Observations on Classification

The orbit is affected by diverse diseases with a significant emphasis on inflammatory reactive changes ( ▶ Table 9.1).

Although the terminology for inflammatory changes continues to be defined and refined, since the mid-1990s tumor pathology has developed considerably and become standardized. In the publications on tumor classification issued by the WHO, the tumor entities currently known are given standardized names and designated with a code (ICD-O key in the currently valid version). Both of these schemata are provided with the TNM classification for malignant epithelial tumors; the result is a comprehensive and mostly precise classification for every tumor. From this, in Anglo-Saxon countries the practice is to refrain from classical textual assessment and undertake the assessment in the form of tabular juxtapositions. This brings considerable advantages with regard to the completeness and accuracy of assessments. It is also beneficial for international comparability of research studies and comprehensibility of assessments across national borders.

Within the context of these classifications the tumors assessed are to be further assessed with regard to their biological significance. It is in this regard that grading of tumors is done. In principle the grading is as follows:

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  G1: good differentiation; the histogenetic assignment of the tumor is without difficulty in the overview stainings. The differentiation of benign/malignant is somewhat difficult.

  
  
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  G2: moderate differentiation; the histogenetic assignment is successful in the overview stainings. There is a discontinuity or “jump” in the differentiation, which clearly enables classification as a malignant tumor.

  
  
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  G3: poor differentiation; the histogenetic assignment can only be done in the overview stainings to a limited extent or not at all. Immunohistochemical procedures may be necessary to enable assignment.

  
  
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  G4: dedifferentiated malignant tumor. Here even immunohistochemistry may no longer help in the assignment.

In the grading of malignant tumors there are additional criteria for a number of entities that have proved to be important for the assessment of the biological behavior. In particular, FNCLCC (Fédération National des Centres de Lutte Contre le Cancer) standards apply for sarcomas. These are:

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  Tumor differentiation (Score 1–3).

  
  
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  Mitosis count (Score 1–3).

  
  
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  Tumor necrosis (Score 1–3).

From these is derived the histological degree:

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  Grade 1: total score 2, 3.

  
  
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  Grade 2: total score 4, 5.

  
  
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  Grade 3: total score 6, 7, 9.

For malignant melanomas the TNM classification is supplemented with a series of histological parameters that, for example, are not (yet) required in carcinomas. From this there results a comprehensive assessment, which should contain the following points:

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  Actual histological diagnosis.

  
  
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  Tumor thickness (according to Breslow).

  
  
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  Invasion level (according to Clark).

  
  
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  Ulceration.

  
  
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  Mitotic rate (per mm²).

  
  
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  Cell types (in different tumor cell groups).

  
  
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  Regression.

  
  
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  Tumor infiltration by lymphocytes (TIL).

  
  
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  Evidence of plasma cells.

  
  
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  Evidence of a neovascularization.

  
  
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  Vascular invasion.

  
  
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  Microscopically small satellites.

  
  
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  Associated preexisting nevus.

  
  
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  Margin of the resection edges.

  
  
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  Additional parameters of the TNM classification (regional lymph nodes, remote metastases).

There results a breakdown as follows for a pathological–anatomical finding:

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  Clinical findings.

  
  
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  Macroscopic findings.

  
  
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  Histologic findings.

  
  
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  Assessment supplemented by the above-mentioned parameters; where necessary, commentary with an explanation (which should always be read and understood).

  
  
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  Where applicable, tabular summary of all significant parameters.

9.2 Inflammations

An inflammation is the tissue’s reaction to biological, chemical, or physical noxae. The nature of the inflammatory reaction permits some conclusions to be made about the influencing noxa (e.g., granuloma in the context of a mycobacteriosis). In the main, however, the appearance of the inflammation is unspecific.

In principle, an acute phase is followed by either healing (ad integrum) or the transition to chronic inflammation. Linked with this is a change in the inflammatory cells involved away from granulocytes to lymphocytes. The final stage of chronic inflammation is scar formation.

A primary chronic inflammation is also possible.

9.2.1 Acute Inflammations

Nonsuppurative (nonpurulent) inflammations These occur mostly as a spreading of inflammations from the sinuses.

Suppurative(purulent) inflammations These occur as purulent inflammations of the orbital soft tissue, mostly infection-induced. The most significant pathogens are staphylococci, often introduced as a result of wounds, with the recognized consequence of a phlegmonous inflammation; also phycomycosis occurs in the context of immunosuppression. The high mortality and grave local complications such as extensive thromboses are feared and difficult to prevent or treat. A distinguishing histologic feature is infiltration of the tissue through alternating densely packed granulocytes. These can be distributed diffusely through the tissue (phlegmonous) or be densely packed alongside each other, merging into necroses and an abscessing inflammation ( ▶ Fig. 9.1).

9.2.2 Chronic Inflammations

Nongranulomatous inflammations Unspecific processes without known cause are most frequently in this form.

Granulomatous inflammations An important example of these is chalazion as a local inflammation of the meibomian glands ( ▶ Fig. 9.2). Granulomatous inflammations are commonly caused by pathogens that include in particular mycobacteria, treponemes, bartonella henselae, fungi, and parasites (trichinosis, schistosomiasis). Autoimmune diseases can likewise feature granulomatous inflammation components (see below).

Cholesterol granulomas are the result of systemic or local metabolic disorders or lipid deposits (xanthelasma; see also xanthomatous tumors of the eyelids) in skin and soft tissue as the result of hematomas.

Systemic diseases such as sarcoidosis, Crohn’s disease, and giant cell polymyositis often likewise lead to granulomas.

Local autoimmune inflammations Sjögren’s syndrome is a disease of the lacrimal and salivary glands. There is a known close connection with the development of lymphomas (see below).

Idiopathic orbital inflammation (pseudotumor orbitae) This is a protracted inflammatory lesion, which is difficult to differentiate from a “genuine” lymphoma in conventional stainings. The inflammation is located in the orbital soft tissue. Histologically, there is a lymphocytic infiltrate of varying density with similarly variable accompanying fibrosis. Classification as a reactive change has been considerably facilitated by new molecular pathology processes (clonality analysis).

As radical removal does not affect survival and therefore a conservative approach is recommended, a reliable diagnosis becomes even more important.

9.3 Systemic Diseases Involving the Orbit

Basedow’s disease is typical within the context of the Merseburg triad; however, the exophthalmos can also occur without tachycardia and struma. Caused by a cross reaction of antibodies, inflammatory changes are produced in the soft tissue of the orbit and with associated exophthalmos. With continual improvement in the treatment of the underlying disease and suppression of the unfavorable influencing factors (smoking), this disorder has become rare in its typical form.

Other systemic diseases that can occur with involvement of the orbit are myasthenia gravis, myotonia dystrophica, myotonia congenita, mitochondrial myopathy, and dermatomyositis.

9.4 Neoplasias (Arranged Topographically)

9.4.1 Tumors of the Optic Nerve

General

Approximately 5 to 8% of all tumors of the orbit grow in the optic nerve. Histogenetically, the tumors can be attributed to the actual nerve tissue, to the sheath tissue and to blood vessels ( ▶ Table 9.2). As nerve tissue is ultimately an outgrowth of the brain, tumors are of glial differentiation. In addition there are meningiomas deriving from meningeal cells as well as angiomas deriving from the blood vessels. As there are melanocytes in the meninges, the occurrence of melanocytic tumors can easily be understood. In addition, mesenchymal cells, like histiocytic cells, can lead to separate tumors.

In contrast, primary tumors of epithelial origin are not to be expected and occur in the optic nerve only as metastases. The primary origin of lymphomas is debatable but here too the assumption of metastasis is the rule.

Hence the variability of primary tumors of the optic nerve is fairly straightforward. Due to the unfavorable location of these tumors, irrespective of whether benign or malignant, they are without exception problematic. Thus tumors that in other locations of the body would simply be excised are treated conservatively in the optic nerve or even simply kept under observation.

Benign Tumors

Meningioma

Meningiomas are tumors of the arachnoid cells, which are situated in the arachnoidal villi of the nerve sheaths. Meningiomas represent the most frequent tumor group in the optic nerve and can occur in all sections of the nerve, but their most common location is the apex (~80%). The biological behavior is benign for the most part (WHO grade I). There are a series of morphological variants ( ▶ Fig. 9.3). Atypical and anaplastic variants (WHO grade II or III) are rare in contrast to intracranial meningiomas. In children these tumors grow much more aggressively. The tumor is nearly always unilateral and occurs somewhat more frequently in women than in men. The age distribution is given variously in the literature. An association with von Recklinghausen’s disease has been reported very rarely.

Due to the very unfavorable location, if the vision is minimally affected a wait-and-see approach is discussed. Fractionated irradiation is performed in order to preserve the nerve. If sight is lost, surgical resection is performed. Recurrences are possible but rare.

Pilocytic astrocytoma

This is a benign tumor deriving from fibrous astrocytes. The frequently visible spindle cell–like offshoots of the tumor cells, which look like hairs, give the tumor its name. Of all tumors of the orbit 1 to 4% are pilocytic astrocytomas; 48% are found in the orbit, 28% in the intracranial section and 24% in both areas. Ninety percent of the tumors occur in the first two decades of life, but only rarely occur congenitally. Girls are more frequently affected (60/40). There is a known link with von Recklinghausen’s disease; 30% of all tumor patients have this disease. These patients can also experience multicentric growth.

Most pilocytic astrocytomas grow very slowly; some stop growing for some time and some show regression. Rapid growth and malignancy are an exception. Radiotherapy and surgical resection are possibilities. Growth in the chiasma or intracranially can lead to considerable difficulties in terms of curability.

Melanocytoma

Melanocytoma is a benign tumor, typically situated in the optic nerve, more rarely in the uvea and conjunctiva. Patients with dark pigmentation are more often affected. The tumor is constructed of densely packed melanocytic cells with a very prominent pigmentation with melanin.

Mostly only mild symptoms are reported and for the most part its discovery is by chance. A gray to black lesion is apparent opthalmoscopically on the optic nerve disc. It is very rare that both sides are affected.

For differential diagnosis, distinction from choroidal melanoma or necrotic juxtapapillary choroidal melanoma is important. Therapeutic inaction is justified in a significant proportion of the cases. Malignant transformation has been reported very rarely.

Astrocytic hamartoma

This is a benign and slow-growing tumorous of the optic disc and rarely of the surrounding retina. The tumor consists of spindle cells and squat astrocytes. There is a known association with tuberous sclerosis and neurofibromatosis (type 2).

Hemangioma

Capillary and cavernous hemangiomas arise at the optic disc and along the optic nerve. Capillary hemangiomas consist of small, densely packed vessels, lined with a flat endothelium without atypia ( ▶ Fig. 9.4). Capillary hemangiomas can grow endophytically and exophytically and into the vitreous humor and the head of the optic nerve. Sessile growth is also possible. There is a known link with von Hippel–Lindau disease. Capillary hemangiomas that feature fatty cells in the stroma and are associated with von Hippel-Lindau disease are termed angiomatosis retinae.

Juvenile xanthogranuloma

This is a benign and self-healing neoplasia with strikingly bluish/brownish and in part also reddish/yellow papules, sometimes as micronodular form or as nodules up to 20 mm. Histologically it is a mixed infiltrate of numerous histiocytes and Touton cells (giant cells) with sparse neutrophil and eosinophil granulocytes as well as lymphocytes. There is a known link with neurofibromatosis (Type 1 by far the majority). It most frequently occurs in the first year of life and is congenital in 5 to 17% of patients.

Tumors with Uncertain Biological Behavior

Hemangiopericytoma

(Current nomenclature is solitary fibrous tumor, SFT.) Origin in the cells of the meninges of the optic nerve is suggested. Histologically, there are bundles of spindle-shaped cells with irregularly shaped blood vessels running through them ( ▶ Fig. 9.5). The tumor tends to recur and in this respect the clinical behavior is not clearly benign. The tumor is noticed when it negatively affects the sight and CT shows a fusiform shape change of the optic nerve.

For a long time the designation of this tumor as a hemangiopericytoma and as a solitary fibrous tumor caused confusion. The latter designation was originally used for a mesenchymal tumor of the pleura. Since early this century it has been discovered that SFT occurs not only in the pleura but also at many other locations, including in the head area and there in the orbit and the nasal and sinus passages. It will be interesting to see how the designation of this tumor develops further.

Malignant Tumors

Malignant Astrocytoma

This is a malignant tumor that only rarely arises in the optic nerve. Histologically, atypical or pleomorphic tumor cells of glial differentiation are observable. Mitoses are numerous and necroses are repeatedly found. Those afflicted are mainly adults in the age range 20 to 80 years; the peak age is 52 years. Patients come to attention through a loss of sight; bilateral affliction via the chiasma occurs. Local destructive growth or infiltration of the dura accompany the growth of the tumor. The prognosis is poor, with a fatal outcome to the disease, mostly in the first year after diagnosis.

Primary malignant melanoma

Only rarely does a malignant melanoma occur as a primary in the optic nerve and the optic disc. The primary melanoma derives from melanocytes of the meninges. Correspondingly, a strong pigmentation of the nerve, as with a nevus ota, is associated with formation of a melanoma. Histologically, the scenario is similar to that in melanomas of other primary localization ( ▶ Fig. 9.6). By far the majority of melanomas in the optic nerve are the consequence of the involvement of juxtapapillary choroid melanomas or represent metastases. The prognosis is poor.

Metastases or secondary involvement

As described above, involvement of the optic nerve is possible through a juxtapapillary choroidal melanoma. Retinoblastomas can also metastasize in the optic nerve.

Within the context of acute and chronic leukemia it is quite common for the nerve (head) to be involved. These occur in various subtypes. Primary leukemias/lymphomas are extremely rare and are the subject of controversial debate.

Carcinoma metastases derive mainly from lung, breast, and stomach cancers. On the whole the prognosis of these metastases or secondary involvement is poor. Exceptions are leukemias/lymphomas. Prognosis has to be seen in relation to the underlying disease.

9.4.2 Tumors of the Conjunctiva and Caruncula

General

Tumors of the conjunctiva and caruncula, together with the tumors of the eyelids, constitute the most common tumors. A basic differentiation can be made between benign, premalignant, and malignant tumors. The most frequent tumors are epithelial, melanocytic, and lymphatic proliferates as well as choristomas, as reported in the case series of the AFIP and Doheny Eye Institute. Squamous cell carcinomas and their precursor lesions are reported to be the most common tumors in adults, while in children papillomas and choristomas represent the most significant tumor group ( ▶ Table 9.3).

In the melanocytic lesions, nevi represent the main group at 45%, but even so 36% have to be classed as melanomas (case series of the Doheny Eye Institute). Melanoses represent a further important group (with or without atypia).

Epithelial Tumors

Benign Tumours

Papillomas

Papillomas occur in all age groups but are more common in children. There is a close link to infection with the human papilloma viruses, in particular with serotypes 6, 11, and 16. Histologically, a deep, acanthotic squamous differentiated epithelium is laid over branching connective tissue branches.

Papillomas occur singly and in multiples. Both eyes can be affected. In children the place of origin is often the area around the caruncle, as well as around the semilunar fold on the inner canthus/fornix. In contrast, with adults the limbus is more often the primary site. Treatment for this is excision. Extensive and frequent recurrences can be treated, inter alia, with topically applied interferon.

Keratoacanthoma

Keratoacanthoma is a very rapidly growing squamous cell epithelial lesion, very similar to a highly differentiated squamous cell epithelial carcinoma. The tumor typically grows in an undermining fashion while forming a so-called shoulder. The differential diagnosis from squamous cell epithelial carcinoma is very difficult and in particular barely possible from the biopsy. This makes the clinical results even more important. A favorite location is the sun-exposed conjunctiva. The lesion grows in a few weeks and then remains stationary or regresses. It is treated by excision.

Hereditary benign intraepithelial dyskeratosis

This is dyskeratosis and acanthosis of the conjunctival epithelium within the context of a very rare autosomal dominant hereditary disease (also known as Witkop–von Sallman syndrome). It affects squamous epithelium of the conjunctiva, which appears in childhood as a grayish coloration of both eyes. The thickened and inflamed epithelium often occurs interpalpebrally (nasally and temporally). The disease goes on to recur chronically. It is treated surgically. Relapses are frequent but malignant transformation has so far not been reported. The diagnosis of this very rare disease emerges not least from the family case history.

Epithelial cysts

Epithelial cysts are translucent, in part bluish, lesions. A few are congenital, but mainly they are acquired (e.g., as the result of inflammation and trauma). The most frequent localizations are lower fornix and nasal conjunctiva. A simple squamous epithelium, in part infiltrated by goblet cells, lines the cysts. Variations with a double-row epithelium are possible. A simple excision is carried out to treat them.

Unspecific keratinizing lesions

These constitute a malfunction of a benign nature in the maturation of the conjunctival epithelium. A series of changes are grouped under this term. Histologically, there are squamous metaplasia and hyperkeratosis, which can appear without an apparent reason. A link has been established with a vitamin A deficiency.

A histologically similar change occurs as the result of conjunctiva that is too dry as in Sjögren’s disease, keratoconjunctivitis sicca, and following radiotherapy.

Pseudoepitheliomatous hyperplasia

Pseudoepitheliomatous hyperplasia is a reactive change of the epithelium in response to an inflammatory irritation. Histologically, there is a remarkable hyperplasia of the metaplastic squamous epithelium in which mitosis and dyskeratotic cells occur. This can make differentiation from squamous cell epithelium difficult (for this reason the name “pseudoepithelioma”). If granuloma occurs, one should think about a fungal infection in particular. After cessation of the cause the hyperplasia generally reduces in size.

Pseudoadenomatous hyperplasia

This is a benign glandlike proliferation that can be similar to a mucoepidermoid carcinoma.

Leukoplakia

The term leukoplakia (“white patch”) is a clinical term under which many benign as well as malignant changes are grouped together. Leukoplakia is caused by a thickening of the squamous (metaplastic) epithelium and/or a fibrosis in the stroma. As a result, the fine blood vessels are seen to a lesser extent and the color changes from reddish to whitish.

Often leukoplakias are caused by light damage, in particular through UVB rays. This causes a squamous metaplasia with the formation of increased keratin and a degeneration of the basic structure of collagen fibers with increased deposition of collagen debris. Three such disorders are prevalent:

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  Solar elastosis (no actual tumor formation): basophilic, stainable, clumpy degenerations are found in the stroma ( ▶ Fig. 9.7). A purely degenerative phenomenon and not spreading further beyond.

  
  
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  Pterygium: The above-described changes of actinic elastosis and keratosis in alternation lead to this interpalpebrally located change involving the cornea ( ▶ Fig. 9.8).

  
  
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  Actinic keratosis: see below under “Precancerous.”

  
  
  
  

  

  
  

  Fig. 9.7 Solar elastosis. Clumpy degenerative basophilic material represents degenerative elastic fibers. This degeneration is due to long-term extensive light exposure (H&E staining, magnification 20 × 10).

  
  
  
  

  

  
  

  Fig. 9.8 Pterygium. Clumpy degenerates of basophilic material in the stroma are located underneath a metaplastic squamous epithelium, which resembles a cutaneous solar elastosis (H&E staining, magnification 40 × 10).

Precancerous

Actinic keratosis

Here the epithelium is damaged, nearly always showing actinic elastosis. Keratinization is disturbed. Dysplasias of different degrees can develop right through to a carcinoma in situ/Bowen’s disease with possible transition to a squamous carcinoma.

Conjunctival intraepithelial neoplasias (IN)

Similarly to the concept of cervical intraepithelial neoplasia, the different stages of further neoplastic development of the conjunctival epithelium can be described in this terminology. Histologically, there is disruption in the structure of the squamous metaplastic epithelium. Slight, moderate, and severe dysplasias are distinguished in disruptions to the layers in the lower, in the lower and middle, and/or in all three parts of the epithelium. No clear distinction is made in the literature between severe dysplasia and carcinoma in situ or Bowen’s disease, or they are used synonymously to some extent.

As in cervical IN, the human papilloma virus is known to be a trigger of conjunctival IN; there are also significant physical or chemical noxae known. Intensified light exposure (working in the open air), the effects of oil raffinates, cigarette smoke, and long-term treatment with chemotherapeutics such as cyclosporine (e.g., in transplantation patients). A link to conjunctival pigmentation is also known. At the very least, severe dysplasias are excised as these are precancerous with a high risk of malignancy. Recurrences are frequent; a “field effect” is recognized.

Malignant Tumors

Squamous epithelial carcinoma (SEC)

This malignant tumor develops from a conjunctival IN and also does so without preliminary stages. Here the preexisting layers of the squamous epithelial differentiated epithelium ( ▶ Fig. 9.9) are raised. The atypia of the cells can be very marked in different ways and determine the various histologic gradings (good, moderate, minimal; or G₁, G₂, G₃). A well-differentiated SEC can be difficult to distinguish from a marked squamous epithelial hyperplasia. The decisive point is the breakthrough into the stroma as the criterion of malignancy.

The risk factors of conjunctival IN obviously also apply for SEC. Actinic damage is the most frequent reason for the development of an SEC. Sun-rich countries have therefore a correspondingly higher incidence (3.5/100,000 in Uganda v. 0.03/100,000 in the United States). The genetically predetermined pigmentation is significant (higher incidence in whites). A higher incidence has been observed in HIV-positive patients (predominantly in Africa: the coupling of two risk factors—light and immunodeficiency). Further risk factors are xeroderma pigmentosum, albinism, and exposure to chemical and physical noxae. HPV is under consideration as the catalyst (bilateral lesions) for the factors named.

Surgical excision with a safety margin of 3 to 5 mm is the goal. An intraoperative check should be made of the resection edges. Recurrences are found in ~6%, depending on operability. With an incomplete resection, chemotherapy drugs are applied topically. If the SEC is not eradicated successfully, the destructive growth and metastases result in a disastrous progression.

Variants of SEC are spindle cell carcinoma, mucoepidermoid carcinoma, and adenosquamous carcinoma.0

Basal cell carcinoma

For this entity refer to the description for tumors of the eyelid in Chapter ▶ 9.4.3.

Carcinoma of the sebaceous glands

Infiltrations of the conjunctiva by cells with a sebaceous differentiation or a carcinoma of the meibomian glands are a rarity. The carcinoma first reveals itself as a chronic inflammation that evades diagnosis for some time. Histologically, there are carcinoma cells with a foamy cytoplasm, in small groups or solid groupings over the entire width of the conjunctiva. The tumor growth is mostly slow. Cryotherapy and surgical excision are treatment possibilities.

Melanocytic Lesions/Tumors

Benign Lesions/Tumors

Melanocytic lesions are collections of melanocytes in atypical differentiation and/or in an unusual place and/or in unusual numbers. Extremely important are distinguishing benign from malignant lesions and ascertaining precancerous changes.

Nevi are far and away the leaders among melanocytic lesions. These occur as the second most frequent tumors in the conjunctiva. The incidence is reported as 0.0012/100,000. Favored locations are the bulbar conjunctiva and the limbus in the area toward the interpalpebral region.

Typically the lesions appear in childhood and then become bigger. Multiple lesions are possible. Malignant degeneration of such changes is very rare, however, which is why these lesions are treated conservatively. In contrast, nevi that appear in adulthood require closer attention. It can be necessary to excise them, particularly when they change shape, show more blood vessel involvement, and change color.

Histologically, a distinction can be made between junctional, compound, and subepithelial nevi. Junctional nevi grow in the epithelium of the conjunctiva. Compound nevi are found in the epithelium as well as in the underlying stroma. Subepithelial nevi are correspondingly only found in the stroma. The latter are not pigmented in general and the designation as melanocytic lesion is therefore confusing. As with amelanocytic melanoma, it nevertheless implies the involvement of melanocytic cells but ones that have lost the property of forming melanin.

Subepithelial lesions include ocular melanocytosis and oculodermal melanocytosis. The latter differs from the former through an involvement of the surrounding skin in the area of the supplying trigeminal nerve branch (nevus of ota). There is indeed increasing incidence overall for melanomas, though not in the conjunctiva.

Further variants are the blue nevus ( ▶ Fig. 9.10) and the Spitz nevus. These nevi are similarly situated in the skin and have the same histological criteria as discussed in Chapter ▶ 9.4.3.

In some racial groups varying pigmentation occurs also on both sides. Likewise, pigmentation alterations may be consequences of metabolic influences as well as of systemic or locally acting noxae. Primary and secondary melanoses can appear unilaterally. These can be significant with regard to a further development into melanomas.

Primary acquired melanosis (PAM) is another variant. PAMs are overwhelmingly one-sided pigmentation disorders of the conjunctiva that are not infrequent (more than 30% of adults). The lesions occur in middle-aged patients as brown flecks that have a tendency to grow. Histologically, melanocytic cells are found in the epidermis. With further development of the condition, there follow hyperplasia of the melanocytes and the formation of cell clusters. A distinction is then made between PAM without atypia and PAM with atypia. The latter is further subdivided into PAM with low risk and those with high risk for developing further into melanoma. The frequency of development into melanoma is given at various rates in the literature (more than 10% of the “high risk” PAMs).

Excision is recommended as treatment where there is enlargement of pigment flecks or in general when the diameter is greater than 2 to 3 mm. Topical chemotherapy drugs are also administered.

Malignant Lesions/Tumors

Malignant melanomas

Of all malignomas of the eye, 2% are conjunctival melanomas. After SEC it is the second most common malignoma. One must differentiate between primary melanomas, melanomas from nevus cell nevi, and melanomas from primary acquired melanoses. Histologically, the same malignant cells are present as described in Chapter ▶ 9.4.3. Melanomas are very rarely found in children and patients with black skin. The peak age lies in the fifth decade of life. The most frequent places of origin are the interpalpebral region and the bulbar conjunctiva.

Treatment is surgical. This is combined with cryotherapy to achieve complete freedom from tumor in the resection edges as well. Radiotherapy and/or chemotherapy can then follow. The local recurrence rate is 25 to 55%. Enucleation is done mostly in the palliative context but even enucleation does not prevent metastases. The first sites of the metastasizing melanoma are preauricular lymph nodes as well as the intraparotidal nodes, followed by the submandibular and cervical nodes.

The Clark or Breslow classification system used for melanomas of the skin cannot be used for conjunctival melanomas. The absolute tumor thickness is decisive. From a thickness of 0.8 mm the prognosis deteriorates considerably. For tumors between 1 and 4 mm, the mortality rate is increased by a factor of 2; if the melanoma is >4 mm in thickness, the factor is 4. The 5-year survival rate lies between 77 and 86%; the 10-year survival between 64 and 73%. In producing or viewing the pathological findings one should pay attention to all of the numerous factors (refer to Chapter ▶ 9.1.2).

Mesenchymal Tumors

Benign

Vascular lesions

Benign lesions include capillary telangiectasias, vascular deformities, and lymphangiectasias. The last two mentioned also occur within the context of syndromes such as the Sturge–Weber syndrome and ataxia telangiectatica. Also to be considered are pyogenic granulomas/capillary hemangiomas, cavernous hemangiomas, and lymphangiomas. Their histological structure equates to those in other sites of the body.

Myxomas

Myxomas are rare benign tumors that occur in isolation or are seen within the context of the Carney complex. Histologically, there is tissue with relatively few cells comprising star-shaped cells with soft cytoplasmic offshoots. In between there is a substantial amount of myxoid substance. Myxomas are painless and well-defined tumors of the bulbar conjunctiva with a typical gelatinlike consistency.

Myxomas need to be differentiated from myxoid neurofibroma, nerve sheath myxoma, spindle cell lipoma, and lymphangioma. In children it must be differentiated from rhabdomyosarcoma. Simple excision is the treatment of choice. There are no reports of recurrences.

Malignant

Fibrous histiocytoma

Benign and malignant lesions are possible. Histiocytomas originate in the stroma of the conjunctiva and show the same histological structure as in other parts of the body. The most favored locations are the limbus and the epibulbar conjunctiva.

Treatment is surgical. Recurrences and metastases depend on the completeness of the excision and also on the histological degree.

Rhabdomyosarcoma

This malignant tumor of childhood occurs in the area of the conjunctiva, predominantly as a botryoid type. Histologically, there are spindle-shaped and round rhabdomyoblasts, which only exhibit cross-striation in a small number of cases. Large hyperchromatic cell nuclei are surrounded by an eosinophilic cytoplasm. In addition, there are smaller spindle tumor cells in the tumor matrix accompanied by cystic changes. Very typical is a ribbonlike infiltrate of several layers of tumor cells subepithelially, which is classed as a cambium layer. Quite often the tumor grows initially without any significant accompanying inflammation, which can lead to a delay in diagnosis. Rapidly growing tumors in childhood are fundamentally suspicious and must be clarified.

Primary chemotherapy and, where applicable, radiotherapy have decisively improved the chances of a cure in the last few decades and enabled the survival of many children.

Kaposi’s sarcoma

Kaposi’s sarcoma is a malignant tumor that appears in ~20% of patients suffering from AIDS. In 4 to 14% of AIDS patients it is the first clinical sign. A classification system has been suggested that makes it possible to assess diagnosis, postoperative management, and further clinical course better. Types I, II, and III are proposed, with a progressive clinical picture.

Local excision with a safety margin (1–2 mm) is aimed at, followed by cryotherapy. Radiotherapy and local injection of chemotherapy drugs and interferons are supplementary measures or alternatives.

Lymphomas

Primary benign and malignant lymphomas include a series of entities. These range from simple (follicular) lymphatic hyperplasia right through to aggressive, destructive lesions. The most frequent subtype is the extranodal marginal zone lymphoma (EMZL) originating from mucosa-associated lymphatic tissue (MALT). It is important to differentiate MALT lymphoma from follicular lymphoma, lymphoplasmacytic lymphoma, and chronic lymphatic leukemia of the B-cell type (B-CLL). Other lymphoma entities can occur but are very rare. Determination of the histological subtype is important for the prognosis and treatment. For example, while EMZL often shows an indolent growth (~70% remain without systemic spread), other lymphomas, such as the diffuse large cell B-cell lymphoma, are distinctly more aggressive and life-threatening (average survival 3 to 5 years).

Plasmocytoma

Plasmocytomas of the conjunctiva occur predominantly within the context of a multiple myeloma. It is rare to find a primary solitary plasmocytoma in the conjunctiva. Plasmocytomas are circumscribed reddish lesions that histologically consist of dense infiltrates of plasmacytoid cells. Various differentiation grades can occur. These tumors mostly occur in the fornix, bulbarly or tarsally. Usually the picture is of inflammation. Slow progression is reported with solitary plasmocytoma.

Metastases

Only rarely are metastases found in the conjunctiva, then mainly from breast and lung cancers as well as melanomas of the skin. Interestingly, metastasizing melanomas of the conjunctiva often have their primary in the lower extremities or the trunk. The prognosis is poor and accordingly treatment is palliative.

Congenital Tumorlike Lesions

Dermoid

Dermoids are cysts lined with layered squamous epithelium, sometimes with skin appendages in the cyst wall ( ▶ Fig. 9.11). Fatty tissue can also occur in the wall. A lining of conjunctival epithelium is also possible. The preferred location is at the inferotemporal limbus. Excision is the usual treatment.

Ectopic lacrimal glands

The lesion’s name is self-explanatory; in this condition the tear duct tissue is of normal form. It can be found in isolation, a combination with a choristoma is possible.

Complex choristoma

A choristoma arises from the proliferation of regular tissue in a location not typical for that tissue (e.g., adrenal cortex in the kidney). Tissue of the tear duct, cartilage, bone, brain tissue, and other tissue can be involved in a complex choristoma of the conjunctiva. Osseous choristoma is a bony lesion supratemporally between the superior rectus and lateralis muscles, and is situated ~5 mm behind the limbus.

9.4.3 Tumors of the Eyelids

General

Given the nature of the eyelids, tumors are found there that can also be found in other areas of the skin. Particular mention should be made basal cell carcinoma and squamous epithelium carcinoma, which often develop as a consequence of damage by light. Tumors can also develop from the skin adnexa. Some particular glands demonstrate similar differentiation in both their benign and their malignant variants (e.g., sebaceous gland adenonomas and carcinomas). Melanocytic tumors should also be considered, which are classified analogously to those of the rest of the skin ( ▶ Table 9.4).

Epithelial Tumors (of the Outer Skin)

Benign

Seborrheic keratosis (verruca senilis, seborrheic warts, basal cell papilloma)

Histologically, these benign lesion of the skin are formed from an expanded squamous epithelium, in part of basal cellular differentiation ( ▶ Fig. 9.12). Horn pearls are found enclosed. Growth variants are possible (hyperkeratotic, acanthotic, adenoid). Intensified pigmentation makes it difficult to differentiate from basalioma among others. Inflammatory irritated forms can be difficult to classify histologically. Malignant transformation is not known. Excision is the treatment of choice.

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