or squamous carcinoma may even be misdiagnosed clinically as malignant melanoma. If the tumor infiltrates the eye, the reaction may masquerade as an anterior uveitis, glaucoma (as the trabecular meshwork is blocked) or as epithelial downgrowth.
Histopathology: In general one finds the presence of multiple areas of squamous carcinoma in situ and dysplasia (arrows 1 in the figure) that





















coexist with invasive nests of squamous cells that infiltrate through the basement membrane of the epithelium. Invasive nests (arrows 2) have a characteristic signature of groups of cells that form pointed extensions (arrows 4), isolated islands, strands or single cells in the collagen of the substantia propria. In these photographs there are numerous invasive nests as well a broad sheets of tumor that infiltrate the substantia propria. There may be associated fibrosis, desmoplasia and retraction artifact (arrow 3) associated with the tumor .





















Various degrees of squamous differentiation may be present as indicated by individual cell dyskeratosis (arrow 2), surface keratinization, squamous eddies, squamous pearls, and intercellular bridges.
Treatment: Complete excision is generally recommended. This has been successfully combined with adjunctive cryotherapy and topical chemotherapy with Mitomycin C and 5FU. Careful dissection to remove the tumor in one piece is helpful for evaluation of margins. A suture should be placed in the specimens at 12 o’clock for orientation and most important the specimen should be placed on filter paper in the operating room and fixed in the flat state so that tangential sectioning is avoided. It is best for the pathologist to examine and ink the margins under a dissecting microscope to ensure that the specimen remains flat. Embedding is best performed with the aid of a dissecting microscope as well.
Prognosis: Generally the tumors invade superficially in the conjunctiva and cornea but in longstanding or aggressive cases the carcinomas may invade locally into the eye and orbit. Regional lymph node metastases occur but are relatively uncommon. Several authors have noted that death from metastatic disease occurs but is quite rare from this tumor (1-2% of most series).

What is a dermoid cyst?

Dermoid Cyst
Definition: a benign congenital cyst in the orbit lined by squamous epithelium and containing adnexal structures in the wall.
Incidence/Prevalence: Dermoid cysts make up between 4-15% of orbital tumors in most series. The lesions are present at birth but may become manifest later in childhood or even adulthood.
Etiology: Dermoid cysts are believed to arise as embryonic epithelial nests that become entrapped during embryogenesis and pinched at suture lines of bones.
Clinical Findings: On clinical grounds dermoid cysts can be divided into superficial and deep masses.
Superficial dermoid cysts are usually situated temporally, and present as painless, firm, 1-2 cm diameter, immobile masses that are noticed during infancy and originate most commonly from the frontozygomatic suture or frontolacrimal suture.
Deep dermoid cysts often present as slow growing masses in later childhood or adulthood and can arise from any suture of the orbit, but most commonly the frontozygomatic. Deep dermoid cysts may protrude through the frontozygomatic suture to take a dumbbell shape. Involvement of sutures on the ethmoid bone, or area around the superior orbital fissure have been reported. The patients present with symptoms and signs referable to the mass effect in the orbit (proptosis, bulging upper eyelid, downward (or upward) displacement of the eye), visual and ocular motor defects, etc. Ruptured dermoid cysts may present as draining fistulas.
Radiologic Findings:
Superficial dermoids are round masses that contain a lucent center (fat or muscle density) and are generally not associated with a defect in the bone.
Deep dermoid cysts are often accompanied by bone defects at the suture. For example, the classic dumbbell shaped lesion may extend thru the frontozygomatic suture into the temporalis fossa. There may be calcification, or an area where adjacent bone is smoothly disrupted.
Histopathology: Histologically, dermoid cysts contain desquamated squamous epithelium and keratin in the lumen (arrow 1) and are encapsulated and lined by keratinized stratified squamous epithelium (arrows 2 and 3). A key for the diagnosis is the presence of adnexal structures including sebaceous glands (arrows 2 and 4 here). Hair roots, sweat glands, apocrine glands and lacrimal glands may also appear in the wall of the cyst. Higher magnification shows that the lumen contains hair shafts and keratin (arrows 5 and 6, respectively). Polarization of the sections will often highlight the hair shafts in the lumen.
If the wall does not bear adnexal structures, the term epidermal or keratin cyst is applied. Intraorbital cysts may also be lined by respiratory epithelium or conjunctival epithelium. Rupture of cyst contents may produce a marked granulomatous reaction and the residual cyst that forms may have its squamous epithelial lining completely replaced by epithelioid histiocytes and multinucleated giant cells (number 7 below). Most ruptured cysts occur between the






















ages of 20-40 and some authors note a relationship between the volume of the cyst (2197 cubic) and the likelihood of finding a hidden rupture (see reference).
Treatment:
Superficial dermoids are often removed before the 5th year of life to avoid traumatic rupture and some authors recommend surgery by the age of 3-4.
Deep dermoids may be very difficult to remove and require careful preoperative assessment of the anatomic structures involved. It is important to attempt removal of the cyst intact and to remove the entire lining. Lesions may extend into the intracranial cavity severely complicating and compromising the attempts to remove them.
Prognosis: Superficial dermoids are generally quite easily handled with little morbidity. Deep dermoids involving complicated orbital structures or extending in the intracranial cavity are prone to complications from either rupture during removal or damage to adjacent structures. A team approach with other services may be necessary.

References:
Dithmar et al. Klin Monatsbl Augenheilkd. 1993 Covered rupture of periocular dermoid cysts.

What is adenoid cystic carcinoma of lacrimal gland?

Adenoid cystic carcinoma
Definition: Adenoid cystic carcinoma is a malignant tumor arising in the lacrimal gland and is composed of malignant ductular elements.
Incidence/ Prevalence: The most common primary malignant tumor of the lacrimal gland.
Etiology: Unknown but numerous candidate genes have been identified. Increased copy number has been noted at 22q13 for salivary gland adenoid cystic carcinoma. Adenoid cystic carcinoma can arise in benign mixed tumor or de novo in the lacrimal gland.
Clinical Findings: The typical presentation is a 40 year old (median age) with less than 8 months of pain in the upper lateral orbit, numbness, diplopia and proptosis. The tumor is slightly more common in women than in men. The age range is about 8-80 and some authors believe there is a bimodal pattern, the young and the old. The pain symptoms, characteristic of this neoplasm, arise from infiltration of nerves and bone involvement.
Radiology: A rounded mass will generally be centered over orbital portion of the lacrimal gland and the orbital roof may appear moth eaten. This is in distinct contrast from a pleomorphic adenoma. The tumor may extend into the temporalis fossa.
Pathology: Grossly, the appearance is grayish white, firm, and nodular. Under a dissecting microscope the swiss cheese pattern is often quite prominent.
Adenoid cystic carcinoma is not encapsulated. A variety of patterns may appear, including the Swiss cheese (cribriform) pattern. In the image a cribriform pattern is evident with back to back glands without any intervening stroma (arrow 1). This is a sign of adenocarcinoma in general and is a very good distinguishing sign from the ductular structures of the epithelial component of pleomorphic adenoma.
In the upper part of the next image the tumor is forming solid nests indicative of the basaloid type of adenoid cystic carcinoma while below the tumor has a more cylindromatous pattern with glandular elements that are compressed by basement membrane laden and hyalinized stroma. If any of the basaloid pattern is found in an adenoid cystic carcinoma with other predominant patterns, most authors would classify it as a basaloid type with a worse prognosis. Although Lee and Campbell could not verify the worse prognosis in their study at the Mayo clinic, all of their patients with any type of adenoid cystic had generally a worse prognosis than those reviewed in a larger series by Gamel and Font that demonstrate poor survival with the basaloid type of carcinoma. Other histologic patterns include tubular, comedo and sclerosing. Adenoid cystic carcinoma has a proclivity for perineural and occasionally neural invasion. In the image of a basaloid adenoid cystic carcinoma, infiltrating nests of cells (arrow 3) insinuate between the perineurium and the actual nerve fibers (2).
Compare to the more usual cribiform type also exhibiting perineural invasion. The nerve here is shown at number 4.
Treatment: Because of the diffuse infiltration of this tumor, exenteration may be recommended, often with removal of adjacent bone. Anecdotes of aggressive therapy with removal of the lateral wall and the roof of the orbit has been suggested by some as providing a better prognosis and a chance for cure but this has neither been proven, nor borne out in some studies. In general, adenoid cystic carcinoma may recur many times and many years after the initial resection. Intra-arterial cytoreductive chemotherapy has recently been introduced with putatively improved results over conventional therapy.
Prognosis: Despite aggressive surgical intervention, the long-term prognosis is poor. Perineural invasion through the superior orbital fissure to the brain may lead to death. Pulmonary metastases are frequent many years after surgery. Presence of the basaloid pattern has been associated with a worse prognosis (5-year survival of 21%) than those tumors without a basaloid component (5-year survival of 71%). Note the numerous mitotic figures in this image of a basaloid type of adenoid cystic carcinoma (arrow 5).

What is pleomorphic adenoma?

MIXED TUMOR OF THE LACRIMAL GLAND (Pleomorphic Adenoma)
Definition: benign primary lacrimal gland neoplasm composed of both stromal and epithelial components.
Incidence/Prevalence: the most common primary neoplasm of the lacrimal gland accounting for about 40-50% of neoplasms in some series.
Etiology: The tumors presumably arise from ductular epithelium based on the ultrastructural characteristics that recapitulate the lacrimal ducts. The stromal cells are myoepithelially derived and the epithelial cells take origin from basal germinal epithelium. Recurrent chromosomal abnormalities involving chromosomes 3, 8, 9, and 12 have been reported similar to benign and malignant salivary gland tumors. There is evidence that mutations in TP53 gene are related to the pathogenesis of salivary gland neoplasms and that exons 5 and 8 are most frequently involved. A similar situation is suspected but not proven for lacrimal gland neoplasms. The tumors have been reported to arise from the glands of Wolfring, Krauss in the eyelid or even Popoff's glands in the caruncle.
Clinical Findings: The mean age is given as 35- 39 years with a range of about 7-77 years. The tumors occur with a male predominance up to about a 2:1 ratio of male:female in some series. Patients present with painless proptosis that has been slowly progressive. Examination shows proptosis, downward and inward displacement of the eye, ptosis, and a palpable mass. If the tumor is large the eye may be indented and retinal striae may be visible.
Radiologic Findings: CT and MRI show a rounded tumor that is generally centered over the region of the orbital portion of the lacrimal gland. There may be pressure induced scalloping of the adjacent zygoma. The sclera may be flattened slightly.
Histopathology: Pleomorphic adenomas are encapsulated tumors (number 2 in the figure shows the capsule) in which the normal lacrimal gland is usually pushed to one side (number 1). The neoplasms are composed of both epithelial and stromal components, hence mixed tumor. The epithelial component usually features strands and cords of epithelium that form ductular structures (arrows 3 and 10). There is often PAS positive hyaline or basement membrane material produced by the ducts (arrow 7 and number 9). There may be calcification in the stroma (number 4). Alternatively squamous epithelium may be present and produce keratin. Associated chronic inflammation is common at the interface between the capsule of the tumor and the lacrimal gland (arrow 5). In addition there may be seromucinous material from more dilated ductular structures (number 8). The stromal component may have a myxoid or loose stromal character with wavy spindle cells (arrow 6). Sometimes the stroma component has a chondroid or cartilaginous appearance (number 8). The epithelial cells are usually enlarged and may vary somewhat in size but they are generally well spaced and there is no back to back gland formation without intervening stroma (a key sign of adenocarcinoma). Mitotic activity is usually very low in these slowly growing tumors.
Treatment: The usual treatment is complete excision by lateral orbitotomy. Some prefer to verify the diagnosis prior to surgery with fine needle aspiration. If this procedure changes the management such as in the case of an uncertain diagnosis or confusion of an epithelial lesion with a lymphoproliferative disorder then FNA seems warranted. Some claim that there may be seeding along the needle tract, and cite a reference to Fechner in the orbit chapter in Spencer's Ophthalmic Pathology. However this reference presents 2 cases, neither of which were mixed tumors or in the orbit or lacrimal gland. However, it is important during surgery to remove the entire tumor with the capsule intact. Frozen sections are generally not necessary and may be inaccurate.
Prognosis: Although benign, long standing mixed tumors (>15 years) are thought to degenerate into malignant lesions such as adenoid cystic carcinoma, malignant mixed tumor and adenocarcinoma.