Vulvar lichen sclerosus and squamous cell carcinoma: A cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia

J. Andrew Carlson, Robert Ambros, John Malfetano, Jeffery Ross, Richard Grabowski, Philina M Lamb, Helen Figge, Martin C. Mihm

Research output: Contribution to journalArticle

180 Citations (Scopus)

Abstract

The histological changes of lichen sclerosus (LS) are frequently found in association with vulvar squamous cell carcinoma (SGG). The importance of chronic inflammation and scarring in oncogenesis is well recognized. Thirty- two patients with symptomatic vulvar LS and 60 with vulvar SCC were studied. Paraffin sections of vulvar LS, and three controls groups (acute scars, normal vulva, and vulvar lichen simplex chronicus [LSG]) were investigated with a panel of seven tissue markers and for DNA content in areas without vulvar intraepithelial neoplasia (VIN). All published cases to date of vulvar LS associated with SCC were reviewed. Of the cohort of symptomatic vulvar LS patients (mean/median age, 60 years), 9% developed VIN lesions and 21% invasive SGC; symptomatic LS preceded the carcinoma by a mean of 4 years (range, 1 to 23 years). Second and third primary tumors developed in three of these patients. Of the series of 60 patients presenting with vulvar SGCa, the clinical setting and histological features of SCCs associated with LS were significantly distinctive compared with SGCas without IS: SCCs associated with LS occurred in an older age-group (74 v 65 years; P = .01), were located on the clitoris (41% v 5%; P = .003), were of conventional SCCa type (85% v 57%; P = .02), were associated with a prominent fibromyxoid stromal response (46% v 10%; P = .004), were not associated with VIN 3 (SCC in situ) (5% v 67%; P = .02) and diffusely expressed tumor suppressor gene product p53 (43% v 19%; P = .01) and cytokine TGF-beta (33% v 9%; P = .05). The epidermis of vulvar LS was similar to that of acute scars and differed significantly compared with normal vulva with respect to keratinocytic expression of markers to keratin AE 1, involucrin and filaggrin, epidermal thickness (0.13 mm [LS] v 0.05 mm [normal]; P < .03), and proliferative index by PGNA and Mib-1 labeling (53/60 [LS] v 15/19 [normal] per 200 basal cells [be]; P < .003). Vulvar LS showed significantly higher expression of p53 than all three control groups (80 [LS] v 3 [normal]/44 [acute scar]/28 [LSC] per 200 be; P < .008), and aneuploidy (33% v diploid controls) in the absence of VIN. Comparing LS with and without associated SCCa found significant increases in age of patients (74 v 66 years; P= .001), and DNA aneuploidy (52% v 11%; P= .0001) and no differences in epidermal thickness, sclerotic thickness, proliferative index, or p53 expression. However, those cases of LS with an aneuploid DNA content showed significantly elevated p53 expression (88 v 60/200 be; P = .01) and epidermal thickness (0.16 v 0.11 mm; P = .005) compared with LS with a diploid DNA content. Review of published cases supports an association between LS and vulvar SGC. The phenomenon of chronic inflammation and scarring giving rise to carcinoma has been well documented. Vulvar lichen sclerosus (LS) is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis (sclerosis). A subset of vulvar SCCs is significantly associated with the presence of LS and diffusely express the p53 gene product. Keratinocytes affected by LS show a proliferative phenotype and can exhibit markers of neoplastic progression such as increased p53 expression and DNA aneuploidy. As a chronic scarring inflammatory dermatosis, vulvar LS could act as both 'initiator and promoter' of carcinogenesis, explaining the frequent coexistence of these diseases. Because keratinocytes of LS significantly express tumor suppressor gene p53 protein, the p53 gene may be involved early in this proposed pathway of carcinogenesis.

Original languageEnglish (US)
Pages (from-to)932-948
Number of pages17
JournalHuman Pathology
Volume29
Issue number9
DOIs
StatePublished - 1998
Externally publishedYes

Fingerprint

Vulvar Lichen Sclerosus
Lichen Sclerosus et Atrophicus
Sclerosis
Case-Control Studies
Squamous Cell Carcinoma
Inflammation
Neoplasms
Cicatrix
Aneuploidy
Carcinogenesis
Vulva
DNA
p53 Genes
Tumor Suppressor Genes
Diploidy
Keratinocytes
Skin Diseases
Keratin-1
Neurodermatitis
Clitoris

Keywords

  • Carcinogenesis
  • Chronic inflammation
  • DNA ploidy
  • Field cancerization
  • Lichen sclerosus
  • p53 tumor suppressor gene
  • Review
  • Scar
  • TGF-β cytokine
  • Vulvar squamous cell carcinoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Vulvar lichen sclerosus and squamous cell carcinoma : A cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. / Carlson, J. Andrew; Ambros, Robert; Malfetano, John; Ross, Jeffery; Grabowski, Richard; Lamb, Philina M; Figge, Helen; Mihm, Martin C.

In: Human Pathology, Vol. 29, No. 9, 1998, p. 932-948.

Research output: Contribution to journalArticle

Carlson, J. Andrew ; Ambros, Robert ; Malfetano, John ; Ross, Jeffery ; Grabowski, Richard ; Lamb, Philina M ; Figge, Helen ; Mihm, Martin C. / Vulvar lichen sclerosus and squamous cell carcinoma : A cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. In: Human Pathology. 1998 ; Vol. 29, No. 9. pp. 932-948.
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abstract = "The histological changes of lichen sclerosus (LS) are frequently found in association with vulvar squamous cell carcinoma (SGG). The importance of chronic inflammation and scarring in oncogenesis is well recognized. Thirty- two patients with symptomatic vulvar LS and 60 with vulvar SCC were studied. Paraffin sections of vulvar LS, and three controls groups (acute scars, normal vulva, and vulvar lichen simplex chronicus [LSG]) were investigated with a panel of seven tissue markers and for DNA content in areas without vulvar intraepithelial neoplasia (VIN). All published cases to date of vulvar LS associated with SCC were reviewed. Of the cohort of symptomatic vulvar LS patients (mean/median age, 60 years), 9{\%} developed VIN lesions and 21{\%} invasive SGC; symptomatic LS preceded the carcinoma by a mean of 4 years (range, 1 to 23 years). Second and third primary tumors developed in three of these patients. Of the series of 60 patients presenting with vulvar SGCa, the clinical setting and histological features of SCCs associated with LS were significantly distinctive compared with SGCas without IS: SCCs associated with LS occurred in an older age-group (74 v 65 years; P = .01), were located on the clitoris (41{\%} v 5{\%}; P = .003), were of conventional SCCa type (85{\%} v 57{\%}; P = .02), were associated with a prominent fibromyxoid stromal response (46{\%} v 10{\%}; P = .004), were not associated with VIN 3 (SCC in situ) (5{\%} v 67{\%}; P = .02) and diffusely expressed tumor suppressor gene product p53 (43{\%} v 19{\%}; P = .01) and cytokine TGF-beta (33{\%} v 9{\%}; P = .05). The epidermis of vulvar LS was similar to that of acute scars and differed significantly compared with normal vulva with respect to keratinocytic expression of markers to keratin AE 1, involucrin and filaggrin, epidermal thickness (0.13 mm [LS] v 0.05 mm [normal]; P < .03), and proliferative index by PGNA and Mib-1 labeling (53/60 [LS] v 15/19 [normal] per 200 basal cells [be]; P < .003). Vulvar LS showed significantly higher expression of p53 than all three control groups (80 [LS] v 3 [normal]/44 [acute scar]/28 [LSC] per 200 be; P < .008), and aneuploidy (33{\%} v diploid controls) in the absence of VIN. Comparing LS with and without associated SCCa found significant increases in age of patients (74 v 66 years; P= .001), and DNA aneuploidy (52{\%} v 11{\%}; P= .0001) and no differences in epidermal thickness, sclerotic thickness, proliferative index, or p53 expression. However, those cases of LS with an aneuploid DNA content showed significantly elevated p53 expression (88 v 60/200 be; P = .01) and epidermal thickness (0.16 v 0.11 mm; P = .005) compared with LS with a diploid DNA content. Review of published cases supports an association between LS and vulvar SGC. The phenomenon of chronic inflammation and scarring giving rise to carcinoma has been well documented. Vulvar lichen sclerosus (LS) is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis (sclerosis). A subset of vulvar SCCs is significantly associated with the presence of LS and diffusely express the p53 gene product. Keratinocytes affected by LS show a proliferative phenotype and can exhibit markers of neoplastic progression such as increased p53 expression and DNA aneuploidy. As a chronic scarring inflammatory dermatosis, vulvar LS could act as both 'initiator and promoter' of carcinogenesis, explaining the frequent coexistence of these diseases. Because keratinocytes of LS significantly express tumor suppressor gene p53 protein, the p53 gene may be involved early in this proposed pathway of carcinogenesis.",
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T2 - A cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia

AU - Carlson, J. Andrew

AU - Ambros, Robert

AU - Malfetano, John

AU - Ross, Jeffery

AU - Grabowski, Richard

AU - Lamb, Philina M

AU - Figge, Helen

AU - Mihm, Martin C.

PY - 1998

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N2 - The histological changes of lichen sclerosus (LS) are frequently found in association with vulvar squamous cell carcinoma (SGG). The importance of chronic inflammation and scarring in oncogenesis is well recognized. Thirty- two patients with symptomatic vulvar LS and 60 with vulvar SCC were studied. Paraffin sections of vulvar LS, and three controls groups (acute scars, normal vulva, and vulvar lichen simplex chronicus [LSG]) were investigated with a panel of seven tissue markers and for DNA content in areas without vulvar intraepithelial neoplasia (VIN). All published cases to date of vulvar LS associated with SCC were reviewed. Of the cohort of symptomatic vulvar LS patients (mean/median age, 60 years), 9% developed VIN lesions and 21% invasive SGC; symptomatic LS preceded the carcinoma by a mean of 4 years (range, 1 to 23 years). Second and third primary tumors developed in three of these patients. Of the series of 60 patients presenting with vulvar SGCa, the clinical setting and histological features of SCCs associated with LS were significantly distinctive compared with SGCas without IS: SCCs associated with LS occurred in an older age-group (74 v 65 years; P = .01), were located on the clitoris (41% v 5%; P = .003), were of conventional SCCa type (85% v 57%; P = .02), were associated with a prominent fibromyxoid stromal response (46% v 10%; P = .004), were not associated with VIN 3 (SCC in situ) (5% v 67%; P = .02) and diffusely expressed tumor suppressor gene product p53 (43% v 19%; P = .01) and cytokine TGF-beta (33% v 9%; P = .05). The epidermis of vulvar LS was similar to that of acute scars and differed significantly compared with normal vulva with respect to keratinocytic expression of markers to keratin AE 1, involucrin and filaggrin, epidermal thickness (0.13 mm [LS] v 0.05 mm [normal]; P < .03), and proliferative index by PGNA and Mib-1 labeling (53/60 [LS] v 15/19 [normal] per 200 basal cells [be]; P < .003). Vulvar LS showed significantly higher expression of p53 than all three control groups (80 [LS] v 3 [normal]/44 [acute scar]/28 [LSC] per 200 be; P < .008), and aneuploidy (33% v diploid controls) in the absence of VIN. Comparing LS with and without associated SCCa found significant increases in age of patients (74 v 66 years; P= .001), and DNA aneuploidy (52% v 11%; P= .0001) and no differences in epidermal thickness, sclerotic thickness, proliferative index, or p53 expression. However, those cases of LS with an aneuploid DNA content showed significantly elevated p53 expression (88 v 60/200 be; P = .01) and epidermal thickness (0.16 v 0.11 mm; P = .005) compared with LS with a diploid DNA content. Review of published cases supports an association between LS and vulvar SGC. The phenomenon of chronic inflammation and scarring giving rise to carcinoma has been well documented. Vulvar lichen sclerosus (LS) is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis (sclerosis). A subset of vulvar SCCs is significantly associated with the presence of LS and diffusely express the p53 gene product. Keratinocytes affected by LS show a proliferative phenotype and can exhibit markers of neoplastic progression such as increased p53 expression and DNA aneuploidy. As a chronic scarring inflammatory dermatosis, vulvar LS could act as both 'initiator and promoter' of carcinogenesis, explaining the frequent coexistence of these diseases. Because keratinocytes of LS significantly express tumor suppressor gene p53 protein, the p53 gene may be involved early in this proposed pathway of carcinogenesis.

AB - The histological changes of lichen sclerosus (LS) are frequently found in association with vulvar squamous cell carcinoma (SGG). The importance of chronic inflammation and scarring in oncogenesis is well recognized. Thirty- two patients with symptomatic vulvar LS and 60 with vulvar SCC were studied. Paraffin sections of vulvar LS, and three controls groups (acute scars, normal vulva, and vulvar lichen simplex chronicus [LSG]) were investigated with a panel of seven tissue markers and for DNA content in areas without vulvar intraepithelial neoplasia (VIN). All published cases to date of vulvar LS associated with SCC were reviewed. Of the cohort of symptomatic vulvar LS patients (mean/median age, 60 years), 9% developed VIN lesions and 21% invasive SGC; symptomatic LS preceded the carcinoma by a mean of 4 years (range, 1 to 23 years). Second and third primary tumors developed in three of these patients. Of the series of 60 patients presenting with vulvar SGCa, the clinical setting and histological features of SCCs associated with LS were significantly distinctive compared with SGCas without IS: SCCs associated with LS occurred in an older age-group (74 v 65 years; P = .01), were located on the clitoris (41% v 5%; P = .003), were of conventional SCCa type (85% v 57%; P = .02), were associated with a prominent fibromyxoid stromal response (46% v 10%; P = .004), were not associated with VIN 3 (SCC in situ) (5% v 67%; P = .02) and diffusely expressed tumor suppressor gene product p53 (43% v 19%; P = .01) and cytokine TGF-beta (33% v 9%; P = .05). The epidermis of vulvar LS was similar to that of acute scars and differed significantly compared with normal vulva with respect to keratinocytic expression of markers to keratin AE 1, involucrin and filaggrin, epidermal thickness (0.13 mm [LS] v 0.05 mm [normal]; P < .03), and proliferative index by PGNA and Mib-1 labeling (53/60 [LS] v 15/19 [normal] per 200 basal cells [be]; P < .003). Vulvar LS showed significantly higher expression of p53 than all three control groups (80 [LS] v 3 [normal]/44 [acute scar]/28 [LSC] per 200 be; P < .008), and aneuploidy (33% v diploid controls) in the absence of VIN. Comparing LS with and without associated SCCa found significant increases in age of patients (74 v 66 years; P= .001), and DNA aneuploidy (52% v 11%; P= .0001) and no differences in epidermal thickness, sclerotic thickness, proliferative index, or p53 expression. However, those cases of LS with an aneuploid DNA content showed significantly elevated p53 expression (88 v 60/200 be; P = .01) and epidermal thickness (0.16 v 0.11 mm; P = .005) compared with LS with a diploid DNA content. Review of published cases supports an association between LS and vulvar SGC. The phenomenon of chronic inflammation and scarring giving rise to carcinoma has been well documented. Vulvar lichen sclerosus (LS) is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis (sclerosis). A subset of vulvar SCCs is significantly associated with the presence of LS and diffusely express the p53 gene product. Keratinocytes affected by LS show a proliferative phenotype and can exhibit markers of neoplastic progression such as increased p53 expression and DNA aneuploidy. As a chronic scarring inflammatory dermatosis, vulvar LS could act as both 'initiator and promoter' of carcinogenesis, explaining the frequent coexistence of these diseases. Because keratinocytes of LS significantly express tumor suppressor gene p53 protein, the p53 gene may be involved early in this proposed pathway of carcinogenesis.

KW - Carcinogenesis

KW - Chronic inflammation

KW - DNA ploidy

KW - Field cancerization

KW - Lichen sclerosus

KW - p53 tumor suppressor gene

KW - Review

KW - Scar

KW - TGF-β cytokine

KW - Vulvar squamous cell carcinoma

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