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Case Reports Indian Pediatrics 2000;37: 1377-1379 |
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Xeroderma Pigmentosum with Multiple Malignancies |
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Xeroderma pigmentosum is an autosomal recessive trait representing the basic problem of solar radiation and skin cancer. Patients with this disease have a greatly increased susceptibility to malignant tumors of skin in light exposed areas. The characteristic skin manifestations include atrophy, telengiectasia, hyperpigmented macules, keratosis and ulcerations occurring in sun exposed areas and neurological abnormalities. Within the first few years of life, basal cell or squamous cell carcinomas, sarcomas or malignant melanomas develop. Here we are reporting a case of xeroderma pigmentosum with multiple malignancies.
A 12-year-female came to our clinic with complaints of pigmented lesions over body, more over the face since the age of 1˝ years with a non-healing lesion on the right cheek since 2 years and loss of vision in left eye since 3 months. She gave history of excision of a growth from the left eye 3 years back and has had problems with her vision since childhood. General examination revealed extensive hyperpigmented and hypopigmented lesions all over the body more so on exposed areas, keratosis on right cheek and nose with a keratosis associated ulcer on right cheek of the size of 2.5 cm across, which was fixed to underlying tissue with thick borders. The lesion was of a constant size since 2 years. Ophthalmic examination of the right eye revealed a foamy xerotic patch temporally with a 6 mm × 4 mm pigmented lesion at limbus at 3 O’clock position which was diffuse, non nodular, elevated and vascular. There were macular opacities in central cornea. The left eye revealed verrucous growth involving lower half of the cornea and a xerotic patch. The vision of right eye was finger counting whereas left eye had no perception of light. With suspicion of a basal cell carcinoma cheek and squamous cell carcinoma limbus, biopsies were taken from lesions of right cheek, left eye, limbus and the right eye pigmented limbal lesion. Histopathology revealed a basi-squamous type of carcinoma of right cheek with squa-mous cell carcinoma of left limbus and dys-plasia in the pigmented lesion of the right eye.
Cleaver(1) showed that patients with xeroderma pigmentosum (XP), who have a propensity for developing light-induced cancers early in life, possessed cells that were defective in the excision repair of UV-induced pyrimidine dimers from their DNA. This defect was correlated with hyper-mutability, when XP cells were exposed to ultra violet radiations (UV). Thus it was suggested that early increase in sunlight-induced cancers was a direct consequence of an increase in mutated cells in the skin of XPs. An alternative hypothesis was proposed which argued that the crucial effect of sunlight which led to the early appearance of skin cancers was not the excessive induction of mutations but the exacerbation by UV of a defect in immune surveillance which resulted in existing transformed cells being able to grow and express their malignant pheno-type(2). This effect of UV was more akin to promotion than initiation. Cells of a patient with Cockayne syndrome were also hyper-mutable by UV(3) and yet such patients were not known to be prone to skin cancers. This suggests that an increase in mutation frequency does not necessarily lead to an increase in cancer. Trichothiodystrophy is a well-defined hereditary disease characterized by sulfur-deficient brittle hair usually associated with varying degrees of mental and physical retardation, ichthyosis, dystrophy of the nails, dental caries and cataract. Many patients are also photosensitive and have been shown to be deficient in excision repair(4). In fact their cells are similarly hyper-mutable by UV(5). Trichothiodystrophy patients, however, show no signs of freckling nor do they appear prone to early skin cancer. It may thus be concluded that not only does an elevated frequency of mutations not neces-sarily lead to an increase in early skin cancer but that a defect in excision repair is also insufficient to lead to early skin cancer. Why then do CP patients who are not given adequate protection against UV suc-cumb to skin cancer? The suggestion that defect in immune surveillance is the reason for the early appearance of tumors is not proven, but the evidence is increasingly compelling. Berkel and Kiran(6) noted that rejection of skin grafts was delayed in their XP patients, an observation that is consistent with remark-ably well-tolerated at-random corneal trans-plant carried out in an XP patient. This patient had reduced in vivo antigen-specific humoral and cell-mediated responses and in vitro, the cell-mediated immune response was in the lower part of the normal range. Moreover, when the group XP patients was subdivided according to the extent of their cutaneous disease there appeared to be an inverse relation between disease severity and the development of contact allergy(7). Thus light-exposed XP patients are susceptible to higher risk of skin cancer because their defect in DNA repair results in an increased frequency of initiated (mutated) skin cells which are able to grow into tumorous colonies early in life, probably because of failure of the immune system to restrict their growth. This failure may be two-fold: a constitutive defect (probably in NK cell func-tion) exacerbated by a UV-dependent impair-ment (probably of cell-mediated immunity and possibly also of residual natural killer cell function)(8). The (presumed constitutive) immune defect in natural killer cell function present in classic XP patients may also be due to a further independently mutated gene, and this may also exist in individuals independently of the DNA repair defect. Such individuals might also be at some increased risk of skin cancer, but this would probably be expressed as single rather than multiple neoplasms (since the mutation frequency would be normal), and the skin cancers might appear earlier than in normal individuals. Mutations, once formed, could persist in stem cells for a very long time. Ultraviolet light may also impair immune surveillance. The combination of these two effects would produce a response which causes acute exposures to be more effective than chronic. To avoid early skin cancer the advice must therefore be to avoid high peak exposures, since these should dominate the risk assessment. In contrast, for cancers appearing in later years as the immune system loses it’s effectiveness, the total lifetime cumulative exposure would be expected to be rela- tively more important, although the effect of peak exposure might still be most important(9). The case presented here has elements of squamous cell, basal cell as well as melano-matous malignancy characters, supporting the hypothesis of impairment of immune surveillance along with defect in excision repair. With the possibility of ophthalmic malignancies, the need to avoid acute exposures of UV radiation to the eyes by use of protective eye gear, UV block glasses or goggles early in the course of disease can not be neglected and should form part of the plan in management of the disease. Contributors: ARN performed clinical evaluation and biopsies of the patient and coordinated the report and will act as the guarantor. SSB and SAN participated in data collection, evaluation of patient and helped in drafting the report. Funding:
Marathwada Medical and Research Institute, Kamalnayan Bajaj Hospital,
Aurangabad.
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