| Abstract|| |
Epidermolysis bullosa dystrophica (EBD) is an inherited disease of the structural proteins in the upper dermis, characterized by blister formation at the site of trauma followed by scarring. Skin fragility and blistering are the hallmarks of this disease. Cutaneous squamous cell carcinoma (cSCC) is a dreadful complication in the epidermolysis bullosa (EB) patients and common cause of death. The recent advances in distinct tumor microenvironment explain the aggressive nature of SCC in recessive Recessive Dystrophic Epidermolysis Bullosa (RDEB) patients and the use of collagen VII re-expression as a possible therapeutic measure. Regular follow-up is a must in preventing complications.
Keywords: Collagen VII, epidermolysis bullosa dystrophica, squamous cell carcinoma
|How to cite this URL:|
Gayathri E, Anbukkarasi K, Lilly S M. Inherited epidermolysis bullosa dystrophica and squamous cell carcinoma- A case report. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Mar 30]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=344185
| Introduction|| |
Epidermolysis bullosa dystrophica (EBD) is an inherited disease of the structural proteins in the upper dermis, characterized by blister formation at the site of trauma followed by scarring. Epidermolysis bullosa (EB) was first described in 1886 and broadly classified into four major types (simplex, junctional, dystrophic, and Kindler syndrome [KS]) based on plane of cleavage of the blister. Twenty-five phenotypic subtypes have been identified and associated with hundreds of different mutations. Patients with recessive disease patterns have an increased incidence of cutaneous squamous cell carcinoma (cSCC) with a poor prognosis which is independent of the ultraviolet (UV) exposure. SCC in EB has a predilection for limbs, bony prominences, and at the sites of blister and scarring. Upregulation of basic fibroblast growth factor, p53 gene mutations, and Reduced activity of natural killer cells are considered to be potential contributors to the pathogenesis.
32-year-old male patient suffering from EBD came with swelling in the left hand for 2 years with a history of pain, itching, and bleeding from the lesion. On examination, an ulceroproliferative lesion was present in the left dorsum of the hand [Figure 1] which bled on touch with well-defined margins.
|Figure 1: Ulceroproliferative lesion present in the left dorsum of the hand|
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E/S: Ulcer proliferative growth in the dorsum of the hand measuring 8.5 cm × 7.5 cm × 4 cm, gray-white, and friable [Figure 1].
C/S: Ulcer proliferative growth extends up to the subcutis and the proximal resected margin is 5.7 cm from the growth. Ulceroproliferative growth extends up to the subcutis and the proximal resected margin is 5.7 cm from the growth.
Microscopy showed skin with exophytic growth composed of hyperkeratotic epidermis with irregular elongated downgrowth with a broad base and pushing margins overlying the fibrocollagenous dermis [Figure 2]. The downgrowth showed the keratin cyst surrounded by oval to polygonal squamous cells with rounded nuclei and prominent nucleoli [Figure 3]. The junction of the neoplasm and dermis showed dense inflammatory cell collection [Figure 4]. The adjacent skin and underlying subcutaneous fat were free of tumor. The proximal resected margin on focus showed the presence of Tumor island and reported as infiltrating well-differentiated SCC with a tiny island in the resected margin.
|Figure 2: Hyperkeratotic epidermis with irregular elongated downgrowth with broad base and pushing margins|
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|Figure 3: Keratin cyst surrounded by oval to polygonal squamous cells with rounded nuclei and prominent nucleoli|
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|Figure 4: The junction of the neoplasm and dermis shows dense inflammatory cell collection|
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| Discussion|| |
EB is a rare inherited blistering skin disorder broadly divided into four types depending on the level of separation which includes dystrophic EB (DEB), EB simplex (EBS), junctional EB (JEB), and KS. DEB can be autosomal dominant or recessive which is characterized by blistering, skin fragility, nail dystrophy, scarring, and milia formation. Mucosal involvement is also common resulting in erosion and scarring in the mouth, esophagus, genitalia, and anus. All cases of dystrophic EB, irrespective of genotype, result from mutation in single gene COL7A1. The gene COL7A1, located on chromosome 3p21, controls the synthesis of collagen type VII. The gene encodes type VII collagen, the major component of anchoring fibril structure beneath the lamina densa, and this stability has been attributed to the affinity of the NC-1(VII) domain to bind the principal components of the cutaneous basement membrane, laminin-311 (laminin-6), laminin-332 (laminin-5), and type IV collagen. It can be differentiated by immunofluorescence antigen mapping (IFM) and electron microscopy (EM). In the severe recessive form, these fibrils are absent or severely reduced. In the dominant forms, Christiano et al. has studied that the classic mutation is designated as G2043R by the substitution of glycine-to-arginine in the triple-helical domain of type VII collagen. Dominant dystrophic EB is usually clinically milder than the recessive disease. In some cases, the glycine substitution mutations are found in both the dominant and recessive dystrophic diseases. To know the molecular pathology in patients with DEB, it important to screen all 118 exons of the gene. In recessive DEB, matrix metalloproteinase-7 (MMP-7) plays a role in the epidermal detachment. In some sporadic cases, the inherited basis can be determined by DNA sequencing. Revertant mosaicism has been described in recessive DEB patients, resulting from a second-site mutation in COL7A19. This manifested as a patch of clinically normal skin on the patient's forearm. Recessive dystrophic EB is subdivided into generalized severe, generalized intermediate, inversa, localized, pretibial, pruriginosa, centripetalis, and bullous dermolysis of the newborn. These patients are prone to many complications which include infectious and nutritional diseases.
A more common and clinically important complication in recessive dystrophic EB patients is the development of SCC. The youngest case of SCC was first reported in a 6-year-old child in the year 1913 in association with EBD. A study by McGrath et al. found that in the case of generalized recessive EBD, the peak age for onset of SCC is between the 20s and 30s when compared to the generalized form. Most carcinomas are on the limbs, often in the sites of chronic, non-healing ulcerations. About 15–20 additional patients were reported over the next 60 years. Goldberg et al. suggested that chronic tissue stress will promote carcinogenesis in the preexisting somatic mutant in the stem cell population. Chung et al. studied that keratinocytes expressing NC-1(VII) domain developed cancer while those keratinocytes which did not express did not develop SCCs. The buildup of carcinogenic mutations was traditionally believed to have occurred following the deterioration of cellular differentiation due to the repetitive cycle of tissue damage and repair. Some have proposed up-regulation of the basic fibroblast growth factor, p53 gene mutations, and reduced activity of natural killer cells as potential contributors to the pathogenesis. A research by Ng et al. showed that the Recessive Dystrophic Epidermolysis Bullosa (RDEB) fibroblast gene expression that potentiates SCC adhesion, invasion, and growth is distinct from that of non-RDEB fibroblast. A recent study by Hoste et al. suggested that colonization of flagellated bacteria in the wound is a promoter for SCC in RDEB. In determining the inherited basis of some sporadic cases of DEB, DNA sequencing may be useful. A study by Smoller et al. summarized that the direct link between the high incidence of A study by Smoller et al. summarized that the direct link between the high incidence of SCC in EBD patient is due to the persistent growth-activated immunophenotype of epidermal keratinocytes and it is associated with dermal scar formation during healing. This leads to the failure of the cell to differentiate in a normal fashion. SCC becomes aggressive and remains the most common cause of death in recessive dystrophic EB patients. It yields a poor prognosis. Death occurs within 5 years of the onset of malignancy. Multiple primary tumors with progressive loss of differentiation for each subsequent cancer is the usual course. Death occurs within 5 years of the first malignancy. Initial tumors may be well-differentiated or verrucous and difficult to distinguish from pseudoepitheliomatous hyperplasia, although successive tumors become progressively less well-differentiated. In recessive variant patients, a trial of isotretinoin has commenced to decrease the risk of development of SCC. Rarely, secondary amyloidosis can also develop in cases associated with persistent chronic inflammation and extensive scarring.
| Conclusion|| |
Inherited EB is a group of rare and life-threatening skin blistering disorder. cSCC is one of the dreadful complications in EBD the patients. Cutaneous squamous cell carcinoma is the most common cause of death in EBD patients with poor prognosis. The reduced life expectancy in these patients is because of distinct tumor microenvironment. So, a regular follow-up is a must in preventing the complications.
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Department of Pathology, Sree Balaji Medical College and Hospital, Bharath University, Chennai - 600 073, Tamil Nadu
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]