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Familial uveal melanoma: report on three sibling cases
  1. G KRYGIER,
  2. K LOMBARDO,
  3. C VARGAS
  1. Medical Oncology Department; Universitary Hospital de Clinicas, Montevideo, Uruguay
  2. Ophthalmology Department; Universitary Hospital de Clinicas, Montevideo
  3. Pathology Department; Universitary Hospital de Clinicas, Montevideo
  4. Medical Oncology Department; Universitary Hospital de Clinicas, Montevideo
  1. I ALVEZ,
  2. R COSTA,
  3. M ROS
  1. Medical Oncology Department; Universitary Hospital de Clinicas, Montevideo, Uruguay
  2. Ophthalmology Department; Universitary Hospital de Clinicas, Montevideo
  3. Pathology Department; Universitary Hospital de Clinicas, Montevideo
  4. Medical Oncology Department; Universitary Hospital de Clinicas, Montevideo
  1. M ECHENIQUE
  1. Medical Oncology Department; Universitary Hospital de Clinicas, Montevideo, Uruguay
  2. Ophthalmology Department; Universitary Hospital de Clinicas, Montevideo
  3. Pathology Department; Universitary Hospital de Clinicas, Montevideo
  4. Medical Oncology Department; Universitary Hospital de Clinicas, Montevideo
  1. V NAVARRO,
  2. L DELGADO,
  3. A VIOLA,
  4. I MUSÉ
  1. Medical Oncology Department; Universitary Hospital de Clinicas, Montevideo, Uruguay
  2. Ophthalmology Department; Universitary Hospital de Clinicas, Montevideo
  3. Pathology Department; Universitary Hospital de Clinicas, Montevideo
  4. Medical Oncology Department; Universitary Hospital de Clinicas, Montevideo
  1. Gabriel Krygier, MD, Blanca del Tabare 2964, Montevideo, Uruguay CP 11300 gkrygier{at}adinet.com.uy

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Editor,—Uveal melanoma is the most common primary malignant intraocular tumour in adults, representing 70% of all malignant ocular tumours.1

They appear sporadically in the absence of clear predisposing genetic factors. However, the family history of some patients suggests that there could be a genetic basis.2 Some cases of family uveal melanoma have been described in the literature, and they point to a dominant autosomal hereditary transmission.34

The family uveal melanoma accounts for only 0.6% of patients with uveal melanoma. Considering the low incidence of uveal melanoma in the general population, the possibility of developing uveal melanoma in a family context is very low. Since the first description by Silcock in 1892 of the case of a mother and her two daughters affected with this illness, only 51 families had been reported until 1996.45

Unidentified mutations on the germinal line might be involved in its pathogenesis.46 There are several reports of simultaneous occurrence of uveal melanoma and breast cancer. Some of them are related to one of the genes already known as predisposing to breast and ovary cancer, the “BRCA2.” 78

Even though there is no demonstration of an implicated gene, many studies suggest that the occurrence of family uveal melanoma is not just a coincidence.9

Three clinical cases of histopathologically proved intraocular malignant melanoma involving first generation members of the same family (siblings) are analysed, and their evolution is reported.

CASE REPORTS

Case 1

A 40 years old male patient, with a history of ocular trauma 2 years earlier, presented with progressive loss of vision in the right eye, being admitted to hospital in March 2000. The earlier examination showed an ulcerated tumour in the right eye that protruded over the lower eyelid, round in shape, 1 cm diameter, pigmented and painful. He underwent a computed tomography (CT) scan of the orbit which showed an external ocular melanoma with extrascleral invasion. Studies for stratification were negative for malignancy. Given the accessibility of the tumour, a biopsy confirmed a malignant melanoma. An exenteration of the right orbit was performed in April 2000. The histopathological report was of a mixed type (spindle B and epithelioid) malignant melanoma, with perineural and perivenular scleral infiltration. A liver ultrasound performed in November 2000 showed multiple, solid, round-shaped hypoechogenic images in both hepatic lobes, compatible with secondary metastasis in the liver, confirmed by CT scan, leading to plan a chemotherapeutic treatment with hepatic intra-arterial cisplatin.

Because of the clear tumour progression in such a short time, a painful hepatomegaly and general deterioration and evidence of liver disfunction, the previous treatment could not be given and a palliative symptomatic treatment was undertaken.

Case 2

A 39 years old healthy female patient suffered a sudden loss of vision in November 1994 and a left eye retinal detachment was found at the ocular examination. The orbital ultrasound suggested a typical choroidal melanoma on the left eye. The orbital CT scan showed an intraocular tumour on the nasal side of the posterior pole of the left eye, in contact with the retina, with 10 mm thickness and probable episcleral infiltration. Her left eye was enucleated on January 1995. Histopathological findings were that of a mixed cell malignant uveal melanoma, with predominance of epithelioid type, with significant scleral invasion.

In November 1997 a right breast nodule was found, measuring 2 cm in diameter. The mammography showed the right breast lump compatible with a primary breast tumour and the biopsy was positive for malignancy. It was finally resected in December 1997. The histopathological report confirmed a breast metastasis of a malignant uveal melanoma with axillary ganglion metastases.

Systemic treatment with polichemotherapy was started in February 1998, based on cisplatin, dacarbazide, and tamoxifen, five series were completed by July 1998. In August 1998 the patient suffered a right coxofemoral pain irradiated to the ipsilateral knee. Pelvicx rays showed multiple lytic lesions in the pelvis.

Bone scintigraphy (September 1998) noted hyperactive areas in the anterior arc of the third rib, pelvic bones, iliac wing, and superior third of the right femoral bone.

She was evaluated because of the risk of a local bone fracture and a surgical fixation was then implemented. Histopathological bone biopsy (November 1998) confirmed bone metastases of a melanocytic tumour, in accordance with the primary ocular melanoma. She died in December 1998 with a progressive disease.

Case 3

A 38 year old female patient, who was operated on her left breast (modified radical mastectomy) in September 1998 because of a 30 × 33 mm ductal infiltrating carcinoma (DIC), with 40% of in situ carcinoma, histological grade II, 0/6 negative axillary nodes. She then received polichemotherapy with four cycles of doxorubicin and cyclophosphamide (AC) followed by radiotherapy, completing the treatment with tamoxifen because of high positive oestrogen receptors.

In March 2000 she suffered a trauma in her right eye. An ocular ultrasound scan showed a retinal detachment and a tumoral image resembling a choroidal metastasis. The ocular computed tomography scan showed no other alterations than the apparently ocular metastatic tumour. Liver function and enzymes were normal.

Because of the family history of ocular melanoma, enucleation of the right eye was performed in June 2000 (despite the ocular ultrasound and the CT scan oriented to a metastatic breast tumour).

The histopathology showed a mixed cell malignant uveal melanoma with predominance of epithelioid variant.

The patient is now being treated for a second breast tumour (at the remnant of the right breast).

COMMENT

The family presented includes not only three individuals affected with this unusual pathology but they are also three siblings belonging to the same generation, which is even more unusual.

All the cases corresponded to mixed uveal melanomas; in one of these cases (case 3) the patient also had a malignant breast tumour which was diagnosed 2 years before the ocular tumour; in this same case, even though the clinical findings and the imaging tests were suspicious of a choroidal metastasis, the history of two ocular melanomas in her siblings led to the enucleation of the eye, with the subsequent diagnosis of ocular melanoma; the patient is still alive but is being treated for a new breast lump.

Case 2 shows another peculiarity: the patient had been enucleated in January 1995 because of a mixed choroidal melanoma; almost 3 years later she was operated because of a probable primary breast tumour, and the mastectomy specimen showed a breast and axillary compromise of the formerly enucleated ocular melanoma. Nine months later, bone metastases of the primary choroidal melanoma were diagnosed and histologically confirmed. The patient died a few months later.

The first case (case 1) was another unusual one: at the diagnosis, the patient had an externalised ocular melanoma with extrascleral invasion allowing a preoperative diagnosis through a biopsy, even though this procedure is difficult to achieve in most of the ocular melanomas. In this patient an orbital exenteration was done owing to its extension beyond the eye itself. The histopathological report was that of a mixed melanoma (with epithelioid component). Seven months later the patient developed progressive liver metastasis with general deterioration, while under palliative care.

Once again this case denotes the aggressiveness of this tumour in this family.

The genealogical family tree (Fig 1) shows that the siblings' parents developed malignant tumours: the father was diagnosed with lung cancer at the age of 59 dying a few months later and the mother had breast cancer diagnosed at the age of 49 dying at the age of 57. Also a maternal aunt was diagnosed with lung cancer at the age of 38 and died 2 years later, while another maternal aunt is still alive with breast cancer diagnosed when she was 43. The paternal family history was irrelevant with no malignancies in any of the first or second generation members.

Figure 1

Genealogical family tree. UM = uveal melanoma, LC = lung cancer, BC = breast cancer, Dg = diagnostic age, De = dead age, Dg/De = diagnostic and dead age, y = years, I = first generation, II = second generation, III third generation.

The family tree shows, in the same generation as the affected patients, five more siblings, all of them aged less than 40 years who are currently healthy but may eventually be affected with ocular melanoma or another malignancy; are there any kind of preventive measures we can take for these patients?.

Anecdotal reports of cases of ocular melanoma occurring in families with inherited susceptibility to breast cancer owing to brca2 germ line mutations have been previously reported.7

Although germ line brca2 mutations may account for a small proportion of all ocular melanoma cases, there may be additional loci contributing to family aggregation of uveal melanoma and to the family association between ocular melanoma and breast cancer.7

Based on the limited data available, an autosomal dominant mode of inheritance with incomplete penetration has been postulated to explain the family involvement in uveal melanoma.5

In order to determine some genetic alteration that could account for this family uveal melanoma, blood samples were recently taken from different members of the family (apart from the affected patients still alive).

The family predisposition to uveal melanoma can be a component of a wider predisposition syndrome to cancer, which could explain the high number of tumours affecting these families, with multiple organs involved and the appearance at younger ages than those observed in the general population.10

Because of no previous evidence of family members with uveal melanoma in the genealogical tree (Fig 1), either an environmental factor that remains undisclosed might be suspected or a new mutation may have arisen. Either way careful monitoring of the remaining siblings would be of great interest.

References

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