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Background

Ocular melanomas are a different disease than its cutaneous counterpart. Uveal (choroidal) melanomas are the most common site comprising 85% of cases. Other sites include: ciliary body, iris, and conjunctiva.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

EPIDEMIOLOGY CHARACTERIZATION
INCIDENCE

CA Cancer J Clin 1991;41:1

1200 new cases diangosed each year
6 cases/6,000,000
Stable in incidence
Second most common location for primary melanoma after the skin

AGE RANGE-MEDIAN Average 55 years

 

DISEASE ASSOCIATIONS CHARACTERIZATION
Dysplastic nevus syndrome

Int J Cancer 1995;60:662

In 211 cases of ocular melanoma, 9% had this syndrome

Neurofibromatosis  
Nevoid basal cell carcinoma syndrome
(Gorlin's syndrome)
 
Breast and ovarian cancer patients with BRCA2 mutations

Eye 1999;13:43

20 fold increased risk of ocular melanomas

 

PATHOGENESIS CHARACTERIZATION
Uveal melanomas

Eye 1999;13:43

Loss of chromosome 3 and duplication of 8q

Patients with both cutaneous and ocular melanomas have shown alterations of 9p13.22 with mutations on p16 gene (CDKN2A)

 

LABORATORY CHARACTERIZATION
FISH  


Distinction of conjunctival melanocytic nevi from melanomas by fluorescence in situ hybridization.
Busam KJ, Fang Y, Jhanwar SC, Pulitzer MP, Marr B, Abramson DH.

Department of Pathology, Ophthalmologic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

J Cutan Pathol. 2010 Feb;37(2):196-203. Abstract quote

A conjunctival melanocytic nevus may on occasion be difficult to distinguish from melanoma both clinically and histopathologically. An unambiguous correct diagnosis is critical because of major differences in management and prognosis.

We evaluated a fluorescence in situ hybridization (FISH) assay, which has previously been shown to be of value for the diagnosis of melanocytic nevi and melanomas of the skin, using probes targeting 6p25 (RREB1), 6q23 (MYB), 11q13 (CCND1) and centromere 6 (CEP6), for its potential to assist in the distinction of conjunctival melanocytic nevi from melanomas. Four melanocytic nevi and eight melanomas of the conjunctiva were analyzed. Two of the melanomas were diagnostically problematic because of suboptimal histopathology. None of the conjunctival melanocytic nevi showed a level of chromosomal aberrations that met FISH criteria for a diagnosis of melanoma. All eight conjunctival melanomas (six unequivocal and two suspicious lesions) met FISH criteria for melanoma. Thus, results from FISH assay targeting 6p25, 6q23, 11q13 and centromere 6 correlated well with the histopathologic diagnoses and supported the histopathologic suspicion in two problem cases.

The findings encourage further exploration of this technique as an ancillary method for the work-up of conjunctival melanocytic proliferations.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
General  
Uveal (Choroidal)

Most common
85% of ocular melanomas

Most form mushroom arising from the choroid, especially if it invades beyond Bruch's membrane

Ciliary body

7-10% of ocular melanomas

Detected later since tumor does not impede vision until it reaches a significant size

Iris

5-8% of ocular melanomas

Mean age of 44 years

Conjunctiva
Least common
2% of ocular melanomas
VARIANTS  
Bilateral diffuse uveal melanocytic proliferation (BDUMP)

Arch Ophthalmol 1982;100:24955.

In rare patients with an extraocular cancer, the uveal melanocytes of both eyes suddenly begin to proliferate and, over the course of a few months, the entire uveal tract becomes thickened

Painless decreased visual acuity secondary to serous retinal detachments and rapidly maturing cataracts
Mild to moderate uveitis and dilated episcleral vessels
Always bilateral

Acquired extraocular hyperpigmentation was documented in five cases of BDUMP:
Oral mucosa
Shoulder
Neck
Head [nevus of Ito]
Vulva
Rectum
Penis
Mouth

No cutaneous melanomas have been reported

Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) Associated With Extraocular Cancers

Am J Surg Pathol 2001;25:212-218

Average patient age at the time of the diagnosis was 63 years (range, 3489 years)

13 women and 7 men
In approximately half of the cases, the ocular symptoms antedated those of the inciting tumor

Most of the inciting tumors were poorly differentiated carcinomas. Most common tumors were from the female genital tract (ovary and uterus) among the women patients and from the lung among the men. Tumors from the breast were rare (one possible case), and tumors of the prostate were conspicuously absent

All five inciting tumors whose histopathology was reviewed expressed neuron-specific enolase, but none prominently expressed antigens more specific for neuroendocrine carcinomas such as chromogranin or synaptophysin:

Undifferentiated endometrial carcinoma
Ovarian carcinomas, moderately and poorly differentiated
Large-cell lung carcinoma (giant cell type)
Poorly differentiated adenocarcinoma of unknown origin

Four of the five tumors showed areas of necrosis

Speculate the loss and dysfunction of the retinal pigment epithelium is caused by outer retinal hypoxia, which is present even though there is a relatively uninvolved choriocapillaris, because of the metabolic load of the numerous proliferating melanocytes

 

HISTOLOGICAL TYPES CHARACTERIZATION
General Trans Am Acad Ophthalmol Otolaryngol 1931;26:131
Spindle A
Cohesive with poorly defined borders and folded nuclei
Spindle B
Larger than A cells with prominent nucleoli rather than nuclear folds
Fascicular
Palisaded arrangement of spindle B cells
Mixed spindle and epithelioid
 
Necrotic
 
Epithelioid
Distinct cell borders with large nuclei and prominent nucleoli
VARIANTS  
Uveal (Choroidal)
86% composed of mixed spindled and epithelioid cells
9% spindle cells
5% epithelioid cells
Ciliary body
 
Iris
Predominately low grade spindle A cells
Conjunctiva
 
VASCULOGENIC MIMICRY  
Distinguishing fibrovascular septa from vasculogenic mimicry patterns.

Lin AY, Maniotis AJ, Valyi-Nagy K, Majumdar D, Setty S, Kadkol S, Leach L, Pe'er J, Folberg R.

Department of Pathology, University of Illinois at Chicago, IL 60612, USA.

Arch Pathol Lab Med. 2005 Jul;129(7):884-92. Abstract quote  

CONTEXT: Molecular analyses indicate that periodic acid-Schiff (PAS)-positive (laminin-rich) patterns in melanomas are generated by invasive tumor cells by vasculogenic mimicry. Some observers, however, consider these patterns to be fibrovascular septa, generated by a stromal host response.

OBJECTIVE: To delineate differences between vasculogenic mimicry patterns and fibrovascular septa in primary uveal melanomas.

DESIGN: Frequency distributions, associations with outcome, and thicknesses of trichrome-positive and PAS-positive looping patterns were determined in 234 primary uveal melanomas. Sequential sections of 13 additional primary uveal melanomas that contained PAS-positive/trichrome-negative looping patterns were stained for type I and type IV collagens, laminin, and fibronectin. Real-time quantitative polymerase chain reaction was performed on RNA from cultured uveal melanoma cells for the expression of COL1A1, COL4A2, and fibronectin.

RESULTS: Trichrome-positive loops were encountered less frequently than PAS-positive loops (10% vs 56%, respectively). Death from metastatic melanoma was strongly associated with PAS-positive (P < .001) but not with trichrome-positive (P = .57) loops. Trichrome-positive loops were significantly thicker than PAS-positive loops (P < .001). The PAS-positive patterns stained positive for laminin, type I and type IV collagens, and fibronectin. Type I collagen was detected within melanoma cells and focally within some PAS-positive patterns. Real-time quantitative polymerase chain reaction revealed 3-fold, 25-fold, and 97-fold increases, respectively, in expression of COL4A2, fibronectin, and COL1A1 by invasive pattern-forming primary melanoma cells compared with poorly invasive non-pattern-forming cells.

CONCLUSIONS: Fibrovascular septa are rare and prognostically insignificant in uveal melanomas, whereas vasculogenic mimicry patterns are associated with increased mortality. Type I collagen, seen focally in some vasculogenic mimicry patterns, may be synthesized by tumor cells, independent of a host stromal response.

Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry.

Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS, Hendrix MJ.

Department of Anatomy, University of Iowa Cancer Center, University of Iowa College of Medicine, Iowa City, USA.

Am J Pathol. 1999 Sep;155(3):739-52 Abstract quote.  

Tissue sections from aggressive human intraocular (uveal) and metastatic cutaneous melanomas generally lack evidence of significant necrosis and contain patterned networks of interconnected loops of extracellular matrix. The matrix that forms these loops or networks may be solid or hollow.

Red blood cells have been detected within the hollow channel components of this patterned matrix histologically, and these vascular channel networks have been detected in human tumors angiographically. Endothelial cells were not identified within these matrix-embedded channels by light microscopy, by transmission electron microscopy, or by using an immunohistochemical panel of endothelial cell markers (Factor VIII-related antigen, Ulex, CD31, CD34, and KDR[Flk-1]). Highly invasive primary and metastatic human melanoma cells formed patterned solid and hollow matrix channels (seen in tissue sections of aggressive primary and metastatic human melanomas) in three-dimensional cultures containing Matrigel or dilute Type I collagen, without endothelial cells or fibroblasts. These tumor cell-generated patterned channels conducted dye, highlighting looping patterns visualized angiographically in human tumors. Neither normal melanocytes nor poorly invasive melanoma cells generated these patterned channels in vitro under identical culture conditions, even after the addition of conditioned medium from metastatic pattern-forming melanoma cells, soluble growth factors, or regimes of hypoxia. Highly invasive and metastatic human melanoma cells, but not poorly invasive melanoma cells, contracted and remodeled floating hydrated gels, providing a biomechanical explanation for the generation of microvessels in vitro. cDNA microarray analysis of highly invasive versus poorly invasive melanoma tumor cells confirmed a genetic reversion to a pluripotent embryonic-like genotype in the highly aggressive melanoma cells.

These observations strongly suggest that aggressive melanoma cells may generate vascular channels that facilitate tumor perfusion independent of tumor angiogenesis.

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
PRIMARY ACQUIRED MELANOSIS

Hum Pathol 1985;16:136

Divided into cases without atypia and with atypia
Atypical lesions are considered premalignant and 45% progress to melanoma

Low-risk and High-risk Histologic Features in Conjunctival Primary Acquired Melanosis With Atypia: Clinicopathologic Analysis of 29 Cases.

*Department of Pathology, Massachusetts General Hospital Harvard Medical School daggerDepartment of Ophthalmology, Massachusetts Eye and Ear Infirmary Harvard Medical School, Boston, MA.

 

Am J Surg Pathol. 2007 Feb;31(2):185-192. Abstract quote

The current World Health Organization classification of conjunctival melanocytic proliferations divides them into conjunctival nevi and invasive melanoma but, in contrast to other anatomic sites, does not recognize melanoma in situ. All atypical intraepithelial conjunctival proliferations are included in a heterogeneous category designated as primary acquired melanosis (PAM) with atypia.

We performed clinicopathologic analysis of 29 cases of PAM with atypia. On the basis of histologic features and frequency of association with invasive melanoma and metastases, we were able to divide our cases into 2 histologic groups. The low-risk group (13 cases) included lesions composed of small to medium size melanocytes with high nuclear to cytoplasmic ratio and small to medium size hyperchromatic nuclei devoid of nucleoli showing predominantly single cell lentiginous growth pattern. Invasive melanoma occurred in only 2 cases from this group. None of these lesions metastasized. The second, high-risk group (16 cases), showed increased frequency of association with invasive melanoma (15/16 cases, 94%) and metastases (4/16 cases, 25%).

These lesions were more heterogeneous architecturally but were all composed of melanocytes showing various degrees of epithelioid features such as abundant cytoplasm, vesicular nuclei, or prominent nucleoli. In 4 cases discrete areas showing high-risk and low-risk features were identified. All 4 lesions were associated with invasion.

Our findings offer a practical approach for prognostically useful subclassification of PAM with atypia, which emphasizes cytologic features of intraepithelial conjunctival melanocytic proliferation.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
Prognostic Factors  

Cytomorphometric Parameters and the Metastatic Potential of Cutaneous and Uveal Melanoma A Comparison with Prognostic Factors

Francisco Burnier Pereira, M.D.; Miguel N. Burnier Jr., M.D., Ph.D.; Henry Shibata, M.D.; Beatrice Wang, M.D.; Wayne Carey, M.D.

From the Henry C. Witelson Eye Pathology Laboratory, Departments of Ophthalmology and Pathology (F.B.N., M.N.B.); The Department of Dermatology (B.W., W.L.); and Department of Oncology (H.S.). The Royal Victoria Hospital, McGill University, Montreal, Canada.

Am J Dermatopathol 2001;23:304-307 Abstract quote

The Mean of the Ten Largest Nuclei (MTLN1) is one of the most important prognostic factors in uveal malignant melanoma.

This study was performed to investigate the applicability of nuclear and nucleolar measurements as a prognostic factor for cutaneous melanoma. A routine light microscope (Carl Zeiss: Axiophot EL-Einnsatz; #451888) at 640 times magnification with a Micrometer Eye Piece (Carl Zeiss: #444034) was used to evaluate the correlation of MTLN1 and Mean of Ten Largest Nuclei (MTLN) with the occurrence of metastasis in 58 primary cutaneous melanoma.

For uveal melanoma, cytologic classification was used for comparison. Prognostic value was determined by univariate and multivariate linear regression analysis. MTLN1 was the only significant factor for uveal melanoma (p = 0.05). For cutaneous melanoma, all factors were significantly associated with disease progression. MTLN1 was the only one to remain significant (p + 0.027) in multivariate linear regression analysis.

Nuclear and nucleolar morphometry are significant prognostic factors for uveal and cutaneous melanoma.

Survival  
Uveal (Choroidal)

J Am Acad Dermatol 1998;38:716

Overall mortality of 25-40%

Ciliary body
40% mortality
Iris
5% due to externally visible location
Conjunctiva

Hum Pathol 1985;16:136

5 and 10 YRS are 85% and 70%
Poorer prognosis due to lymphatic access
Poorer prognosis with cases derived from primary acquired melanosis and cases which show pagetoid spread

Metastasis Uveal melanomas have marked propensity to metastasize to the liver
Treatment  
Uveal (Choroidal)
Enucleation or radiation
Ciliary body
 
Iris
 
Conjunctiva
 


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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.


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Last Updated February 2, 2010

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