|Year : 2015 | Volume
| Issue : 3 | Page : 142-145
Xeroderma pigmentosum: Composite cutaneous malignancies A nightmare
Vinod V Prabhu1, Shriniketan Kale1, Sagar More2
1 Department of Surgery, Bharati Medical College, Bharati Vidyapeeth University, Sangli, Maharashtra, India
2 Department of Pathology, Bharati Medical College, Bharati Vidyapeeth University, Sangli, Maharashtra, India
|Date of Web Publication||10-Jul-2015|
Vinod V Prabhu
Shreyas, Behind Central Warehouse, Miraj - 416 410, Maharashtra
Source of Support: Nil., Conflict of Interest: There are no conflicts of interest.
Xeroderma pigmentosum (XP), is an autosomal recessive genetic disorder of enzymes in which the ability to repair damage caused to DNA by UV light is deficient. As this disorder is commonly due to exposure to sunlight and requires protection from sunlight such patients with the disease are often commonly referred to as “children of the night”. In this disorder, the patients suffer from various cutaneous malignancies such as basal cell carcinomas (BCC), malignant melanoma (MM), and squamous cell carcinoma (SCC). It is a rare disorder with an incidence of 1:250,000 in the United States. This disease involves both sexes and all races, with a common occurrence in Japanese people. The disease is characterized by a mutation in nucleotide excision repair (NER) enzymes resulting in a reduction or elimination of NER which is required for repair of UV light induced deoxyribonucleic acid damage thus increasing susceptibility to cutaneous malignancies. These patients rarely survive beyond 20 years of age. This case reports a rare occurrence of three malignancies in a single tumor BCC, SCC, and the rarely occurring sebaceous carcinoma, which is not known to be associated with UV radiation exposure.
Keywords: Composite malignancies, nucleotide excision repair, sebaceous carcinoma, ultraviolet light, Xeroderma pigmentosum
|How to cite this article:|
Prabhu VV, Kale S, More S. Xeroderma pigmentosum: Composite cutaneous malignancies A nightmare. Indian J Paediatr Dermatol 2015;16:142-5
|How to cite this URL:|
Prabhu VV, Kale S, More S. Xeroderma pigmentosum: Composite cutaneous malignancies A nightmare. Indian J Paediatr Dermatol [serial online] 2015 [cited 2019 Dec 14];16:142-5. Available from: http://www.ijpd.in/text.asp?2015/16/3/142/160650
| Introduction|| |
Xeroderma pigmentosum (XP) is a terminology coined by the Hungarian dermatologist Moritz Kaposi, who wanted to describe a characteristic disease picture originating in a pigmented and dry skin. This condition is characterized by occurrences of cutaneous malignancies at a much earlier age than normal.
The basic defect stems due to a mutation leading to an absence or deficiency of nucleotide excision repair (NER) enzymes which are important to repair deoxyribonucleic acid (DNA) damaged by ultraviolet (UV) radiation, resulting in the development of various cutaneous malignancies. XP patients below the age of 20 years have a more than 1000-fold risk of developing cutaneous malignancies. The median age of onset of skin cancers reported in patients with XP is 8 years, compared to 60 years in the otherwise healthy population. This difference is an indication of the significance of DNA repair in protecting against the development of skin cancer in normal individuals. XP is also associated with cutaneous, ocular, neurological, and oral lesions. The incidence is low in India.
It usually begins with freckles, keratosis, skin hyperpigmentation which should be recognized early so as to detect XP. A high degree of suspicion will go a long way in helping patients from debilitating sequelae of malignancies making treatment easier with lesser morbidity.
Consanguinity plays a very important etiological factor, as XP patients are more often than not issues of a consanguineous marriage. We present an interesting case of a 14 years male from a 2° consanguineous marriage who presented to us with a cauliflower like growth over nasolabial region along with another pigmented lesion below the right ear lobule.
| Case report|| |
An uncooperative and irritable 14 year old male child presented to us with a growth over the nasolabial region since 6 months [Figure 1] and another pigmented lesion in the infra lobular region of right ear.
The informant gave a history of excision of a swelling on nape of neck 2 years back and a history of enucleation of the left eye 1 year back. Details of this were unavailable. On examination, there was a cauliflower like growth on the nasolabial fold measuring 15 cm × 15 cm in size with areas of necrosis and a foul smelling discharge. A second pigmented lesion was seen just below the right ear lobule with irregular margins and a black scab over it. The face and the trunk showed dark colored pigmented spots with discharging foci scattered all over the body [Figure 1]. The skin was dry and scaly all over. He had an eviscerated left eye and a narrow palpebral fissure on the right side. There were no palpable cervical lymph nodes. The hematological investigations were within normal limits. There were no neurological abnormalities. The right eye examination revealed neovascularization of cornea and keratitis with no vision. The chest X ray and ultrasonological examination of the abdomen were normal. He had an enucleated left eye with corneal neovascularization in right eye with no vision.
Excisional biopsy of both the lesions was done. The bare areas were grafted with a split thickness skin graft. It is a 3 week postoperative period and the grafts are fully accepted. The patient is advised follow up for nasal reconstruction. The nasolabial tumor revealed a composite, three different foci of malignancies. The first focus revealed SC showing lobules of round to polygonal foamy cells with sparse intervening stroma. The cells show hyperchromatic pleomorphic nuclei and abundant foamy vacuolated cytoplasm [[Figure 2]a].
|Figure 2: (a) Nests and clusters of malignant sebaceous cells having foamy vacuolated cytoplasm. Few necrotic tumor cells are seen at 10 O'clock position (H and E, ×40). (b) Keratin pearl in squamous cell carcinoma (H and E, ×40). (c) Islands of basaloid tumor cells. Stroma showing macrophages (H and E, ×40)|
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The second focus showed nests and clusters of well differentiated squamous cells with nuclear atypia and many keratin pearls suggesting squamous cell carcinoma (SCC) [[Figure 2]b].
The third focus revealed nests of basaloid cells with ovoid vesicular nuclei with inconspicuous nucleoli and evidence of intracytoplasmic melanin granules. The nests showed peripheral palisading of tumor cells suggesting a pigmented BCC [[Figure 2]c]. The other lesion below the right ear lobule showed a BCC.
Thus, the authors feel it is a rare case wherein three different malignancies are seen in a single tumor out of which the presence of SC which is unrelated to UV radiation exposure makes it more unusual.
| Discussion|| |
Xeroderma pigmentosum is characterized by photohypersensitivity of sun exposed tissues leading to UV exposure and several fold increased risk of malignant neoplasms of the skin and eyes. This is further facilitated by use of high intensity discharge light sources such as energy saving fluorescent lamps which emit high levels of UV radiation (blue light) which are more damaging than the low intensity incandescent light sources (yellow and red end of spectrum).
Inherited molecular defects in NER genes are responsible for the debilitating autosomal recessive condition, XP. The DNA is damaged by UV radiation which in the normal course is repaired by NER, but this is rendered inactive by a genetic mutation leading to an accumulation of damaged DNA’s and uncontrolled proliferation of tissues leading to malignancy.
To elaborate, following detection of DNA damage, an open complex is formed. The product of XPC is involved in the initial identification of DNA damage. The XPG gene product is required for the open complex formation along with the XPB and XPD gene. The XPF and XPG proteins act as DNA endonucleases to create single strand cuts in the 5’ and 3’ sides of the damaged DNA with resulting excision of about 28–30 nucleotides, including the photoproduct (damaged DNA). DNA polymerases replace the resultant gap with the correct sequence, and a DNA ligase completes the repair. Subsequently, the damaged DNA is removed and the resulting gap is filled in with new DNA by the action of polymerases. This process is deficient in XP and the damaged DNA is left unrepaired and proliferates uninhibited, leading to malignancies.
This is facilitated by various other factors like sunny weather, outdoor living, fair skin, smoking, poor availability of diagnostic facilities, delayed diagnosis due to lack of awareness about the disease, and poor protection from sunlight. XP is commonly observed in populations where consanguineous marriage is common. This has been reported in varying degrees from Egypt, Pakistan, and Nigeria among some of the countries that report a high incidence of XP. XP is classified into eight groups depending on the gene involved [Table 1].
This disease involves the skin, eyes, nerves and the most common occurring cutaneous BCC, SCC, melanomas. This case presents a composite malignancy that includes pigmented BCC, well differentiated SCC, and the rarely seen sebaceous carcinoma (SC) in a single growth over the nasolabial region along with a synchronous BCC below the right ear. The occurrence of SC is rare in the pediatric age group as it is not known to be associated with UV radiation exposure. In addition, to the defects in the repair genes, UV B radiation also has immunosuppressive effects, and reduces cell mediated immunity. This could be a possible reason for the development of SC in the present case. Besides, the specimen was fixed in paraffin hence lipid stains could not be done to confirm SC. Immunohistochemistry confirmation could not be done due to economic constraints and lack of facilities for the same. Hence, we relied on histological characteristics to diagnose SC.
The discovery by James Cleaver of defective DNA repair in XP opened up a variety of DNA repair related disorders and encouraged a study of the detrimental effects of UV radiation on DNA of patients inflicted with XP. UV B and UV C radiation from the sun are cytotoxic and mutagenic. UV C is usually filtered by the ozonic layer whereas UV B reaches the earth. This causes a generation of large quantities of cyclobutane pyrimidine dimer (CPD) which is responsible for the mutation in the POLH gene causing XP.
The other challenge faced is the use of volatile anesthetic agents like sevoflurane in these patients as there are reports that these agents are genotoxic and may be detrimental, suggesting that it is preferable to use injectable anesthetics which was done in this case, though there are no clear recommendations. Furthermore, radiotherapy could not be used as an adjuvant therapy as it causes DNA breaks which would aggravate the disease.
The treatment of these lesions tests the patience of the patient. The cutaneous malignancies are treated by wide excision which was done in this case, with the necessary reconstruction. However, it would be more prudent if the basic etiology is addressed. There have been recent studies suggesting that the DNA repair mechanism could be corrected using targeted gene therapy. These studies rely on the ability of engineered nucleases known as meganucleases, zinc finger nucleases, and TALE nucleases to produce an exact double strand break at a specific locus and promote targeted homologous recombination with an exogenous DNA repair matrix which corrects the mutant gene. It has given encouraging results. A more preventive aspect would be to detect the defect in the antenatal period using amniotic examination in consanguineous conceptions.
Another potential therapy examined is the use of topical applications like T4N5 liposome lotion prepared by mixing T4N5 liposomes into a 1% hydrogel lotion (Lipo Chemical, Inc. USA) which can prevent the new appearance of actinic keratosis. Photoreactivation using photolyase enzyme which repairs DNA and binds to CPD”s and removes them on exposure to a light complex of wavelengths of 300–500 nm thus restoring immune competence to UV irradiated antigen presenting cells. These modalities are yet to be available worldwide.
Besides this, there is a requirement of counseling centers and XP speciality clinics which counsels the relatives as to the precautions to be taken and treats the patient. The patient should be advised to remain indoors or cover himself up if he has to go outdoors so as to avoid exposure to sunlight.
| Conclusion|| |
Timely identification of this disease is paramount, first for a proper counseling of the patient and parents and secondly to advise the patients protective measures to be taken in order to avoid cutaneous malignancies. At the same time a screening of the siblings to detect this disease early and formation of XP groups to spread awareness among the general population, particularly in regions and communities where consanguineous marriages are common are some of the steps that need to be taken.
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[Figure 1], [Figure 2]