Vulvar cancers in women with vulvar lichen planus: A clinicopathological study Sigrid Regauer, MD,a Olaf Reich, MD,b and Barbara Eberz, MDc Graz and M€ urzzuschlag, Austria Background: Vulvar squamous cell carcinomas (SCCs) arising in association with vulvar lichen planus (LP) are poorly documented. Objectives: We sought to present clinicopathological features of 38 patients (median age 61 years, range 39-90 years) with LP-associated vulvar SCCs. Methods: Evaluated were location of vulvar SCC and metastases at presentation, recurrences, survival, precursor lesions, presence of human papillomavirus DNA, p16ink4a, and p53 expression. Results: In all, 32 solitary (5 pT1a, 20 pT1b, 7 pT2) and 6 multifocal SCCs, located in the vestibulum (n = 20) and in nonhair-bearing modified and glycogenated mucosa (n = 18), arose in erosive (n = 13) and nonerosive (n = 25) LP. All SCCs were human papillomavirus DNA and p16ink4a negative. Sixteen of 38 (42%) women had inguinal metastases at presentation. Treatment was surgery with clear margins (36/38) and chemoradiation (2/38). Fourteen of 36 (39%) surgically treated patients developed between 1 and 5 new SCCs in the residual diseased mucosa. Of all recurrences, 68% developed within 12 months via precursors revealing various histologic features including elongated, but also flat rete ridges, basaloid and hypertrophic differentiation with inconsistent p53 expression. Fourteen of 38 (37%) patients died of SCCs. Limitations: Retrospective study and lack of a standardized treatment protocols are limitations. Conclusion: LP-associated SCCs were located in nonhair-bearing vulvar mucosa. Patients had a high rate of inguinal metastases, recurrent vulvar cancers in diseased mucosa, and disease-related death. ( J Am Acad Dermatol 2014;71:698-707.) Key words: differentiated vulvar intraepithelial neoplasia; human papillomavirusenegative vulvar carcinoma; precursor lesions; vulvar dermatosis; vulvar squamous cell carcinoma.
L
ichen planus (LP) is a chronic inflammatory autoimmune dermatosis with a prevalence of 1% to 2% in the general population. LP may involve extragenital and genital skin along with mucosal surfaces. In the vulva, presentation of LP depends on site of involvement. In vulvar hair-bearing skin of mons pubis and labia majora, and modified mucosa of interlabial sulci, labia minora, clitoris, and perineum, LP is characterized by individual white or skin-colored papules or
From the Institute of Pathologya and Department of Gynecology,b Medical University Graz; and General Gynecology Practice, M€ urzzuschlag.c Funding sources: None. Conflicts of interest: None declared. Accepted for publication May 25, 2014. Reprint requests: Sigrid Regauer, MD, Institute of Pathology, Reference Center for Anogenital Diseases, Medical University
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Abbreviations used: d-VIN: HPV: LP: SCC:
differentiated vulvar intraepithelial neoplasia human papillomavirus lichen planus squamous cell carcinoma
plaques. The erosive variant of LP with typical Wickham striae is seen in the glycogenated squamous mucosa of vestibule, introitus vaginae
Graz, Auenbruggerplatz 25, A-8036 Graz, Austria. E-mail: sigrid.
[email protected]. Published online July 7, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.05.057
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and vagina, often referred to as ‘‘lichen ruber are tumors greater 2 cm in greatest diameter or with planus.’’1,2 The risk of a patient developing a stromal invasion greater than 1.0 mm; pT2 SCCs are squamous cell carcinoma (SCC) depends on the tumors of any size with extension to adjacent site of involvement of LP. Although LP in extragenital structures (lower third urethra, lower third vagina, skin has no cancer risk, a 5% risk has been described anus); and pT3 SCCs are tumors of any size with in oral and esophageal mucosa.3 Recently, LP has extension to the following structures: upper two been recognized as an associated condition in huthirds of urethra, upper two thirds of vagina, bladder man papillomavirus (HPV)mucosa, rectal mucosa, or negative penile SCCs.4,5 In fixed to pubic bone. Entry CAPSULE SUMMARY contrast, although the associcriteria were an unequivocal ation of vulvar LP and SCC (clinical and histologic) diagLichen planus (LP) in oral and was reported as early as nosis of LP and a minimum esophageal mucosa has a cancer risk of 1989,6 the association of follow-up of 12 months, unup to 5%, and LP is recognized as a risk vulvar SCC with LP is poorly less the end point death or factor for penile human papillomaviruse documented with either case recurrence occurred earlier. negative cancer. The association of reports only or brief mention LP was divided into erosive vulvar LP and cancer, however, is poorly in larger series dealing with and nonerosive forms, and documented. diagnoses and treatment of extent of vulvar scarring was Vulvar LP-associated human vulvar LP.1,7-12 Only 1 larger reported.1 LP was diagnosed papillomavirusenegative squamous cell series reported the associaclinically and confirmed carcinomas are located in nonhairy tion of LP in 5 of 23 histologically, following pubvulvar mucosa, particularly in the anogenital SCCs.13 The risk lished criteria.21 Formalinvestibulum, have a high percentage of for cancer in vulvar LP is fixed and paraffin-embedded inguinal metastases at presentation, and unknown, as are the typical archival tissues from the have a high rate of recurrent cancer in sites of involvement, the Institute of Pathology at the residual diseased mucosa. type of precursor lesions, Medical University Graz, The high risk for squamous cell and clinical characteristics of Austria, were evaluated carcinoma in vulvar mucosal LP suggests LP-associated SCC. for HPV DNA (INNO-LiPA Vulvar SCCs can be the need for regular and close HPV Genotyping Extra, divided according to cause monitoring. Innogenetics Diagnostic, into cancers induced by HPV Heiden, Germany). All priand those arising indepenmary and recurrent invasive dently of HPV14 through precursor lesions called SCCs and precursors were evaluated by immunohis‘‘differentiated vulvar intraepithelial neoplasia’’ tochemistry with monoclonal antibody to p53 (clone (d-VIN),14,15 originally described as ‘‘differentiated DO-7; DAKO, Corp, Capinteria, CA) and p16ink4a 16 simplex in situ SCC.’’ The origin of HPV-negative (Roche Diagnostics, Indianapolis, IN, formerly MTM SCCs is unclear, although mutations in the p53 gene Laboratories, Heidelberg, Germany), an indirect have been suggested17,18 and the association of marker for a transforming infection with HPV HPV-negative SCC with lichen sclerosus, a common high-risk genotypes. Institutional ethics committee vulvar dermatosis with a prevalence of up to 8% in approval and research study approval for this gynecologic practices,19 is well accepted. The aim of study was obtained (Medical University, EK number this article is to document clinical and histologic 20-255ex 08/09). All patients gave consent to features of a large series of vulvar SCCs arising in the photographic documentation. background of LP to elucidate possible LP-specific characteristics. RESULTS I Clinical characteristics of primary LP-associated SCC METHODS See Table I. In all, 38 women (median age 61 years In all, 38 patients with a primary LP-associated at diagnosis; range 39-90 years; 9 premenopausal vulvar SCC were treated at the Department of and 29 postmenopausal) with a primary vulvar SCC Gynecology at the Medical University Graz, Austria, arising in nonerosive vulvar LP (n = 25) (Fig 1, A to during the past 12 years. All cancers were H ) and erosive LP (n = 13) were evaluated. classified according to the seventh edition of TNM The nonerosive form of LP presented either as classification of malignant tumors20: pT1a SCCs are skin-colored or white, individual or multiple papules tumors 2 cm or less in greatest diameter and with (n = 13) (Fig 1, A and C to F ) or larger, partly stromal invasion no greater than 1.0 mm; pT1b SCC d
d
d
Patient; age at diagnosis
Clinical type of LP
TNM classification size of SCC
1; 39 y
Papules
pT1a
2; 39 y
Papules
pT1b
3; 40 y
Hypertrophic pT1b (m2)
4; 44 y
Hypertrophic pT1b (m2)
5; 45 y 6; 46 y
Hypertrophic pT1b Papules pT1b; L1; V1 Papules, pT1b plaques
7; 47 y
Localization of first SCC
Between clitoris and urethra (Fig 1, D, and Fig 2, A and B) Clitoral hood (Fig 1, A) Periclitoral, labium minus Periclitoral hymenal ring Labium minus Interlabial sulcus
TNM classification lymph node met at first diagnosis
TNM classification distant mets at first diagnosis
First recurrence in months
Second recurrence in months
Third recurrence in months
Fourth recurrence in months
Fifth recurrence in months
Survival in months
pN0 (sn)
Alive; 18 mo
pN0 (sn)
Alive; 48 mo
pN1a (sn)
Chemoradiation 25 mo SCC pT1a 12 mo SCC pT1b 7 mo pT1b
pN0 pN0 (sn) pN2b
Skin, LN obturator
17 mo d-VIN
Alive; 51 mo Alive; 120 mo Alive; 49 mo 9 mo DoD
7mo SCC, pT1b L1, V1
Between clitoris pN0 (sn) and urethra (Fig 1, E, and Fig 2, C and D) Clitoral hood pN2c (sn) Periclitoral pN0 (sn) (Fig 1, B)
Alive; 36 mo
10; 55 y 11; 56 y
Papules pT1b Papules and pT1b; L1 plaques
Labium minus Between clitoris and urethra
pN0 (sn) pN2c
12; 63 y
Papules
pN0 (sn)
13; 64 y
Hypertrophic pT1b
Between clitoris and urethra (Fig 1, F ) Periclitoral
14; 66y
plaques
pT1a
inner side labium minus
pN0
15; 66 y
Atrophic plaques
pT1a
Between clitoris and urethra
pN0
16; 66 y 17; 67 y
Papules pT1b Hypertrophic pT2; L1
Periclitoral Periclitoral
pN1a (sn) pN1a Skin
Pelvic LN; skin
pN0
Alive; 45 mo DsD car accident 11 mo Alive; 12 mo Alive; 22 mo
11 mo SCC pT1b 11 mo SCC with pelvic pT1b and pelvic exenteration recurrence
Alive; 108 mo
12 mo SCC pT1b 11 mo SCC pT1b 41 mo d-VIN (m)
18 mo SCC pT1b 7 mo SCC pT1b
25 mo d-VIN
7 mo SCC 30 mo SCC 95 mo DoD pT1b pT2 (m7) lost to follow-up after 44 mo Alive; lost to follow-up after 31 mo Alive; 36 mo 14 mo SCC 42 mo DoD pT1b (m)
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Papules pT1b; L1 Hypertrophic pT1b
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8; 50 y 9; 50 y
pT1b
First treatment other than surgery
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Table I. Lichen planuseassociated vulvar squamous cell carcinomas
pT2
Between urethra pN0 (sn) and clitoris, labium minus Interlabial sulcus pN0 (sn)
Hypertrophic pT1b (Fig 1, C )
20; 71 y
Erosive
21; 71 y
Erosive
22; 72 y 23; 73 y
Papules plaques Erosive
24; 74 y
Erosive
pT2
Between urethra pN0 (sn) and clitoris
25; 75 y
Erosive
pT2; L1; V1
Between urethra pN1a and clitoris
26; 76 y 27; 77 y
Papules Papules
pT1b pT1a
Labium minus Periclitoral
pN2b pN0 (sn)
28; 68 y 29; 78 y
Erosive Erosive
pT1b pT1b
pN1a pN0
30; 80 y
Erosive
pT2
31; 80 y
Hypertrophic pT1b (m2)
32; 81 y
Papule
pT1b
Labium minus Between clitoris and urethra Between clitoris and urethra, hymenal ring Periurethral, periclitoral (Fig 1, H ) Labium minus
33; 81 y
Erosive
pT1a
34; 83 y 35; 84 y
Erosive Papules
pT1b
Between urethra and clitoris pT1b (m2) Bilateral labium minus pT2 (m2) L1 Between urethra and clitoris pT1b Vestibulum, hymenal ring
Inner labium minus, vestibulum pT2 Hymenal ring pT2 and Hymenal ring, pT1b (m3) perineum
55 mo d-VIN
Alive; 83 mo
7 mo SCC pT1b (Fig 1, I)
77 mo DoD
pN2b (sn) Lung pN2c
Liver; pelvic LN
24 mo DoD Chemoradiation and surgery
12 mo DoD
pN1a pN2b
pN1a
Alive; 132 mo Vaginal mets und pelvic LN Skin
10 mo SCC pT2; L1
17 mo DoD
Alive; lost to follow-up after 92 mo 8 mo DoD
6 mo mons pubis and pelvic disease (M1) 31 mo d-VIN
7 mo d-VIN (Fig 2, E and F)
5 mo d-VIN
pN0
108 mo SCC 11 mo d-VIN pT1a, pN0 (sn)
8 mo DoD
Alive; 33 mo
pN0 (sn)
12 mo d-VIN
Alive; 43 mo Alive; 69 mo
Alive; 12 mo 48 mo DoD
32 mo SCC pT1a 4 mo SCC pT1b (2) 7 mo omentum (M1)
pN0 (sn)
pN0 (sn) pN0
8 mo SCC 12 mo d-VIN pT1b (Fig 2, G and H)
12 mo SCC pT1b; pN1a
5 mo SCC pT1b
15 mo SCC 5 mo SCC Alive; 151 mo pT1b pT1a (m2) DsD pneumonia; 66 mo 42 mo DoD 37 mo DoD
Continued
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19; 70 y
74 mo SCC pT1b
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18; 69 y
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Erosive 38; 90 y
pT2; L1
Hypertrophic pT1b 37; 88 y
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Bold indicates presence of lymph node metastases at presentation and death of disease. d-VIN, Differentiated vulvar intraepithelial neoplasia; DoD, died of disease; DsD, died independent of disease; L1, invasion of lymphatic vessels; LN, lymph node; LP, lichen planus; (m), indicates multiple SCC; M1, distant metastases; met, metastasis; SCC, squamous cell carcinoma; (sn), classification based in sentinel lymph node dissection only; V1, invasion of venous blood vessels.
7 mo DoD
Alive; 16 mo
14 mo DoD
Periclitoral, pN2b interlabial sulcus Hymenal ring, pN1a (sn) perineum (Fig 1, G) Entire vestibulum pN2c and hymenal ring, crater pT1b Papules plaques 36; 87 y
Clinical type of LP Patient; age at diagnosis
Table I. Cont’d
TNM classification size of SCC
Localization of first SCC
TNM classification lymph node met at first diagnosis
TNM classification distant mets at first diagnosis
First treatment other than surgery
First recurrence in months
Second recurrence in months
Third recurrence in months
Fourth recurrence in months
Fifth recurrence in months
Survival in months
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hypertrophic plaques with increased skin markings (lichenification) and varying amounts of hyperkeratosis (Fig 1, B, G, and H ). Five of 38 patients had a solitary pT1a SCC (13%), 18 of 38 patients had a solitary pT1b SCC (47%), 9 of 38 women presented with a solitary pT2 SCC (24%) (Fig 1, A to G), and 6 of 38 women had multifocal SCCs at presentation (16%) (Fig 1, H ). Sixteen of 38 (42%) women had inguinal lymph node metastases at presentation. There was a wide variation of vulvar architectural changes reflecting the different disease stages of LP. In early disease stages and all pT1a SCC, the vulvar anatomy was not or only mildly altered, mainly perceived as stiffening and mild or focal adhesion of labia minora and the periclitoral mucosa (Fig 1, A, D, E, and F ). Advanced LP stages were characterized by partial or complete loss of normal vulvar architecture, eg, the labia minora were partially or completely fused, the clitoris was buried, and periclitoral tissues were scarred (Fig 1, B and G to I ). Varying degrees of stenosis of the vaginal introitus were documented in 18 women (Fig 1, G and H ). In some patients, it was therefore difficult to determine the exact anatomic location of the cancers. The primary SCCs were located in modified mucosa of clitoral hood (n = 2) (Fig 1, A), on the labium minus (n = 5), near the clitoris (n = 8) (Fig 1, B and H ), and in the interlabial sulcus (n = 3) (Fig 1, C ). SCCs was located in the vestibulum in 20 patients. Thirteen of 20 vestibular SCCs were located between clitoris and urethra (Fig 1, D to F ), 4 of 20 SCCs were located in the posterior vestibulum involving the hymen and perineum (Fig 1, G), and 3 of 20 SCCs were located at the vestibular border facing the inner side of labium minus. All pT2 SCCs involved the entire vestibulum. The multifocal SCCs involved the vestibulum, labia minora, and periclitoral mucosa with LP separating the cancers (Fig 1, H ). SCCs in hair-bearing vulva were not identified. Of 38 women, 27 women had no prior diagnoses of LP or had not been in regular gynecologic or dermatologic follow-up for their LP or been treated according to standard protocols when they presented with their SCC. Many patients reported a rapid development of SCC, but it was documented only in 4 women. Two women had a biopsy specimen of a LP plaque between clitoris and urethra revealing a d-VIN 4 and 5 months before a pT1a SCC was excised. The third patient with advanced LP had been in regular 6-month gynecologic control visits for 3 years when she noted a hyperkeratotic plaque 5 months after the last uneventful gynecologic visit, which was biopsied and diagnosed as SCC. The resection, performed 6 weeks later, revealed a pT1b SCC (patient 9) (Fig 1, B). She remained free of vulvar
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recurrence and metastases until she died in a car accident 11 months later. The fourth woman was in yearly follow-up for a hypertrophic LP when she presented with a pT1b SCC 11 months after the last uneventful control visit. Treatment and clinical course of LP-associated SCC Treatment was primary chemoradiation in 2 patients, followed by subsequent surgical excision in 1 of 2 patient. Surgical excision with clear margins of at least 1 cm in 36 women left residual lesions of LP behind in all patients. All women underwent either complete inguinal lymph adenectomy or sentinel lymph node excision. In all, 21 of 38 (55%) women had no metastases and 17 of 38 (45%) women had regional LN metastases greater than 2 mm at presentation. Distant metastases (skin, pelvic lymph nodes, lung, liver) at presentation were present in 7 of 38 (18%) patients. The patient with primary chemoradiation therapy without surgery developed 4 recurrences at the site of the original SCCs, which were all resected. Fourteen of 36 (39%) women with surgical treatment developed between 1 and 5 local vulvar recurrent SCC (Fig 1, I, and Fig 2, E and G). Five of 14 women (36%; 2 pT1b and 3 multifocal SCC) had a single recurrence (4 of 5 within 5-12 months, 1 of 5 after 41 months). Nine of 14 women (1 pT1a, 4 pT1b, 2 pT2 SCC, and 2 multifocal SCC) developed multiple recurrences. In all, 23 of 34 (68%) of all vulvar recurrent cancer and precursors occurred within 5 to 12 months (Table I). Longer disease-free survival was associated with wider primary resections of SCC. Three of 38 patients were lost to follow-up; 19 of 38 women are presently alive with a mean follow-up of 57 months (range 12-151 months). Two of 38 women died of unrelated causes without recurrent disease and 14 of 38 (37%) women (7 pT1b, 5 pT2 SCC, 2 multifocal SCC) died of disease after a mean of 31 months (range 7-94 months) after initial diagnosis. Histomorphologic characteristics of LP-associated SCC The SCCs were moderately differentiated, focally keratinizing cancers, but nonkeratinizing areas were common at the invasion front. Thirty of 38 SCCs had active disease with a moderate to dense inflammatory infiltrate (Fig 2, A to C and F ). Only 8 of 38 primary SCCs had no or scant lymphocytic infiltrates. All SCCs, peritumoral intraepithelial precancerous lesions, and precursor lesions before recurrent SCC were devoid of HPV-DNA and p16ink4a overexpression. Elongated rete ridges with basal atypia, numerous mitoses, and premature squamatization in
basal and suprabasal cells with normal superficial keratinization typical of d-VIN was identified adjacent to the primary invasive SCC in 22 of 38 patients (Fig 2, E and F ). The remaining peritumoral and recurrent precursors revealed atypical basaloid differentiation (Fig 2, G and H ), or were flat or hypertrophic verrucous proliferations with or without hyperkeratosis. Nuclear p53 expression in invasive tumor cells (Fig 2, C and D) and in d-VIN was observed in 24 of 38 patients (67%).
DISCUSSION To our knowledge, this is the largest series of vulvar HPV-negative SCCs associated with LP. The majority of SCCs were ulcerated large cancers. About one third of LP-associated SCCs arose in erosive LP, the remaining SCCs in papules and plaques of nonerosive forms of LP. All SCCs were located in nonhair-bearing vulvar mucosa, eg, vestibular glycogenated mucosa and modified mucosa. The vestibulum, in particular the glycogenated mucosa between clitoris and urethra, was a typical location of SCCs in our patient cohort. A group of gynecologists has described a similar location for p16ink4a and p53-negative vulvar SCCs in younger women22 and proposed a third type of vulvar cancer. The p53 negativity in immunohistochemical analysis and inconsistent p53 staining in HPV-negative SCCs, however, is widely recognized and these cancers belong into the HPV-negative group of vulvar cancers defined by the World Health Organization.14 Although the authors did not comment on presence or absence of dermatoses in these patients, it is very likely that these cancers were (possibly missed) cases of LP-associated SCCs. Both clinical and histologic features of early and nonerosive forms of LP in this area are extremely subtle and often not recognized. The rarity of anogenital LP may be another contributing factor for inadequate recognition, particularly when LP is not suspected especially, which is more common in subspecialties not as familiar with the various manifestations of LP as dermatologists. Recognition of small lesions of LP lesions may require a vulvoscopic and colposcopic examination and are easier to identify in a hairless (preoperative) vulva than in a routine gynecologic practice setting. Obvious clinical findings such as the erosive and hypertrophic variants of LP were observed only in 50% of patients. LP-associated SCCs are aggressive malignancies with a high rate of regional lymph nodes metastases at presentation and over 30% of disease-related deaths, mainly within the first 1 to 3 years. We observed a high rate of recurrent cancers in the residual diseased skin, with 68% of all recurrences
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Fig 1. Lichen planus (LP)-associated vulvar squamous cell carcinomas (SCCs). A, Ulcerated pT1b SCC (arrow) on the clitoral hood of a 40-year-old woman (patient 2) with numerous skincolored plaques of LP (arrowheads) on both labia minora, which are small and stiff, and in the right interlabial sulcus, and lichenification of periclitoral mucosa (arrowhead ). Note mild architectural changes of posterior labial adhesion. B, Periclitoral invasive pT1b SCC (arrow) with peritumoral erosion in a 52-year-old woman (patient 9) in advanced LP. The clitoris is completely buried, and both labia minora are completely fused and reveal confluent plaques of LP with increased skin markings (arrowhead). C, Primary pT1b SCC of a 70-year-old woman (patient 19) arising in the interlabial sulcus in a hypertrophic LP. D, A pT1a SCC (arrow, maximal invasion depth 0.4 mm) of a 39-year-old woman (patient 1) between clitoris and urethra. Note the numerous plaques of LP on the clitoris, periclitoral tissues, and vestibulum
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occurring within 5 to 12 months. The high rate of recurrent canceredespite complete removal of the cancer with a minimum margin of 1 cmeis puzzling. One possible explanation may be the trend towards minimal surgery, which removes the cancer, but leaves LP-affected skin and mucosa behind. It is conceivable that a d-VIN was already present at time of excision of the primary cancer, but not recognized clinically as a precursor lesion or mistaken as a plaque of LP. Another explanation may be that the residual LP was not adequately treated, eg, poorly controlled, suggesting that an active LP is a risk factor for recurrent SCC. The fast development of recurrent cancer supports indirectly that d-VIN is a rapidly progressing precursor lesion. The HPV-negative precursor lesions of d-VIN showed a variety of atrophic and flat lesions, but also verrucous and exophytic proliferations, and basaloid differentiation as reported before in lichen sclerosuseassociated cancers.23-25 Criteria for d-VIN are often subtle in daily surgical practice with hematoxylin-eosinestained sections. Lack of p16ink4a overexpression and proof of HPV negativity are helpful for a correct etiologic identification. This distinction is essential because d-VIN with a fast progression to SCC needs immediate treatment and cannot be treated expectantly or with topical immune modulators for several weeks such as HPV-induced precursors. Furthermore, our data suggest that active LP in general is at risk for malignant transformation, because the majority of our patients received no standardized treatment for their LP before development of SCC. The aim should be a reduction of lymphocytes, thus reducing tissue destruction and possibly preventing malignant transformation. In conclusion, LP-associated SCCs are HPVnegative cancers located in glycogenated and
=
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modified vulvar mucosa, but not in hair-bearing vulvar skin. LP-associated SCCs arise via the precursor d-VIN. The aggressive SCCs have a high rate of LN metastases at initial presentation and 30% disease-related deaths. Almost 40% of patients had recurrent cancer in the residual diseased LP, mostly within the first 12 months postoperatively, which calls for close oncologic follow-up. We further propose that women with LP with or without a prior vulvar SCC need regular follow-up and appropriate treatment for control of their LP. REFERENCES 1. Cooper SM, Wojnarowska F. Influence of treatment of erosive lichen planus of the vulva on its prognosis. Arch Dermatol 2006;142:289-94. 2. Lewis FM, Bogliatto F. Erosive vulval lichen planusea diagnosis not to be missed: a clinical review. Eur J Obstet Gynecol Reprod Biol 2014;171:214-9. 3. Gandolfo S, Richiardi L, Carrozzo M, Broccoletti R, Carbone M, Pagano M, et al. Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus: a follow-up study in an Italian population. Oral Oncol 2004;40:77-83. 4. Mannweiler S, Sygulla S, Beham-Schmid C, Razmara Y, Pummer K, Regauer S. Penile carcinogenesis in a low incidence area: a clinicopathological and molecular analysis of 115 invasive carcinomas with special emphasis on chronic inflammatory skin diseases. Am J Surg Pathol 2011;5:998-1006. 5. Mannweiler S, Sygulla S, Winter E, Regauer S. Two major pathways of penile carcinogenesis: HPV-induced penile cancers overexpress p16, HPV-negative cancers associated with dermatoses express p53, but lack p16 overexpression. J Am Acad Dermatol 2013;69:73-81. 6. Ruocco V, Satriano RA, De Rosa G, Pettinato G, Gombos F. Malignancy in lichen planus. Int J Dermatol 1989;28:542-4. 7. Bradford J, Fischer G. Management of vulvovaginal lichen planus: a new approach. J Low Genit Tract Dis 2013; 17:28-32. 8. Chiu TL, Jones RW. Multifocal multicentric squamous cell carcinomas arising in vulvovaginal lichen planus. J Low Genit Tract Dis 2011;15:246-7. 9. McPherson T, Cooper S. Vulval lichen sclerosus and lichen planus. Dermatol Ther 2010;23:523-32.
(arrowhead). E, A pT1b SCC (arrow, maximal invasion depth 1.4 mm) located between the clitoris and urethra in a 47-year-old-woman. Multiple plaques of LP (arrowhead) are seen around the clitoris, clitoral hood, and inner side of labia minora and vestibulum (patient 7). F, Ulcerated pT1b SCC located between urethra and clitoris of a 63-year-old woman (patient 12) with numerous individual plaques in periclitoral mucosa and interlabial sulcus. Note the stiffening of labia minora and labial fusion in the posterior aspects. G, Extensively ulcerated pT1b SCC (arrow) in the posterior vestibulum/perineum (arrowhead ) in an 88-year-old woman (patient 37). Note the numerous confluent plaques of advanced hypertrophic LP and the extensively scarred vulva with buried clitoris and loss of periclitoral tissue and labia minora. Blue dye is from injection of radioactive tracer substances for sentinel lymph node identification. H, Multifocal pT1b SCC (arrows) in advanced LP with massive architectural changes including complete loss of labia minora, completely buried clitoris, and stenosis of vaginal introitus of a 80-year-old woman (patient 31). Note numerous plaques of hypertrophic LP. I, Second recurrent cancer of patient 19 is an ulcerated pT1b SCC (arrow) in left posterior vestibulum. Scar of excision of prior primary SCC (asterisk). Plaques of LP and erosive LP in the vestibulum (arrowhead). Architectural changes include a completely buried clitoris, and stenosis of vaginal introitus.
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Fig 2. Histologic features of lichen planus (LP)-associated squamous cell carcinomas (SCCs) and precursors. A, Nonkeratinizing, human papillomavirus (HPV)-negative pT1a SCC (arrow) arising in glycogenated squamous mucosa between clitoris and urethra (patient 1 [Fig 1, D]) with a moderate lymphohistiocytic infiltrate. B, Invasion was measured from the point of deepest invasion to the closest nontumorous epithelial rete adjacent to the SCC. C, An ulcerated, only partly keratinizing invasive pT1b SCC (patient 7). D, Reveals p53-positive invasive tumor cells and a peritumoral p53-positive intraepithelial precancerous lesion (immunohistochemistry with antibody to p53). E, A recurrent differentiated vulvar intraepithelial neoplasia (d-VIN) (arrow) arising in an area of erosive LP of patient 27. F, Shows elongation of epithelial rete, keratinocyte atypia and premature squamatization (arrow) and hyperkeratosis. Note inflammatory infiltrate. G, Recurrent d-VIN in patient 27 after excision of lesion shown in E. H, Reveals a basaloid atypical intraepithelial proliferation in hematoxylin-eosinestained section. This lesion was p16ink4a and HPV-negative and expressed p53 on immunohistochemical analysis.
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