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Intraocular (Uveal) Melanoma Treatment (PDQ®)

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Last Modified: 04/11/2014

Classification and Stage Information for Intraocular (Uveal) Melanoma

Tumor Size
Metastatic Disease
Staging
        Definitions of TNM
        Prognostic features



Tumor Size

Uveal melanoma most often assumes a nodular or dome-shaped configuration, but occasionally tumors can be flat or diffuse and involve extensive areas of the uvea with little elevation.

Tumor size classifications according to boundary lines used in a Collaborative Ocular Melanoma Study (COMS) are as follows:[1]

  1. Small: Range from 1.0 mm to 3.0 mm in apical height and largest basal diameter of 5.0 to 16.0 mm.[1]
  2. Medium: Range from 3.1 to 8.0 mm in apical height and a basal diameter of not more than 16.0 mm.[2]
  3. Large: Greater than 8.0 mm in apical height or a basal diameter more than 16.0 mm, when the apical height is at least 2.0 mm.

Although most ocular melanomas have a raised configuration, about 5% grow in a diffuse pattern that also may have prognostic significance. The tumors have a horizontal, flat-growth pattern, with the thickness measuring approximately 20% or less than the greatest basal dimension. This uncommon variant of uveal melanoma seems to have a poorer prognosis, particularly when the diameter is large, and the margins are poorly defined.[3]

In clinical practice, the tumor base may be estimated in average optic disc diameters (1 dd = 1.5 mm). The average elevation may be estimated in diopters (3 diopters = 1 mm). Other techniques, such as ultrasonography, should be used to provide more accurate measurements.

An important function of ophthalmic ultrasonography is the detection of extrascleral extension.[4,5] Extrascleral extension measuring 2 mm or more in thickness can be demonstrated provided it is located behind the equator where the intraocular tumor, sclera, and adjacent orbital fat are readily imaged.[6] Orbital extraocular extension of choroidal melanoma may be found in eyes with medium and large tumors, but it is very rare in eyes with small melanomas.

Metastatic Disease

Systemic metastases are evident in only 1% to 4% of patients at the time of diagnosis of the primary ocular melanoma.[7] Because the uveal tract is a vascular structure without lymphatic channels, tumor spread occurs principally by local extension and by dissemination through the blood stream. Lymphatic spread is rare but may occur after local extension into the conjunctiva and its lymphatics.[8] Given the rarity of nodal metastases, sentinel node biopsies of nonclinically involved nodes are not done as part of the staging procedure.[7]

Systemic metastases are generally hematogenous in origin, and the first site identified is usually the liver.[9] Lung, bone, and subcutaneous sites are also common.[9] In the COMS trials, the liver was the only site of detectable metastasis in 46% of patients with metastases reported during follow-up or at the time of death; 43% had metastases diagnosed in the liver and other sites.[9] In patients with a history of ocular melanoma who present with hepatic metastases of unknown origin, metastatic melanoma should be considered in the differential diagnosis.

It is particularly unusual for choroidal melanomas of any size to invade the optic nerve or its meninges.[10] Metastasis of choroidal melanoma to the contralateral choroid is also rare.[9,11]

Staging

Definitions of TNM

An American Joint Committee on Cancer staging system has been developed for melanoma of the uveal tract.[7]

Table 1. Primary Tumor (T)a,b
All Uveal Melanomas  
TXPrimary tumor cannot be assessed.
T0No evidence of primary tumor.
Iris c
T1Tumor limited to the iris.
T1aTumor limited to the iris not more than 3 clock hours in size.
T1bTumor limited to the iris more than 3 clock hours in size.
T1cTumor limited to the iris with secondary glaucoma.
T2Tumor confluent with or extending into the ciliary body, choroid, or both.
T2aTumor confluent with or extending into the ciliary body, choroid, or both, with secondary glaucoma.
T3Tumor confluent with or extending into the ciliary body, choroid, or both, with scleral extension.
T3aTumor confluent with or extending into the ciliary body, choroid, or both, with scleral extension and secondary glaucoma.
T4Tumor with extrascleral extension.
T4aTumor with extrascleral extension ≤5 mm in diameter.
T4bTumor with extrascleral extension >5 mm in diameter.
Ciliary Body and Choroidd
T1Tumor size category 1.
T1aTumor size category 1 without ciliary body involvement and extraocular extension.
T1bTumor size category 1 with ciliary body involvement.
T1cTumor size category 1 without ciliary body involvement but with extraocular extension ≤5 mm in diameter.
T1dTumor size category 1 with ciliary body involvement and extraocular extension ≤5 mm in diameter.
T2Tumor size category 2.
T2aTumor size category 2 without ciliary body involvement and extraocular extension.
T2bTumor size category 2 with ciliary body involvement.
T2cTumor size category 2 without ciliary body involvement but with extraocular extension ≤5 mm in diameter.
T2dTumor size category 2 with ciliary body involvement and extraocular extension ≤5 mm in diameter.
T3Tumor size category 3.
T3aTumor size category 3 without ciliary body involvement and extraocular extension.
T3bTumor size category 3 with ciliary body involvement.
T3cTumor size category 3 without ciliary body involvement but with extraocular extension ≤5 mm in diameter.
T3dTumor size category 3 with ciliary body involvement and extraocular extension ≤5 mm in diameter.
T4Tumor size category 4.
T4aTumor size category 4 without ciliary body involvement and extraocular extension.
T4bTumor size category 4 with ciliary body involvement.
T4cTumor size category 4 without ciliary body involvement but with extraocular extension ≤5 mm in diameter.
T4dTumor size category 4 with ciliary body involvement and extraocular extension ≤5 mm in diameter.
T4eAny tumor size category with extraocular extension >5 mm in diameter.

aReprinted with permission from AJCC: Malignant melanoma of the uvea. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 547-59.
bThese definitions apply to both clinical and pathologic staging.[12] Note: In clinical practice, the largest tumor basal diameter may be estimated in optic disc diameters (dd, average: 1 dd = 1.5 mm). Tumor thickness may be estimated in diopters (average: 2.5 diopters = 1 mm). However, techniques such as ultrasonography and fundus photography are used to provide more accurate measurements. Ciliary body involvement can be evaluated by the slit-lamp, ophthalmoscopy, gonioscopy, and transillumination. However, high-frequency ultrasonography (ultrasound biomicroscopy) is used for more accurate assessment. Extension through the sclera is evaluated visually before and during surgery, and with ultrasonography, computed tomography, or magnetic resonance imaging. Note: When histopathologic measurements are recorded after fixation, tumor diameter and thickness may be underestimated because of tissue shrinkage.
cIris melanomas originate from, and are predominantly located in, this region of the uvea. If less than half of the tumor volume is located within the iris, the tumor may have originated in the ciliary body and consideration should be given to classifying it accordingly.
dPrimary ciliary body and choroidal melanomas are classified according to four tumor-size categories.

Table 2. Regional Lymph Nodes (N)a
aReprinted with permission from AJCC: Malignant melanoma of the uvea. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 547-59.
NXRegional lymph nodes cannot be assessed.
N0No regional lymph node metastasis.
N1Regional lymph node metastasis.

Table 3. Distant Metastasis (M)a
aReprinted with permission from AJCC: Malignant melanoma of the uvea. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 547-59.
M0No distant metastasis.
M1Distant metastasis.
M1aLargest diameter of the largest metastasis ≤3 cm.
M1bLargest diameter of the largest metastasis 3.1–8.0 cm.
M1cLargest diameter of the largest metastasis ≥8 cm.

Table 4. Anatomic Stage/Prognostic Groupsa
Stage T N M 
aReprinted with permission from AJCC: Malignant melanoma of the uvea. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 547-59.
IT1aN0M0
IIAT1b–dN0M0
T2aN0M0
IIBT2bN0M0
T3aN0M0
IIIAT2c–dN0M0
T3b–cN0M0
T4aN0M0
IIIBT3dN0M0
T4b–cN0M0
IIICT4d–eN0M0
IVAny TN1M0
Any TAny NM1a–c

There are a variety of other factors that are not part of the AJCC staging system but that may help in refining estimates of prognosis.[7]

Prognostic features

There are a number of key prognostic features that are important to collect in malignant melanoma of the uvea, even though they are not included in staging algorithms. These include the following:[7]

Molecular features
  1. Chromosomal alterations.
    1. Chromosome 3 status (loss or no loss; complete or partial).
    2. Chromosome 6p status (gain or no gain).
    3. Chromosome 8q status (gain or no gain).

      Indicate:

      • Technique used for assessing chromosome status may include the following:
        • Karyotyping.
        • Fluorescence in situ hybridization.
        • Comparative genomic hybridization.
        • Loss of heterozygosity using DNA polymorphism analysis (e.g., single nucleotide polymorphism, microsatellite).
        • Other.

      • How specimen was obtained may include the following:
        • Enucleation.
        • Local resection.
        • Biopsy.
        • Fine-needle aspiration biopsy.

      • For needle biopsies, whether cytopathologic evaluation was performed to confirm the presence of tumor cells.

  2. Gene-expression profile: class 1 or class 2.

    Indicate:

    • Technique used for gene-expression profiling (e.g., microarray, pathologic complete response).
    • How specimen was obtained (e.g., enucleation, local resection, biopsy, fine-needle aspiration biopsy).
    • For needle biopsies, whether cytopathologic evaluation was performed to confirm the presence of tumor cells.
Clinical and histopathologic features
  1. Clinical.
    1. Positron-emission tomography/computed tomography.
      • 18-Fluorine-labelled 2-deoxy-2-fluoro-D-glucose standardized uptake values (higher values in primary tumor may be associated with shorter survival).
    2. Confocal indocyanine green angiography.
      • Identification of complex monocirculatory patterns (i.e., loops, networks, arcs with branching, parallel with cross-linking or a combination of these patterns may be associated with shorter survival).
  2. Histopathologic.
    1. Mitotic count.
      • Number of mitotic figures per 40 high-power fields (typical field area 0.15–0.19 mm2, higher counts are associated with shorter survival).
    2. Mean diameter of the ten largest nucleoli.
      • Mean of the longest nucleoli (MLN) is measured along a central 5-mm long strip, e.g., after silver staining (larger values are associated with shorter survival).
    3. Presence of extravascular matrix patterns.
      • Loops.
        • Absent.
        • Present (shorter survival).
      • Loops forming networks.
        • Absent.
        • Present (shorter survival).
      • Other complex patterns (arcs with branching, parallel with cross-linking; absent or present).

        The patterns are assessed with light microscopy under a dark green filter after staining with periodic-acid Schiff without counterstain.

    4. Microvascular density.
      • Number of immunopositive elements labeled with markers for vascular endothelial cells (e.g., CD34 epitope, factor VIII-related antigen) in areas of densest vascularization (typical field area 0.31 mm2, higher counts are associated with shorter survival).
    5. Insulin-like growth factor 1 receptor (IGF1-R).
      • Percentage of immunopositive tumor cells (high expression is associated with shorter survival).
    6. Tumor-infiltrating lymphocytes.
      • Few (longest survival).
      • Moderate numbers.
      • Many (shortest survival).
    7. Tumor-infiltrating macrophages.
      • Few (longest survival).
      • Moderate numbers.
      • Many (shortest survival).

        The number can be compared with standard photographs.[13]

    8. HLA Class I expression.
      • Percentage of immunopositive tumor cells (low expression is associated with longer survival).
References
  1. Factors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol 115 (12): 1537-44, 1997.  [PUBMED Abstract]

  2. Diener-West M, Earle JD, Fine SL, et al.: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, II: characteristics of patients enrolled and not enrolled. COMS Report No. 17. Arch Ophthalmol 119 (7): 951-65, 2001.  [PUBMED Abstract]

  3. Shields CL, Shields JA, De Potter P, et al.: Diffuse choroidal melanoma. Clinical features predictive of metastasis. Arch Ophthalmol 114 (8): 956-63, 1996.  [PUBMED Abstract]

  4. Scott IU, Murray TG, Hughes JR: Evaluation of imaging techniques for detection of extraocular extension of choroidal melanoma. Arch Ophthalmol 116 (7): 897-9, 1998.  [PUBMED Abstract]

  5. Romero JM, Finger PT, Iezzi R, et al.: Three-dimensional ultrasonography of choroidal melanoma: extrascleral extension. Am J Ophthalmol 126 (6): 842-4, 1998.  [PUBMED Abstract]

  6. Echography (ultrasound) procedures for the Collaborative Ocular Melanoma Study (COMS), Report no. 12, Part I. J Ophthalmic Nurs Technol 18 (4): 143-9, 1999 Jul-Aug.  [PUBMED Abstract]

  7. Malignant melanoma of the uvea. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 547-59. 

  8. Dithmar S, Diaz CE, Grossniklaus HE: Intraocular melanoma spread to regional lymph nodes: report of two cases. Retina 20 (1): 76-9, 2000.  [PUBMED Abstract]

  9. Diener-West M, Reynolds SM, Agugliaro DJ, et al.: Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol 123 (12): 1639-43, 2005.  [PUBMED Abstract]

  10. Shields CL, Santos MC, Shields JA, et al.: Extraocular extension of unrecognized choroidal melanoma simulating a primary optic nerve tumor: report of two cases. Ophthalmology 106 (7): 1349-52, 1999.  [PUBMED Abstract]

  11. Singh AD, Shields JA, Shields CL, et al.: Choroidal melanoma metastatic to the contralateral choroid. Am J Ophthalmol 132 (6): 941-3, 2001.  [PUBMED Abstract]

  12. Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010. 

  13. Mäkitie T, Summanen P, Tarkkanen A, et al.: Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci 42 (7): 1414-21, 2001.  [PUBMED Abstract]