0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Research Letters |

Sudden Growth of a Choroidal Melanoma and Multiplex Ligation-Dependent Probe Amplification Findings Suggesting Late Transformation to Monosomy 3 Type FREE

Sonia A. Callejo, MD, PhD, FRCSC; Justyna Dopierala, BSc; Sarah E. Coupland, MBBS, PhD, FRCPath; Bertil Damato, PhD, FRCS, FRCOphth
[+] Author Affiliations

Author Affiliations: Ocular Oncology Service, St Paul's Eye Clinic, Royal Liverpool University Hospital (Drs Callejo and Damato) and Department of Pathology, School of Cancer Studies, University of Liverpool (Ms Dopierala and Dr Coupland), Liverpool, England.


Arch Ophthalmol. 2011;129(7):958-960. doi:10.1001/archophthalmol.2011.181.
Text Size: A A A
Published online

Current wisdom is that uveal melanomas develop monosomy 3 very early.1 It is hypothesized that metastatic spread commences years before presentation,2 and therefore ocular treatment may not influence survival.3 We describe a melanoma with apparently delayed transformation from disomy 3 to monosomy 3.

In 2001, a 65-year-old woman was referred with an inferonasal, pigmented, choroidal tumor in her left eye. The lesion was 10.1 mm wide and 1.6 mm thick (Figure 1A and B). Scattered drusen were noted. Orange pigment and subretinal fluid were not seen. The differential diagnosis included nevus and melanoma. The patient was monitored every 6 months. She underwent photocoagulation for diabetic retinopathy in 2005 and epiretinal membrane peel in 2006. The tumor appeared unchanged in serial evaluations, but by December 2007 its thickness had increased to 2.3 mm (Figure 1C and D).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Fundus photographs (A, C, and E) and corresponding ultrasonography (B, D, and F). A and B, At the initial visit in 2001, the pigmented lesion had no associated orange pigment or subretinal fluid and measured 1.5 mm in thickness. C and D, In 2007 following panretinal photocoagulation, the lesion was unchanged by ophthalmoscopy and measured 2.2 mm in thickness. E and F, In 2009, the lesion had a collar-stud shape and measured 10.5 mm in thickness.

In 2009, the patient had an acutely painful left eye with visual acuity of light perception and an intraocular pressure of 40 mm Hg. Ophthalmoscopy and ultrasonography showed the tumor to have a collar-stud shape, measuring 14.0 mm basally and 10.5 mm in thickness (Figure 1E and F). The eye was enucleated.

Microscopy showed a choroidal melanoma with extensive necrosis but with viable epithelioid cells at its apex and spindle cells at its base (Figure 2A-C). The mitotic rate was 4 per 40 high-power fields. Closed connective tissue loops were not present and lymphocytic infiltrate was minimal. Melanoma cells were also present on the surface of the iris extending into the chamber angle. The ciliary body was infiltrated by a melanoma satellite. Following microdissection, molecular genetic evaluation using multiplex ligation-dependent probe amplification revealed monosomy 3 and chromosome 6p gains in the melanoma cells at the tumor apex and disomy 3 at the base (Figure 2D). The patient was well 6 months postoperatively with no evidence of metastasis.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Histopathological examination and cytogenetic analysis. A, Low-power histopathological section revealed a mushroom-shaped, partially pigmented melanoma with extensive areas of necrosis, particularly in the apical region (hematoxylin-eosin, original magnification ×400). Viable tumor cells consisted of a mixture of spindle cells located at the base of the lesion (B) and epithelioid cells at the apex (C) (hematoxylin-eosin, original magnification ×1000). D, In multiplex ligation-dependent probe amplification analysis, all chromosomes tested (chromosomes 1, 3, 6, and 8) were essentially normal at the base; however, chromosomal abnormalities were detected in the apex. Those abnormalities included monosomy 3, gain of chromosome 6p, loss of chromosome 6q, loss of chromosome 8p, and gain of chromosome 8q. Chromosome 1p was normal in both areas. B indicates borderline.

We report the case of a melanoma that, after 8 years of apparent quiescence, suddenly enlarged. It developed a collar-stud shape, became necrotic, and made the eye acutely painful. It was still possible to recognize epithelioid cells at the tumor apex and spindle cells at the base. The apex melanoma cells were demonstrated to be monosomy 3, and the spindle cells at the base were demonstrated to be disomy 3. Our findings would suggest that after years of apparent dormancy, a choroidal melanoma suddenly enlarged because it had transformed from an indolent, disomy 3, spindle type to an aggressive, monosomy 3, epithelioid type. Genomic changes in other human cancers have been reported.4

An alternative explanation is that the indolent tumor was a choroidal nevus that transformed into a monosomy 3 melanoma; however, if this had been the case, one would have expected to see nevus cells in the basal part of the tumor and not the melanoma cells that predominated. Furthermore, slow growth of the tumor had been documented, which is rare with nevi. Whether the panretinal photocoagulation stimulated tumor growth is uncertain but, in our opinion, highly unlikely.

It has been suggested that disomy 3 and monosomy 3 melanomas are distinct from their inception.1 Our case suggests, however, that monosomy 3 can arise at any stage during tumor development. This implies that if a small choroidal melanoma is not treated promptly, there is always the risk that the tumor may undergo transformation to the monosomy 3 type, developing rapid growth and a higher risk of metastatic spread. This case supports our current data indicating that intratumoral genetic heterogeneity exists in most uveal melanomas.5 The histologic and multiplex ligation-dependent probe amplification results suggest the emergence of a highly malignant clone of melanoma cells. This event is suggested by the following: (1) the sudden tumor growth; (2) the concurrence of epithelioid cells with chromosome 3 loss and chromosome 8q gain in the apical part of the tumor, which is where such rapid growth recently occurred; and (3) the absence of such high-grade morphological and genotypic features in the basal part of the tumor, which is oldest part of this neoplasm. Finally, the case also demonstrates how any opportunities for conserving the eye and vision may be lost if a melanoma is not immediately treated.

Further studies are needed to determine whether early treatment of uveal melanomas may prevent later conversion into a monosomy 3 genotype and, by implication, metastatic death.

Correspondence: Dr Callejo, Ocular Oncology Service, St Paul's Eye Clinic, Royal Liverpool University Hospital, Liverpool L7 8XP, England (guilleyso@hotmail.com).

Financial Disclosure: None reported.

Tschentscher F, Hüsing J, Hölter T,  et al.  Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities.  Cancer Res. 2003;63(10):2578-2584
PubMed
Eskelin S, Pyrhönen S, Summanen P, Hahka-Kemppinen M, Kivelä T. Tumor doubling times in metastatic malignant melanoma of the uvea: tumor progression before and after treatment.  Ophthalmology. 2000;107(8):1443-1449
PubMed   |  Link to Article
Augsburger JJ, Corrêa ZM, Trichopoulos N. An alternative hypothesis for observed mortality rates due to metastasis after treatment of choroidal melanomas of different sizes.  Trans Am Ophthalmol Soc. 2007;105:54-60
PubMed
Ding L, Ellis MJ, Li S,  et al.  Genome remodelling in a basal-like breast cancer metastasis and xenograft.  Nature. 2010;464(7291):999-1005
PubMed   |  Link to Article
Dopierala J, Damato BE, Lake SL, Taktak AF, Coupland SE. Genetic heterogeneity in uveal melanoma assessed by multiplex ligation-dependent probe amplification.  Invest Ophthalmol Vis Sci. 2010;51(10):4898-4905
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Fundus photographs (A, C, and E) and corresponding ultrasonography (B, D, and F). A and B, At the initial visit in 2001, the pigmented lesion had no associated orange pigment or subretinal fluid and measured 1.5 mm in thickness. C and D, In 2007 following panretinal photocoagulation, the lesion was unchanged by ophthalmoscopy and measured 2.2 mm in thickness. E and F, In 2009, the lesion had a collar-stud shape and measured 10.5 mm in thickness.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Histopathological examination and cytogenetic analysis. A, Low-power histopathological section revealed a mushroom-shaped, partially pigmented melanoma with extensive areas of necrosis, particularly in the apical region (hematoxylin-eosin, original magnification ×400). Viable tumor cells consisted of a mixture of spindle cells located at the base of the lesion (B) and epithelioid cells at the apex (C) (hematoxylin-eosin, original magnification ×1000). D, In multiplex ligation-dependent probe amplification analysis, all chromosomes tested (chromosomes 1, 3, 6, and 8) were essentially normal at the base; however, chromosomal abnormalities were detected in the apex. Those abnormalities included monosomy 3, gain of chromosome 6p, loss of chromosome 6q, loss of chromosome 8p, and gain of chromosome 8q. Chromosome 1p was normal in both areas. B indicates borderline.

Tables

References

Tschentscher F, Hüsing J, Hölter T,  et al.  Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities.  Cancer Res. 2003;63(10):2578-2584
PubMed
Eskelin S, Pyrhönen S, Summanen P, Hahka-Kemppinen M, Kivelä T. Tumor doubling times in metastatic malignant melanoma of the uvea: tumor progression before and after treatment.  Ophthalmology. 2000;107(8):1443-1449
PubMed   |  Link to Article
Augsburger JJ, Corrêa ZM, Trichopoulos N. An alternative hypothesis for observed mortality rates due to metastasis after treatment of choroidal melanomas of different sizes.  Trans Am Ophthalmol Soc. 2007;105:54-60
PubMed
Ding L, Ellis MJ, Li S,  et al.  Genome remodelling in a basal-like breast cancer metastasis and xenograft.  Nature. 2010;464(7291):999-1005
PubMed   |  Link to Article
Dopierala J, Damato BE, Lake SL, Taktak AF, Coupland SE. Genetic heterogeneity in uveal melanoma assessed by multiplex ligation-dependent probe amplification.  Invest Ophthalmol Vis Sci. 2010;51(10):4898-4905
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

857 Views
9 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
The 2 × 2 Table