Nonneoplastic Disorders of the Vulva and Their Relationship to Vulvar Cancer
Institute of Pathology
University of Graz, Graz, Austria
The majority of vulvar malignant tumors are squamous cell carcinomas (SCC). About 30% of vulvar SCC
are HPV-induced. The majority of the remaining cases arises in association with lichen sclerosus (LS).
LS is the only vulvar dermatosis known to be associated with an increased risk of cancer. While
HPV-induced vulvar carcinogenesis is rather well understood, relatively little is known about the
etiology of LS and the pathophysiological chain of events leading to the development of vulvar SCC in the
background of LS. This handout attempts to give an overview of our current understanding of LS and its
association with vulvar SCC.
I. CLASSIFICATION AND ETIOLOGY OF LICHEN SCLEROSUS
LS occurs in genital skin of children, adolescents and adults of both sexes. LS begins with
uncharacteristic symptoms and advances slowly to atrophic disease with white plaques and areas of
lichenification. In vulvar LS, synechia of the labia minora and stenosis of the introitus vaginae
represent the irreversible late stages of LS with high morbidity. End stage LS has been known for over
100 years under various names (ichthyosis, leukoplakia, craurosis, lichen sclerosus et atrophicus, white
spot disease, dystrophy), but the preferred terminology for all disease stages is Lichen sclerosus  . The etiology of LS remains unclear. Familial
cases of LS in twin sisters, siblings, mothers and daughters, and HLA class II DQ antigen restrictions
support the notion of a genetic predisposition
. Hormonal factors and the spirochete
borrelia have been suggested but not substantiated as triggers for the onset of LS. The high incidence
of concomitant autoimmune diseases (thyroiditis, alopecia areata, vitiligo, pernicious anemia) with
tissue and organ-specific auto-antibodies in patients with LS and their first degree relatives links LS
to autoimmune diseases  . Although no disease-specific auto-antibodies or antigens have
been identified in LS, an "immune dysregulation" in the etiology of LS is presently the most accepted
theory. Fetal microchimerism (transfer of fetal progenitor cells into maternal circulation and
engraftment into maternal tissues during pregnancy) has been implicated in the development of autoimmune
diseases, especially Hashimoto's thyroiditis and systemic sclerosis
. Despite the
strong association of LS with autoimmune thyroid disease and some similarities of LS with systemic
sclerosis, fetal microchimerism is common in vulvar skin and appears to be
etiologically irrelevant for the development of LS  .
II. HISTOLOGICAL FEATURES OF VULVAR LS
End stage LS with an atrophic flat epidermis, hyperkeratotic hair follicles and acrosyringia,
dystrophic hair, extensive dermal sclerosis with scarce, highly sclerotic and ectatic vessels, and a
lymphocytic infiltrate of varying degrees poses clinically and diagnostically no problem. In contrast,
early LS presents clinically with uncharacteristic symptoms. Histopathologically, early LS shows a
variety of typically subtle features, which may involve all or individual compartments of the skin /
mucosa (Table 1):
Table 1 - Histological Features of Early Lichen Sclerosus
|Epidermis ||Normal or|
|Mild acanthosis with slightly irregular plump rete ridges|
|Intraepithelial lymphocytes, mostly in basal or suprabasal location|
|In the presence of intraepidermal lymphocytes: Spongiosis, Vacuolar basal keratinocyte and melanocyte degeneration can be found|
|Basement membrane ||Normal or focally thickened (PAS-reaction!)|
|May be obscured by band-like lichenoid lymphocytic infiltrate|
|Dermis ||Homogenized collagen of papillary dermis|
|Interstitial lymphocytic infiltrate|
|Vessels ||Normal numbers or slightly reduced|
|Ectatic capillaries in dermal papillae, often located immediately beneath the basement membrane|
|Hyalinized vessel walls|
|Perivascular lymphohistiocytic infiltrates|
|Vasculitis: lymphocytic - lymphohistiocytic - rarely leukocytoclastic vasculitis|
|Inflammatory Infiltrate ||Intraepidermal lymphocyte exocytosis with epidermal spongiosis and keratinocyte vacuolization|
|Dermal infiltrates: lichenoid with intraepidermal extension - interstitial - nodular perivascular|
|Hair/Folliculo-sebaceous Unit ||Acanthosis of epithelium of follicular ostiae and sebaceous glands isthmus|
|Luminal hyperkeratosis and hypergranulosis|
|Perifollicular basement membrane thickening|
|Dystrophic hair shafts|
|Sweat glands ||Acanthosis of acrosyringial epithelium with|
|Luminal hyperkeratosis and hypergranulosis of ostiae|
|Basement membrane thickening|
The changes of early LS are focal and serial sectioning of small biopsies and
PAS-reactions are necessary for their identification. Early LS typically involves the adnexal
structures, and in biopsies of early LS the changes of adnexal structures are more prominent and observed
before the interfollicular epidermis shows the characteristic features. The modified mucosa and
epidermis are either of normal thickness with regular keratinization or show a mild acanthosis and
irregular rete ridges. The ostiae of hair follicles, sebaceous glands and sweat glands show epithelial
acanthosis with prominent luminal hyperkeratosis and hypergranulosis. The basement membrane displays a
focal subtle thickening, which is best demonstrated in a PAS-reaction. The papillary dermis / submucosa
appear homogenized with prominent ectatic hyalinized capillaries, some of which are located immediately
beneath the basement membrane. The lymphocytic infiltrate is either focal or diffuse. Lichenoid
infiltrates are often associated with intraepidermal exocytosis of lymphocytes which may result in
intraepidermal edema (spongiosis), squamatization or vacuolization of basal keratinocytes. The dermis in
early LS may contain numerous melanophages, reflecting the destruction of melanocytes and subsequent
phagocytosis of melanosomes. Vascular changes in of all stages of LS include a lymphohistiocytic
("granulomatous") and a lymphocytic vasculitis. Very rarely, a leukocytoclastic vasculitis can be
The histopathological differential diagnosis of an early LS includes a Candida infection, which must be excluded with a PAS-reaction. Lichen planus is
in the differential diagnosis of early LS with a band-like lymphoid infiltrate, but the rete ridges are
saw-tooth-like elongated in lichen planus rather than flattened or plump as typical for LS. Lichen
planus features a wedge-shaped epidermal hypergranulosis and shows no adnexal involvement. Epidermal
vesiculation and occasional eosinophilic granulocytes are indicative for hypersensitivity reactions and
contact allergies. Vulvar psoriasis demonstrates the strikingly regular psoriasiform epidermal
hyperplasia with intraepidermal pustules containing neutrophilic granulocytes. The para- and
hyperkeratosis is less prominent in vulvar mucosa and modified mucosa than in keratinized skin.
III. IMMUNE DYSREGULATION IN LICHEN SCLEROSUS
LS is a progressive lymphocyte-mediated dermatosis. In early LS, the lymphocytic infiltrate is
typically scant. The dense lichenoid and interstitial lymphoid infiltrates in fully developed LS result
in keratinocyte destruction with epithelial atrophy, massive basement membrane thickening, dermal
sclerosis with rarefied sclerotic vessels. In late stage of LS, the lymphocytic infiltrate can vary.
Lymphocytic and lymphohistiocytic vasculitis is a feature of all disease stages of LS  .
Between 20% and 50% of vulvar and penile LS harbor T-cells with a monoclonally rearranged T-cell receptor
γ-chain gene (mTCRγ). mTCRγ can be found in all disease stages of LS, in young and old patients, and
biopsies with dense or scant lymphocytic infiltrates
. The amount of clonal DNA
with mTCRγ is typically below 20% of total analyzed DNA. In our hands, the amount of clonal DNA ranges
between 1.4% and 23.1% DNA and can be observed in biopsies and excision of LS of children and adults
(age range 4 - 82 years) personal observation. The lymphocytic infiltrates in biospies with
mTCRγ consist of B-cells, CD4 > CD8 +T-cells, dendritic cells expressing CD21, CD35, CD106, and
granzyme-B and TIA-1-positive cytotoxic T-cells  . The monoclonal T-cells in LS represents
a reactive infiltrate with an immunoprofile highly indicative of an antigen-mediated immune response.
Currently, the antigen stimulating the TCR modulation is unknown and we do not know at which time point
in the evolution of LS the T-cell clones emerge. An exceptional serological demonstration of clonal DNA
initially demonstrated in a biopsy of LS of the foreskin has been observed in a 31-year-old man who
presented 13 years later with the same clone in the blood and in other skin lesions
The appropriate clinical management of patients with LS containing monoclonal T-cells in the tissue
infiltrates of LS is challenging, mainly due to the lack of experience and long-term follow up of these
IV. THE RELATIONSHIP OF LS TO VULVAR CANCER
It is believed that longstanding vulvar LS carries a slightly increased risk for development of a
vulvar SCC . The association of LS with SCC is only known in genital skin. The exact
incidence of SCC arising in LS is unknown, but estimated to be around 4-5% of women suffering from LS.
The risk to develop a vulvar SCC for a woman with LS is about 15-times increased compared to the "normal"
population. LS is observed in up to 60% of vulvectomy specimens for SCC, and represents often an
incidental finding . Vulvar SCC may be considered a complication of advanced untreated LS,
since LS-associated SCC develops typically in older women suffering from late stage advanced LS with
atrophic, lichenified, cigarette-paper thin skin, resorption and synechiae of the labia minora and
secondary changes after decades of disease progression . However, depending on the age at onset of LS
and the rapidity of disease progression, patients with SCC arising in vulvar LS may be as young as 25
years. Evidence is accumulating that SCC in LS may develop very rapidly, usually within less than 6
months, which makes yearly appointments for vulvar cancer screening in these patients questionable.
Presently, it is not clear if LS should be classified as precancerous lesion, since there are no
documented clinical long term experiences about the natural course of untreated LS. Presently, only a
correct early diagnosis will ensure early treatment of LS and prevent or at least delay the progression
to atrophic mutilating LS and possibly to SCC.
Several theories have been raised to explain the carcinogenesis in LS:
In summary, vulvar LS is a lymphocyte-mediated disease of genital skin and mucosa. Early LS is
treatable, although not curable, and long disease-free intervals can be achieved. Only early recognition
/ diagnosis and treatment will delay disease progression, prevent the high morbidity of endstage LS and
possibly prevent the development of SCC. At our present understanding, t he gold standard of therapy is
the reduction of the lymphocytic infiltrate, which can be achieved with corticosteroids and
immunomodulators. It is presently not known if and how long-term treatment with glucocorticoids
contributes to a local immunodeficiency and vulvar carcinogenesis in the background of LS.
- SCC has been postulated to arise from localized squamous hyperplasia within a lesion of LS
. Immunohistochemical demonstration of p53 in SCC and adjacent hypertrophic / hyperplastic LS
has lead to the assumption that hyperplastic lesions are precursors of SCC  . However,
immunohistochemical demonstration of p53 is a common finding in LS. In our own survey of 200 patients
with LS, which included pediatric and adult patients at various disease stages, p53-staining of nuclei of
basal keratinocyte was observed commonly. While early LS and young patients revealed mostly individual
positive nuclei, about 60% of fully developed LS showed nuclear basal keratinocyte staining.
Hypertrophic LS revealed staining in 70% basal and suprabasal keratinocyte nuclei. p53-staining was
associated with sclerosis of dermis and blood vessels, and lymphoid infiltrates and explained by
inflammation and ischemic stress due to poor oxygenation secondary to rarified sclerotic blood vessels
and vasculitis. p53-expression is a poor screening tool for identifying precancerous lesions, since
p53-expression does not correlate with dysplasia (unpublished personal data, abstract /oral presentation
section D, Monday afternoon) or p53 gene mutations, which are late events in vulvar carcinogenesis
 . True neoplastic hypertrophies and hyperplasias in LS have to be distinguished from reactive
pseudo-epitheliomatous hyperplasias in the vicinity of ulcerations, edges of epithelial regeneration and
ruptured hair follicles, particularly when fibrin and inflammation is present. Pseudoepitheliomatous
hyperplasia is a self-limited condition without progression to SCC  and typically observed in
advanced LS complicated by secondary changes.
- Differentiated vulvar intraepithelial neoplasia (d-VIN) has been
postulated to be a precursor lesion for non-HPV-related vulvar cancer with a rapid progression to
invasive SCC. d-VIN has been described as acanthotic epidermis with elongated and anastomosing rete
ridges and lack of HPV-associated cell changes. The enlarged atypical basal keratinocytes are
p53-positive, show occasional mitoses and premature eosinophilic cytoplasmic differentiation. d-VIN
can be observed in the immediate vicinity of SCC in about 25% of vulvectomy specimens for SCC
In a survey of over 200 patients, only 2% of biopsies and excisions of lone LS revealed d-VIN.
However, we were able to identify d-VIN in 8/33 (24%) vulvectomy specimens for SCC arising in the
background of LS (unpublished personal data, abstract /oral presentation section D, Monday afternoon).
d-VIN may also be considered a complication of longstanding LS which occurs in endstage disease
independent of the patients age. Our youngest patients with d-VIN adjacent to the SCC in the background
of LS were 25 and 23 years resp. In the vast majority of cases, d-VIN is identified retrospectively
adjacent to vulvar SCC. In my opinion, d-VIN has only a limited value as a prospective screening marker
for assessing the cancer risk in an individual patient. Again, there are no long-term clinical follow-up
data on the natural course of LS and d-VIN, and the importance and significance of d-VIN as a
precancerous lesion is still undefined.
- The observed local immune dysregulation in LS may lead to a reduction of TCR diversity in the
lymphoid infiltrate. The demonstration of mTCRg gene in the lymphoid infiltrate in LS
is interpreted as antigen-driven selection of T-cells after prolonged exposure of the host
immune system to a local antigen. The restricted TCR-usage may result in subsequent immune dysregulation
and inadequate tumor response of the tumor infiltrating lymphocytes, creating a permissive environment
for the development of SCC in LS patients. All investigators of LS agree on the non-neoplastic nature of
the infiltrate despite the lack of a thorough understanding of the etiology of LS. Antigen-driven
selection of T-cells and restricted TCR-usage may reflect prolonged exposure of the host immune system to
a local (? infectious, ? putative LS-associated) antigen. The lack of long-term follow-up of LS patients
with documented mTCRg , however, defers a final judgment on the clinical significance of our
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