ARTICLE
Auteur(s) : Jordi
Rubió Casadevall1, Begoña Graña-Suárez1,
Xavier Hernandez-Yagüe1, Jordi Vayreda
Ribera2, Oscar Huc Grasa3, Joan Brunet
Vidal1,4
1Department of Medical Oncology, Catalan
Institute of Oncology, Hospital Josep Trueta, AV Francia s/n
17007 Girona. Spain
2Department of Radiotherapy, Catalan Institute
of Oncology, Girona, Spain
3Department of Plastic Surgery, Hospital Josep
Trueta, Girona, Spain
4Girona Biomedical Research Institute (IDIBGI)
accepté le 7 Octobre 2008
Xeroderma pigmentosum (XP) is a rare autosomal recessive
genodermatosis characterized by defects in the DNA nucleotide
excision repair (NER) pathway. Patients are at an increased risk of
suffering skin cancers in sun-exposed sites, due to faulty repair
of ultraviolet light damage to DNA [1, 2]. We present a patient
with XP diagnosed as having a primary squamous cell skin carcinoma,
spread to a neck node. The tumour was treated with chemotherapy,
radiotherapy and, ultimately, cetuximab.
Case report
A 37-year-old man presented for evaluation of a level II, fixed,
growing, cervical node. He had been clinically diagnosed with
xeroderma pigmentosum early in his infancy. His face showed
multiple teleangiectases as well as atrophy and spotty
hypopigmentations. He showed loss of vision due to clouding of the
corneas. No relevant neurological abnormality had ever been
reported. Several squamous and basal cell carcinomas had been
surgically removed since he was an adolescent. Three months before
consultation, a squamous cell carcinoma of his outer left ear was
completely excised. A computed tomographic scanning (CT) and a
magnetic resonance imaging of the neck revealed a left 60 by
30 mm node with a cutaneous fistula. The node infiltrated the
sternocleidomastoid muscle and involved neck vascular structures.
A fine needle aspiration of the node was performed, which
confirmed the diagnosis of squamous cell carcinoma. Neither
otolaryngology endoscopies nor radiology image techniques revealed
a new primary site. Therefore, he was diagnosed as suffering an N3
node recurrence of a primary skin carcinoma. Pre-treatment
evaluation by a multidisciplinary team dismissed surgery. It was
decided to start with induction chemotherapy followed by radiation
and/or surgery, depending on the response.
Although the effect of loss of the NER pathway on the response
to therapeutic agents is not well known, we decided to use the
schema: cisplatin 50 mg per m2 day 1, and
5-fluorouracil 1000 mg per m2 days 1-3, every two weeks,
in order to avoid toxicity. After four cycles we stopped
chemotherapy due to delayed grade 3 thrombocytopenia and lack of
objective response.
Three months after the initial consultation the patient began
radiotherapy, receiving a total dose of 50 Gy. The metastatic neck
node decreased in diameter by more than 50%, achieving a partial
response without any relevant acute radiation side effect.
Chemotherapy was continued with weekly vinorelbine, which was
stopped because of refractory grade 2 leukopenia after 8 weeks of
treatment.
The patient progressed only locally six months after the end of
radiotherapy (figure
1A). A new TC excluded distant metastases. Cetuximab
was then started at a load dose of 400 mg per m2
continuing with 250 mg per m2 every week.
Immunohistochemical staining for the EGF receptor was not
performed. After 12 weeks of treatment, the cutaneous fistula
closed definitively, the patient decreased the use of analgesia and
he improved his quality of life. At this time, the node experienced
a good clinical response (figure 1B) and almost a
50% diameter reduction measured by computed tomography and magnetic
resonance. After eleven months of treatment with weekly cetuximab,
patient suffered neck node enlargement and jaw bone infiltration.
He was referred to palliative care, dying two years after his
initial consultation.
The patient was referred for genetic counselling before dying.
He had an older sister also affected by xeroderma pigmentosum, who
suffered from melanoma, a carcinoma of the lower lip, several
squamous cell skin carcinomas and blindness. The pedigree shown
consanguinity, the xeroderma pigmentosum cases in the family
resulted from marriage between cousins. The father had survived a
Hodgkin disease diagnosed in his adolescence while the paternal
grandfather died of lung cancer. Both our patient and his sister
refused any molecular genetic testing. After our patient’s death,
his sister blamed her parents for their XP diagnosis and refused
any follow up by medical and social services.
Discussion
Xeroderma pigmentosum is an autosomal recessive photosensitive
genodermatosis belonging to an expanding family of diseases with
defects in the DNA nucleotide excision repair (NER) pathway.
Patients have a genetic inability to repair DNA damage induced by
ultraviolet light. There are two NER systems: 1)
transcription-coupled repair, and 2) global genome repair. Many
factors involved in these pathways are related to the pathogenesis
of XP [1]. Genetically, xeroderma pigmentosum is a very
heterogeneous disease that can be subdivided into seven
complementation groups (XPA through XPG) and a XP Variant (XPV).
Recently, the isolation and characterization of the genes
responsible for XP have made it possible to use molecular
biological techniques to diagnose XP patients, for carrier
detection and for prenatal diagnosis [2].
Xeroderma pigmentosum is characterized by a more than 1000-fold
increase in the frequency of all types of major skin cancers (basal
cell cancers, squamous cell cancers, malignant melanoma) in areas
exposed to sunlight, compared to the normal population. The age of
onset of the first skin cancers is 8 years-old [3]. The worldwide
incidence of XP is 1: 250,000 live births, usually presenting at
age 1-2 years with photosensitivity and burning after minimal sun
exposure. Cutaneous manifestations also include increasing dryness
of skin, freckling, and telangiectasia. Ocular abnormalities
include photophobia, ectropion, conjunctival injection, keratitis,
and tumours. About 20-30% of patients with XP also have
neurological abnormalities. XP patients may also be at increased
risk for the development of internal neoplasias (brain tumors,
sarcomas, leukaemia and lung cancers). Although heterozygotes
(carriers) are asymptomatic, it is unknown whether they have a
higher risk of developing cancer comparing to normal population
[4].
Patients affected by XP should be referred for genetic
counselling and regular follow up by a multidisplinary medical team
early in life. Support and information for XP patients and their
families is invaluable in order to help them to understand the
condition and improve the prognosis and quality of life of these
individuals [5].
The goal of treatment of xeroderma pigmentosum is to make an
early diagnosis and to protect the patient from sunlight as there
is no cure for this disease. Currently, there is a lack of
information about the efficacy and safety of conventional treatment
in patients affected by XP and with wide-spread cancer. The use of
cisplatin in these patients could both increase the expected
toxicity and efficacy, as the XP cells are unable to repair DNA
adducts induced by this agent [6, 7]. T4 endonuclease liposome
lotion [8] and oral retinoids like isotretinoin [9] have a role in
the chemo-prevention of skin cancer and have also been used
concomitantly with radiotherapy with safety and a good response
[10].
Considering radiotherapy for XP patients, very few reports have
been published and show conflicting outcomes: from no toxic events
[10] to life-threatening side effects before ending radiotherapy
[11].
Cetuximab is a monoclonal antibody against the epidermal growth
factor receptor (EGFR). EGFR is commonly overexpressed in squamous
cell carcinomas of the head and neck and its genetic alterations
are correlated with the patient’s clinical outcome [12]. According
to the literature published at the time we treated our patient [13]
and recently, [14] when it is used in monotherapy it could achieve
a response rate of 13% and a disease control rate of 46%. It has
also shown activity with cisplatin in refractory patients [15].
Nowadays, cetuximab is accepted as an option for first line
treatment with concurrent radiotheraphy for locally advanced head
and neck cancer [16].
In this case, a recurrent squamous cell skin carcinoma diagnosed
in an XP patient was treated with cetuximab as a monotherapy agent
in a palliative setting. The use of this targeted therapy
facilitated a long stabilization of the disease with very low
toxicity. Cetuximab could be an acceptable treatment for XP
patients affected with advanced squamous skin cell carcinomas.
There are no reports of the use of cetuximab concurrent with
radiotherapy in XP patients.
Acknowledgements
Authors disclose no conflict of interest and no financial support.
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