STUDY. Histopathologic Study of Hidradenitis Suppurativa Following Long-Pulsed 1064-nm Nd:YAG Laser Treatment

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STUDY

Histopathologic Study of Hidradenitis

Suppurativa Following Long-Pulsed 1064-nm

Nd:YAG Laser Treatment

Lisa Y. Xu, MD; Dakara Rucker Wright, MD; Bassel H. Mahmoud, MD, PhD; David M. Ozog, MD; David A. Mehregan, MD; Iltefat H. Hamzavi, MD

Objective:To assess clinical and histopathologic changes occurring after long-pulsed 1064-nm Nd:YAG laser treat-ment of hidradenitis suppurativa (HS).

Design:Prospective, controlled clinical and histologic study of patients with Hurley stage II HS disease.

Setting:Outpatient dermatology department at Henry Ford Hospital, Detroit, Michigan.

Participants:Nineteen patients with Fitzpatrick skin types II to VI with Hurley stage II HS lesions of the ax-illa and groin.

Interventions:Two monthly laser sessions were per-formed using the long-pulsed 1064-nm Nd:YAG laser.

Main Outcome Measure:Clinical response was scored using the modified Sartorius scale for HS reflecting Le-sion Area and Severity Index (LASI). Histologic changes were examined before treatment and 1 week, 1 month, and 2 months after treatment.

Results:The percentage change in HS severity after 2 ses-sions of laser treatment was –31.6 over all anatomic sites (P⬍.005), –24.4 for the axillary site (P=.008), and –36.8 for the inguinal site (P=.001). Histologic changes corre-sponded to clinical response. Findings from serial biopsy specimens showed increased inflammation at 1 week after treatment and decreased inflammation with resulting fibro-sis and scarring at 1 month and 2 months after treatment.

Conclusions:The long-pulsed 1064-nm Nd:YAG laser

is a novel effective treatment option for HS. Our histo-pathologic data suggest that HS is primarily a follicular disorder. The Nd:YAG laser penetrates for selective pho-tothermolysis of the follicular unit and destruction of or-ganized inflammatory lesions in the superficial to mid dermis. Our study offers insight into the pathogenesis of HS and the mechanism of the Nd:YAG laser in treat-ment of patients with this chronic, debilitating disease. Arch Dermatol. 2011;147(1):21-28.

Published online September 20, 2010. doi:10.1001/archdermatol.2010.245

H

IDRADENITIS SUPPURA

-tiva (HS) is a chronic, re-current inflammatory dis-ease primarily affecting the skin flexures, such as the axilla, inframammary, and inguinal areas. It can lead to clinically significant morbidity and has been shown to nega-tively affect quality of life substantially more than skin conditions such as pso-riasis and atopic dermatitis.1,2Although

the etiology of this condition has been debated, recent histopathologic studies demonstrate follicular occlusion as the in-citing event, with resulting perifollicular inflammation, rupture of the follicular in-fundibulum, formation of painful

nod-ules and abscesses, and, finally, sinus tract formation and scarring. The apocrine glands seem to be secondarily involved rather than the origin of the disease.3 Hi-dradenitis suppurativa is also termed acne inversa and is part of the follicular occlu-sion tetrad, in conjunction with acne con-globata, dissecting cellulitis, and piloni-dal sinuses.4

Various medical and surgical regimens have been tried and are dependent on the stage and severity of the disease according to the Hurley scaling system.5,6Stage I dis-ease consists of 1 or more abscesses with no sinus tracts or scarring; stage II disease is characterized by 1 or more widely sepa-rated recurrent abscesses with tract forma-tion and scarring; and, finally, stage III dis-ease consists of multiple interconnected tracts and abscesses throughout the area.7 Mild disease can generally be managed with lifestyle changes, such as weight loss,

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ing cessation, and wearing loose-fitting clothes. Pharma-cologic treatments, such as topical and oral antibiotics, as well as intralesional corticosteroids, can be added.8,9 Hor-mone therapy, retinoids, and immunosuppressive and bio-logic therapies constitute other medical treatments that have been tried in small series with variable results.10-13Haslund et al14performed a systematic review of articles studying the treatment of HS with tumor necrosis factor inhibi-tors. They found that in the majority of cases the treat-ment was effective; however, in most publications, fol-low-up was insufficient to allow a systematic exploration, and therefore the authors recommended more standard-ized reporting of the outcomes as well as randomstandard-ized con-trolled trials in HS disease. Surgical treatments range from incision and drainage procedures to debridement and wide surgical excision of interconnected tracts and abscesses in stage II and stage III disease.15Other treatment modali-ties have been reported, including radiotherapy and car-bon dioxide and diode laser treatments, as well as photo-dynamic therapy.16,17However, many of these treatment options arise from small retrospective or observational se-ries, and well-designed, randomized controlled trials both with and without histologic characteristics are lacking.18 Effective treatments are limited, and recurrences often oc-cur, even with wide surgical removal of involved tissue.5 A retrospective follow-up study19described 34 patients with Hurley stage II HS who were treated with scanner-assisted carbon dioxide laser surgery. The mean duration of follow-up time after laser surgery was 34.5 months. The mean healing time was about 4 weeks, with 4 patients hav-ing recurrences at the surgical site. Twenty-five patients had flares of HS lesions in an area other than the treated

site.19Another study, by Hazen and Hazen,20describing the effect of treatment of HS using carbon dioxide laser excision and marsupialization, showed effective therapy for management of persistent or late-stage HS and mini-mal risk of recurrence within the treated areas.

Recently, our group published a report21of a prospec-tive, randomized controlled trial showing the effective-ness of the long-pulsed 1064-nm Nd:YAG laser in treat-ing HS. We postulated that if the hair follicle is the nidus for recurrent chronic inflammation, then using the Nd: YAG hair removal laser would lead to disease improve-ment. The study21was conducted in 22 patients with stage II to stage III disease and showed that after 3 monthly sessions with the laser, there was a statistically signifi-cant improvement in HS severity of 65.3% averaged over all body sites treated. In a follow-up study,22our group showed that after 4 monthly laser sessions, patients were in remission for at least 2 months thereafter. We also pro-vided preliminary pathologic evidence in 4 patients, sug-gesting that the laser works through selective photother-molysis of the follicular unit and subsequently decreases inflammatory lesions.22

The primary goal of this study is to further examine the mechanism by which the 1064-nm Nd:YAG laser works to treat HS lesions by investigating histologic changes in the skin after laser treatment at different time points. A second goal is to determine whether clinical improve-ment in disease measured by the modified HS Lesion Area and Severity Index (LASI) scoring system described by Sar-torius et al23(Table 1) correlated with improvement in inflammation seen on pathologic specimens.

METHODS

Twenty patients (17 women and 3 men) ages 23 to 54 years clinically diagnosed as having HS were enrolled in the study conducted in the Department of Dermatology, Henry Ford Medi-cal Center, Detroit, Michigan, from June 2008 to May 2009. This study was approved by our institutional review board. A sample size calculation was performed with power analysis (␣=.05).

Patients with Hurley stage II disease (ⱖ1 widely separated recurrent abscesses with tract formation and scars) were in-cluded in the study. Exclusion criteria were (1) concomitant use of systemic treatments for HS, which must be discontin-ued for 2 weeks prior to start of the study, and (2) exacerba-tion of the patient’s original condiexacerba-tion expressed clinically by a shift from Hurley stage II to stage III, which may necessitate systemic treatment. Topical treatments were allowed.

Two monthly laser sessions were performed using a long-pulsed 1064-nm Nd:YAG laser (Cutera Inc, Brisbane, Califor-nia), treating the entire area with a single pulse and then double stacking on inflamed lesions at the first treatment and triple stacking lesions at the second treatment. A topical cooling gel was used, as well as ice packs before and after laser treatment. No anesthetic was used. A contact metal-tipped cooling de-vice was immediately placed onto the area before and after ir-radiation (Cutera Inc). Settings were chosen based on Fitzpat-rick skin type as follows: skin type I to III: spot size, 10 mm; pulse duration, 20 ms; fluence, 40 to 50 J/cm2; and skin type

IV to VI: spot size, 10 mm; pulse duration, 35 ms; fluence, 25 to 35 J/cm2.

Treatment response was scored using the modified HS LASI described by Sartorius et al23(Table 1). In addition, patient symp-Table 1. Modified Hidradenitis Suppurativa Lesion, Area,

and Severity Index (HS-LASI)a

Characteristic Score Type of Lesion Fistula 4 Nodule 2 Abscess 1 Scar 1

Longest distance between 2 lesions or size of single lesion, cm

⬍5 2

ⱖ5 to ⬍10 4

ⱖ10 8

All lesions separated by normal skin

Yes 0 No 6 Modified HS-LASI Drainageb 0-3 Tendernessc 0-3 Erythemad 0-3 Edema 0-3 Final scoree

aAs described by Sartorius et al.23

bPurulent drainage of total plaque surface area involvement: 0, no draining; 1, 25% of plaques draining; 2, 50% of plaques draining; 3, 100% of plaques draining.

cTenderness: 0, no pain; 1, 12 hours per day or less with pain; 2, more than 12 hours per day with pain; and 3, pain wakes the patient up at night.

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toms were assessed by adding scores for the extent of ery-thema, edema, pain, and purulent drainage at each anatomic site. Erythema and edema were graded on a visual analog scale of 0 to 3 (0, absent; 1, mild; 2, moderate; 3, severe). Purulent drainage was assessed through measuring the surface area that showed purulent discharge compared with the total surface area affected using the following scale: 0, no drainage; 1, 25% of in-volved area draining; 2, 50% of inin-volved area draining; 3, 100% of involved area draining. Tenderness was graded by patient assessment of duration of daily pain as follows: 0, no pain; 1, 12 or less hours of pain daily; 2, more than 12 hours of pain daily; 3, pain wakes patient at night.24

Patients were randomized according to anatomic site of dis-ease: bilateral axilla, inframammary region, or groin. If only 1 anatomic site was involved, then 1 side was treated and the con-tralateral side served as the untreated control. If 2 anatomic sites were involved, then both sides were treated for 1 anatomic site and the other anatomic site served as control.

Four-millimeter skin punch biopsy specimens were ob-tained from active lesions on the treated site before laser treat-ment, after 24 hours (for the first 7 specimens) and at day 7, day 30, and day 60 (for all patients). On day 60, an active lesion from an untreated site was biopsied as control. All hematoxylin-eosin–stained slides were reviewed by a board-certified der-matopathologist (D.A.M.). The percentage of improvement was calculated for the laser-treated and control sides by compar-ing the modified HS-LASI score at baseline with the score at each laser treatment (on days 30 and 60).

The mean (SD) percentage of change was calculated for each patient over all anatomic sites combined and for each ana-tomic site individually. The P value was calculated for the mean percentage of change values using Wilcoxon signed rank. The Pearson correlation coefficient with accompanying P value was calculated for clinicopathologic correlation. The mean (SD) val-ues for these correlation graphs were calculated with a paired

t test to determine the resultant P value.

RESULTS

Twenty patients were enrolled in this study. One female patient did not complete the study because her active le-sions resolved before the end of it. Nineteen patients com-pleted the 2 months of study treatments. Five skin punch biopsy specimens were obtained from 18 patients, and 4 punch biopsy specimens were obtained from the remain-ing patient as she did not return for her 2-month visit be-cause she moved to another state. There were a total of 94 pathology specimens. The mean age of the patients was 37 years, and there was a greater proportion of women (n=16 [84.2%]) than men (n=3 [15.8%]) in the study. Patients had Fitzpatrick skin types ranging from II to VI (Table 2). The distribution of treated anatomic sites included 11 pa-tients (57.9%) with groin disease and 8 papa-tients (42.1%) with axillary disease. For the 11 patients with inguinal dis-ease, the entire groin area was treated, and 1 side (the left or right side of the groin) was chosen for serial biopsies. The more inflamed side was chosen as the biopsy site. The specimen for the control biopsy at month 2 was taken from a different involved site, including the axilla, suprapubic region, or gluteal folds. Of the 8 patients with axillary dis-ease, 7 received laser treatments to both axilla, and 1 side (left or right axilla) was chosen for serial biopsies. The speci-men for the control biopsy at month 2 was taken from an involved suprapubic or groin region. One patient with

ax-illary disease as the only involved anatomic site received treatment to her left axilla, and her right axilla served as the control biopsy site at month 2.

PERCENTAGE OF IMPROVEMENT IN HS WITH 2 Nd:YAG LASER TREATMENTS The percentage of change in modified HS-LASI score af-ter 2 months of treatment was –31.6% (P⬍.001) aver-aged over all anatomic sites, –24.4% (P=.008) for the ax-illary region, and –36.8% for the inguinal region (P=.001) (Figure 1). Overall, the mean HS-LASI scores trended downward from baseline to 1 month and 2 months after treatment for both axilla and inguinal sites (Table 3).

HISTOLOGIC CHANGES AFTER Nd:YAG LASER TREATMENTS For our first 7 patients, serial biopsy specimens were taken at baseline, 24 hours, 1 week, and 2 months after the first laser treatment to determine the temporal changes that occurred at the histologic level after treatment (Table 4). At 24 hours, there was dense perifollicular inflamma-tion with a mixed infiltrate of neutrophils, eosinophils, plasma cells, and giant cells. Granulation tissue was promi-nent, and only 1 specimen showed periapocrine gland inflammation. All specimens at this time point showed acute inflammation and did not differ substantially from control specimens. Therefore, for the next set of 12 pa-tients, the 24-hour time point was removed from our pro-tocol, and instead the serial biopsy specimens were taken at baseline, 1 week, 1 month, and 2 months after treat-ment. The 1-month time point was added for these re-maining 12 patients.

At 1 week after treatment, there was more pro-nounced perifollicular inflammation and granulation tis-sue compared with baseline. A superficial and deep mixed inflammatory infiltrate was again present. At 1 month af-ter treatment, the inflammatory reaction decreased with markedly less perifollicular inflammation, occasional mixed inflammatory infiltrate with eosinophils, and re-maining dilated hair follicles, some of which contained broken hair shafts. At 2 months, the dermis was re-placed by scarring and fibrosis, and inflammation was

Table 2. Demographics of the 19 Study Patients

Characteristic No. (%)

Age, mean (range), y 37 (23-54) Sex

Female 16 (84.2)

Male 3 (15.8)

Fitzpatrick skin type

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minimal. If present, the inflammation was in the deeper dermis and mostly spared the apocrine glands. Of note, most of the specimens at various time points showed fol-licular plugging.

CLINICOPATHOLOGIC CORRELATION For the patients who responded most to laser treat-ment, their clinical improvement in HS-LASI scores cor-related with decreased inflammation and fibrosis seen on final pathologic findings at 2 months after laser treat-ment (Figures 1,2,3, and4show clinical and patho-logic photographs of 2 representative patients). Overall, the response of 15 of the 18 patients transitioned from a marked superficial and deep inflammatory response seen on pathologic findings at baseline to a minimal inflam-matory response (mainly deep if present) and/or scar-ring and fibrosis seen at 2 months after laser treatment. This change at the microscopic level corresponded with a decrease in the HS-LASI scores of these patients. This correlation is evidenced by 15 patients having higher scores at baseline (month 0) when corresponding

patho-logic findings showed superficial and deep inflamma-tion, and lower scores at 2 months after treatment when pathologic findings showed minimal inflammatory re-action and/or scarring. The Pearson correlation coeffi-cient was –0.481 (P = .007). The mean (SD) LASI score

A B C

Figure 1. Right axilla. A, Before laser treatment; B, 1 month after laser treatment; C, 2 months after laser treatment. The percentage of change in the Hidradenitis Suppurativa Lesion Area and Severity Index score from baseline to month 2 was –33.3% for the right axilla (biopsy side).

Table 3. Mean HS-LASI Scores at Baseline and 1 Month and 2 Months After Treatment

Location Mean HS-LASI Scores (Range) Axilla (n = 7 patients) Baseline 23.7 (9-34) 1 mo 17.3 (4-32) 2 mo 17.2 (6-28) Groin (n = 12 patients) Baseline 38.6 (6-100) 1 mo 28.7 (5-82) 2 mo 22.6 (0-49)

Abbreviation: HS-LASI, Hidradenitis Suppurativa Lesion Area and Severity Index.

Table 4. Histologic Changes at Different Time Points After Laser Treatment

Time Point From Laser Treatment Histopathologic Findings No./Total No. of Cases (%) Baseline Active perifollicular inflammation

Fibrosis Granulation tissue

12/19 (63) 11/19 (58) 7/19 (37) 24 ha Granulation tissue with eosinophils

and plasma cells Perifollicular inflammation Mixed superficial and deep

inflammatory infiltrate with multinucleated giant cells Inflammation of periapocrine glands

4/7 (57) 3/7 (42) 2/7 (29) 1/7 (14)

1 wk Increased superficial and deep inflammation

Increased perifollicular inflammation Increased density of granulation tissue

12/19 (63) 6/19 (32) 4/19 (21) 1 mob Mixed inflammatory infiltrate

with eosinophils

Decreased perifollicular inflammation Dilated hair follicle/broken-down

hair shaft

7/12 (58) 5/12 (42) 5/12 (42)

2 moc Minimal inflammatory reaction, mainly deep

Scarring and fibrosis Deep inflammation around

the apocrine glands

12/18 (67) 6/18 (33) 1/18 (6)

aBiopsy specimens were taken at 24 hours for the first 7 patients, but this time point was dropped from the protocol for the remaining 12 patients.

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at baseline was 35.5 (13.6) and at month 2 was 21.7 (11.3). This change in mean LASI scores was significant with P⬍.001.

However, 3 patients continued to show inflamma-tion at the microscopic level, and their HS-LASI scores did not show clinically significant improvement, al-though the statistical analysis for this group is limited by the small sample size. The Pearson correlation coef-ficient was –0.359 (P = .49). The mean (SD) LASI score at baseline was 33.7 (8.1) and at month 2 was 27.7 (10.8). This change in mean LASI scores was nonsignificant (P=.10), likely owing to the limited statistical power from the very small sample size of 3 patients.

COMMENT

Hidradenitis suppurativa is primarily a follicular disease with secondary apocrine gland involvement. In a groundbreak-ing study by Sellheyer and Krahl,3176 specimens of HS from the axillae or inguinal regions were reviewed. They noted that early lesions are similar to the open comedones in acne

and show follicular hyperkeratosis and infundibula dila-tation. Apocrine glands are not involved. At a later stage, the dilated follicular infundibulum ruptures, mainly at the inferior portion, spilling keratin debris into the surround-ing dermis. This evokes an acute inflammatory response around the follicles. The acute neutrophilic infiltrate is gradually replaced by granulomatous infiltration with mul-tinucleated foreign body giant cells. If the follicular rup-ture is more florid, an abscess forms, which may extend deep into the subcutaneous tissue. Inflammation around the apocrine gland occurs as an extension of the inflam-matory process, leading to apocrine gland destruction. Af-ter extensive tissue destruction has occurred, naked hair shafts may remain. Residual follicular epithelium may pro-liferate in long-standing lesions and form sinus tracts, sur-rounded by fibrosis, which connect to the epidermis. These sinus tracts may also rupture, later forming additional coa-lescent sinus tracts, fistulas, and scarring.3,5A histologic study by Jemec et al25showed a homogeneity of HS le-sions, in which no primary apocrine involvement was seen, and eccrine involvement was seen more often than

apo-A B C

Figure 2. Right axilla (pathologic characteristics corresponding to Figure 1) (hematoxylin-eosin, original magnification⫻25). A, Baseline, showing perifollicular and deep inflammation with follicular plugging; B, 1 month after laser treatment, showing mild perifollicular inflammation with no hair shaft seen; C, 2 months after laser treatment, showing mild superficial inflammation; apocrine glands are uninvolved.

A B C

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crine involvement. Those findings again supported the re-classification of HS as a primary follicular disease. Boer and Weltevreden26suggested that the use of the term acne in-versa is more appropriate than HS because the results of their study revealed that the primary event in HS is an in-fundibulofolliculitis with secondary involvement of apo-crine glands. Another retrospective pathologic study of 118 skin resection specimens from 101 patients with HS showed that follicular occlusion by keratinous material, with sub-sequent active folliculitis and secondary destruction of the skin adnexae and subcutis, occurs as an integral step in the pathogenesis of HS.27

Based on these pathologic studies, our group chose to use the long-pulsed Nd:YAG laser as a noninvasive treatment option for moderate HS.22The wavelength of the long-pulsed 1064-nm Nd:YAG laser in the near-infrared electromagnetic spectrum selectively targets hair shafts and follicles via absorption by the melanin chro-mophore, while relatively sparing melanin in the super-ficial epidermis owing to its deeper dermal penetration of approximately 5 to 7 mm and lower absorption of mela-nin in the epidermis owing to its lower concentration at this wavelength.28,29 This longer wavelength can pen-etrate deeper to reach the hair bulb in most anatomical areas than other lasers used for selective photothermoly-sis of hair follicles, such as the ruby (694-nm), alexan-drite (755-nm), and diode (810-nm) lasers.28-31The long pulse duration is closer to the hair follicle’s thermal re-laxation time (10-100 ms).30Our previous study22showed that this laser led to clinical improvement after 3 to 4 monthly treatments as well as remission of disease for up to 2 months after treatment cessation.

In this study, we sought to determine the mechanism of action of the Nd:YAG laser by examining histologic changes over time. On initial histologic findings before laser treatment, active lesions were noted to have a brisk mixed inflammatory infiltrate centered around the fol-licle with surrounding granulation tissue and some fi-brosis. No major histologic difference was noted 24 hours after treatment from baseline; therefore, this data point

was removed from our study for the remaining 12 pa-tients. At 1 week after treatment, the superficial and deep inflammatory reaction increased, with more perifollicu-lar inflammation and granulation tissue noted, suggest-ing acute effects of photothermolysis. Some patients re-ported an increase in tenderness and drainage during this first week, which was then followed by rapid disease im-provement. This was noted to be clinically similar to a surgical incision and drainage procedure. One and 2 months after treatment, there was markedly decreased perifollicular inflammation, and the dermis was re-placed by scarring and fibrosis in most patients. If present, inflammation involved the deeper dermis only and mostly spared the apocrine glands. Based on these findings, we postulate that the wavelength of the laser could not pen-etrate deeply enough to affect lesions in the lower der-mis and dermal subcutaneous junction. However, most of the active lesions biopsied showed inflammation pre-dominantly in the mid-reticular dermis, which may ex-plain the effectiveness of the laser. The gross effects of the Nd:YAG laser on granulation tissue, when double puls-ing, was to cause coagulation, Also, histologically there was increased coagulation of the granulation tissue. Our histologic analysis also showed that as early as 1 month after treatment, there was a significant decrease in in-flammation, followed by fibrosis at 2 months after treat-ment. This suggests that Nd:YAG laser treatment may have resulted in the inflammatory lesions progressing more quickly through their cycle of acute, then granuloma-tous, inflammation to fibrosis, without the formation of abscesses and sinus tracts. Moreover, after 2 months, no recurrence of the superficial inflammation was present, signifying stabilization of disease. The Nd:YAG laser may also be decreasing inflammation by targeting water as a secondary minor chromophore and generating heat in the dermis via photothermolysis, and thus disrupting the inflammatory infiltrate. This may explain why even pa-tients with Fitzpatrick skin types II and III and lighter hairs responded well to the laser treatments. The de-crease in inflammation explains the relative dede-crease in

A B C

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the postinflammatory scarring and fibrosis that occurs as a final step in the disease progression. In addition, the photothermolysis theory also explains the improve-ment of the already fibrosed and scarred lesions by maxi-mizing the tissue effects of normalization of both neo-collagenesis and collagenolysis leading to optimum scar remodeling. A similar mechanism was demonstrated in a previous study32of laser treatment of surgical scars. How-ever, because of the small sample size of this group of patients, we could not perform a statistical analysis by Fitzpatrick type with enough power. It may be interest-ing to characterize the treatment response in larger sub-sets of patients with lighter skin types in future studies. Our study further confirmed that clinical improve-ment in disease as measured by the HS-LASI score corre-sponded to lesion improvement seen on histopathologic characteristics. The overall percentage of change in modi-fied HS-LASI score for all anatomical sites combined after only 2 monthly laser treatments was −31.6%. As with our previous study,21both the inguinal (−36.8%) and axillary regions (−24.4%) responded well, suggesting that areas with dark, coarse terminal hairs respond to the follicular deoc-clusion mechanism of the laser. In the current study, there were no patients with mammary or perianal involvement, but our previous study21showed that the mammary re-gion improved the least, at 53.1% reduction in clinical se-verity compared with inguinal and axillary score sese-verity reductions of 73.4% and 62%, respectively, after 3 laser treat-ments. In this study, 15 patients showed the best patho-logic response, with minimal inflammatory reaction and/or scarring seen at 2 months after laser treatment. This re-sponse seen on pathologic examination correlated signifi-cantly with clinical improvement as measured by LASI scores (P=.007). Conversely, the 3 patients who contin-ued to show inflammation 2 months after treatment did not have statistically significant changes in their LASI scores (P=.10), although the statistical power in this latter group was limited by the small sample size. Nevertheless, to our knowledge, this is the first study correlating the clinical and pathologic response to Nd:YAG laser treatment, thus elu-cidating the effectiveness of the laser from a mechanistic viewpoint.

One of the limitations of this study is sampling error of the biopsy sites. Biopsy specimens were taken from an area as close as possible (within 5 mm) to the previ-ously biopsied site to follow the same area longitudi-nally on pathologic examination. However, this longi-tudinal follow-up was often difficult, because we could not take a biopsy specimen of exactly the same lesion at baseline and various time points. Also, disease severity may wax and wane owing to the natural course of HS, which complicated our interpretation of the pathologic data. Nevertheless, at follow-up visits, most patients were noted to have significant clinical improvement at 1 and 2 months after treatment. Because this clinical improve-ment as measured by LASI scores correlated with dis-ease remission seen on pathologic findings, this sug-gests that our pathologic specimens closely depicted treatment response at the microscopic level. Another limi-tation is the small sample size; however, the sample size was calculated to be adequate based on a power analysis performed at the beginning of the study.

To our knowledge, this is the largest prospective, con-trolled histologic study examining the mechanism of the long-pulsed 1064-nm Nd:YAG laser in treating moder-ately severe (Hurley stage II) HS. Our data suggest that the Nd:YAG laser penetrates deeply enough for selec-tive photothermolysis of the follicular unit and destruc-tion of organized inflammatory lesions in the superfi-cial to mid dermis. The laser seems to speed the healing of active lesions and subsequently induces remission. Our pathologic data further confirm that HS is primarily a fol-licular disorder, which explains the effectiveness of the long-pulsed Nd:YAG hair removal laser in treating this condition. This is also the first study showing clinico-pathologic correlation following laser treatment. In con-clusion, the 1064-nm Nd:YAG laser is a noninvasive, well-tolerated, and effective treatment option for patients with this chronic, debilitating disease.

Accepted for Publication: July 20, 2010.

Published Online: September 20, 2010. doi:10.1001 /archdermatol.2010.245

Correspondence: Iltefat H. Hamzavi, MD, Department of Dermatology, Henry Ford Hospital, 3031 W Grand Blvd, Ste 800, Detroit, MI 48202 (ihamzav1@hfhs.org). Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analy-sis. Study concept and design: Xu, Wright, Mahmoud, Ozog, and Hamzavi. Acquisition of data: Xu, Wright, Mah-moud, Mehregan, and Hamzavi. Analysis and interpreta-tion of data: Xu, Wright, Mahmoud, Mehregan, and Hamzavi. Drafting of the manuscript: Xu, Wright, Mah-moud, and Hamzavi. Critical revision of the manuscript for important intellectual content: Xu, Wright, Mah-moud, Ozog, and Hamzavi. Obtained funding: Xu. Administrative, technical, and material support: Wright, Mahmoud, and Ozog. Study supervision: Hamzavi. Financial Disclosure: None reported.

Funding/Support: This study was supported by the Henry Ford Resident research grant.

Disclaimer: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and in-terpretation of data; or in the preparation, review, or ap-proval of the manuscript.

Additional Contributions: We gratefully acknowledge the support from the HS-USA Foundation and the Hi-dradenitis Suppurativa Foundation. Gordon Jacobsen, BS, performed the statistical analysis.

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13. Rose RF, Goodfield MJ, Clark SM. Treatment of recalcitrant hidradenitis suppu-rativa with oral ciclosporin. Clin Exp Dermatol. 2006;31(1):154-155. 14. Haslund P, Lee RA, Jemec GB. Treatment of hidradenitis suppurativa with tumour

necrosis factor-alpha inhibitors. Acta Derm Venereol. 2009;89(6):595-600. 15. Rompel R, Petres J. Long-term results of wide surgical excision in 106 patients

with hidradenitis suppurativa. Dermatol Surg. 2000;26(7):638-643. 16. Downs A. Smoothbeam laser treatment may help improve hidradenitis

suppu-rativa but not Hailey-Hailey disease. J Cosmet Laser Ther. 2004;6(3):163-164. 17. Gold M, Bridges TM, Bradshaw VL, Boring M. ALA-PDT and blue light therapy for hidradenitis suppurativa. J Drugs Dermatol. 2004;3(1)(suppl):S32-S35. 18. Lam J, Krakowski AC, Friedlander SF. Hidradenitis suppurativa (acne inversa):

management of a recalcitrant disease. Pediatr Dermatol. 2007;24(5):465-473. 19. Lapins J, Sartorius K, Emtestam L. Scanner-assisted carbon dioxide laser

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Notable Notes

Syphilis in Greek Poetry: A Uniquely Positive Perspective

In Greek literature, poets, whether syphilitic or not, referred to syphilis with a uniquely positive social perspective. In 1925, Kostas Karyotakis, a syphilitic and a dismal, satirical poet, wrote

Song of Insanity, which was later renamed Ochra Spirochaete

(also known as Treponema pallidum).1When it was

pub-lished in Hesperus magazine, the last stanza said: “She was so

beautiful, our bought girlfriend,/through the twilight of that re-mote winter/when she gave us her lips, with an enigmatic smile,/ and foresaw the potential future, the upcoming abyss.”1These

verses speak expressively about syphilis, especially with the words “bought girlfriend,” as prostitutes were considered the major cause of syphilis’ transmission; “enigmatic smile,” as a smiling face hid the disease; and “abyss,” as abyss repre-sented the dark prognosis of syphilis.2

Romos Filyras, a syphilitic lyric romantic poet, expressed himself in a similar way about syphilis. In 1927, Filyras was confined in a mental institution, where he spent the last 15 years of his life writing delusional poems under the influ-ence of neurosyphilis,3thus reminding the reader of the

fi-nal writings of another Greek syphilitic writer, Mihail Mit-sakis.2Two of Filyras’ poems seem to refer to the disastrous

effects of syphilis that are lurking behind a naive affair: “A

bird that sang/for the wind of youth/on a blooming, fragile branch/of a first love,/and its song changed/into a sudden bitter lament./I wasn’t meant to become/what I was dreaming of . . . ”3

and “I’d like to offer you the unrestrained bliss/that you didn’t

find in your first romance/you would become the Muse of my joy/ even though you were leading me to destruction.”

The most important literary references on syphilis are pro-vided by Nikos Kavvadias, a realistic poet and globe-trotting sailor, whose writings are considered to be a source of tradi-tional beliefs from many countries.3Kavvadias’ poems are

swarming with references to syphilis, with expressions such as malafrantza, which was created from the words malady and

France; and “To Palos we transported the incurable pimple,”3

indicating the Columbian theory of syphilis’ origins, as Pa-los is the port whence Columbus departed.2However, in his

novel Vardia (1954), Kavvadias calls the disease a “great medal,”2,3thus associating syphilis with sexual

emancipa-tion and rebellion against conservative values, which seems to be unique in literature.

Considered by most to be a disgraceful disease, syphilis was probably never socially considered as a sign of libera-tion by popular literature before Kavvadias and his Vardia.

Antonis A. Kousoulis,MD Marianna Karamanou,MD George Androutsos,MD

Author Affiliations: History of Medicine Department, Medical School, University of Athens (Drs Kousoulis, Karamanou,

and Androutsos), and Society of Junior Doctors (Dr Kousoulis), Athens, Greece.

Contact Dr Kousoulis at History of Medicine Department, Medical School, University of Athens, 131 L Katsoni St, Mos-chato, Athens 18344, Greece (antonis.kousoulis@gmail.com).

1. Karyotakis K. Poems and Prose [in Greek]. Athens, Greece: Ermis; 1991.

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