biological basis of keloid formation lies on the substantial proliferation, apoptosis inhibition of

fibroblasts and imbalance between collagen synthesis and degradation. 12,13 Keloid fibroblasts are
considered to proliferate more rapidly, with oversecretion of type I collagen fibers and high
expression levels of vascular endothelial growth factor, transforming growth factor- β1̸β2 and
platelet-derived growth factor-α.12 TGF-β has been implicated in the collagen synthesis1 by
increasing the effect of epidermal growth factor (EGF) in fibroblast population, which stimulates
epithel differentiation and initiates DNA and RNA synthesis. 8

5-fluorouracil is administered once every one or two weeks, up to thrice a week, adjusted
according to the extent of the lesions, but the dosage given should not exceed 100 mg/ session
(2 mL). The solution is injected into the central aspect of scar tissue, until slight blanching is
clinically visible, usually 0.05 cc or less/injection site, approximately 1 cm apart. 1 5-FU dosage
should be adjusted in patients with liver dysfunction. 14 Contraindications to 5-FU include
pregnancy, infiltrate of PR was predominantly T cells with an increased CD4-to-CD8 ratio as well as
an increased proportion of Langerhans cells, which are common findings in other inflammatory skin
condi- tions thought to be driven by cell-mediated immunity. No significant difference was found
between the her- ald patch and fully developed PR lesions. 39 Another study looking specifically at
the cytokine profile of PR found increased interleukin-17, interferon-γ, vascular endothelial growth
factor, and interferon-inducible protein-10 (CXCL10). Interleukin-17 and interferon-γ in particular
were mentioned as evidence that the cytokine profile in PR was not specific for, but con- sistent
with, a viral-induced disease process. 40 Lastly, an autoimmune pathogenesis for PR has been
investi- gated, but to date no compelling autoantigens or sup- porting evidence has been found. 38

DIAGNOSIS
The diagnosis of PR is usually clinical, and in the case of classic PR fairly straightforward. The
various atypical presentations, however, can pose a diagnos- tic challenge. A set of clinical
diagnostic criteria was proposed in 2003. 41,42 In these criteria, the patient had to have 3 essential
features and at least 1 of 3 optional

features. The 3 essential features were discrete cir- cular or oval lesions, scaling on most lesions,
and a peripheral collarette of scale with central clearance on at least 2 lesions. The optional criteria
included a truncal and proximal limb distribution with less than 10% of lesions distal to the mid-
upper-arm and mid-thighs, distribution of most lesions along the ribs, and a herald patch appearing
at least 2 days before the eruption. They also proposed 3 exclusion features, including multiple
small vesicles at the center of 2 or more lesions, most lesions on palmar or plantar skin surfaces,
and clinical or serological evidence of secondary syphilis.

LABORATORY TESTING
Routine blood tests are typically normal in PR. Although various abnormalities, including leukocy-
tosis and an elevated erythrocyte sedimentation rate may be found, blood tests are nonspecific. As
such, blood tests are not needed nor are they recommended in the diagnosis of PR.

PATHOLOGY
The histologic features of PR are nonspecific and patients with the classic presentation often do not
require skin biopsy as the diagnosis can confidently be made on clinical grounds alone. The
epidermal changes seen include parakeratosis which may be focal, mul- tifocal, or confluent;
orthokeratosis; mild acanthosis; a thinned granular layer; and spongiosis often with some degree of
lymphocyte exocytosis (Fig. 31-10). In the dermis there is typically a superficial perivascular
lymphocytic infiltrate and variable extravasated red

Figure 31-10 Typical epidermal changes seen in pityriasis rosea, including mounded parakeratosis
with lift off, mild acanthosis, and spongiosis. (A 4-mm punch biopsy, hema- toxylin and eosin stain,
×10 magnification, used with per- mission from Dr. Paul Harms.)
Chapter 31 :: Pityriasis Rosea

4
524
CLINICAL COURSE AND
PROGNOSIS
PR typically self-resolves after an average of 45 days, but ranges from 2 weeks to 5 months have
been reported.2,17 As previously stated, eruptions lasting longer than 3 months may fit into the
proposed cat- egory of persistent PR. Upon resolution the only sequela is typically
postinflammatory hyperpigmen- tation or hypopigmentation. As with other inflamma- tory
conditions this dyspigmentation is more common in individuals with a darker skin color. There are
no other significant long-term clinical outcomes from PR. As stated above, recurrence can occur,
but it is very uncommon. When recurrence does happen, it is usu- ally only once and also does not
have any long-term health consequences.

MANAGEMENT
INTERVENTIONS
As discussed, PR is self-limited and therefore no treat- ment is necessary in many cases. Also given
that many cases of PR have minimal to no symptoms the benefits of any treatment must be
weighed against the poten- tial side effects of the intervention on a case-by-case basis. Counseling
patients on the natural history of PR and reassurance regarding its self-limited nature is paramount
given the anxiety often associated with PR. Although there is no good data to support their use
topical steroids and antihistamines are safe and may be helpful for associated pruritus. The
macrolide erythromycin has been reported to hasten the clear- ance of PR. 16 In addition, a 2007
Cochrane review found one small, good-quality study that demon- strated benefit from
erythromycin.47 However, subse- quent studies evaluating the efficacy of the macrolide antibiotics
erythromycin and azithromycin failed to show any benefit when compared to placebo. 48-50 Acy-
clovir also has been studied as a potential therapy for PR. Drago and colleagues initially found that
treat- ment with high-dose acyclovir (800 mg 5 times daily) for 1 week led to a 78.6% rate of
complete clearance at 2 weeks compared to only a 4.4% rate of complete clearance in the placebo
group, but this study was not randomized and the investigators were not blinded. 51 Several
subsequent trials have all shown that acyclo- vir at varying doses may hasten the resolution of the
rash, improve associated pruritus, and, in some cases, improve associated systemic symptoms. 52-55
Therefore, given the low cost and good safety profile of acyclovir and its derivatives, these
therapeutic agents may be reasonable to consider in PR patients, particularly in those with
significant pruritus, an extensive rash, or significant systemic symptoms. It should be noted that
the mechanism of action of acyclovir in the treatment of PR is unclear given that acyclovir’s effect
is depen- dent on thymidine kinase, an enzyme whose gene is

not expressed by HHV-7.2 Ultraviolet B phototherapy also is reported to have some benefit in PR
clearance time, although results vary on whether or not it helps with the associated pruritus. 56,57

PREVENTION
There is currently no data available on prevention of PR.

ACKNOWLEDGMENTS
The authors acknowledge the contributions of Andrew Blauvelt, the former author of this chapter.

REFERENCES
1. Gibert CM. Traité Pratique Des Maladies de La Peau et de La Syphilis, Volume 2. H. Plon, Paris,
France; 1860.

2. Drago F, Broccolo F, Rebora A. Pityriasis rosea: an update with a critical appraisal of its possible
herpes- viral etiology. J Am Acad Dermatol. 2009;61(2):303-318.
3. Broccolo F, Drago F, Careddu AM, et al. Additional evi- dence that pityriasis rosea is associated
with reactiva- tion of human herpesvirus-6 and -7. J Invest Dermatol. 2005;124(6):1234-1240.

4. Rebora A, Drago F, Broccolo F. Pityriasis rosea and herpesviruses: facts and controversies. Clin
Dermatol. 2010;28(5):497-501.

5. Canpolat Kirac B, Adisen E, Bozdayi G, et al. The role of human herpesvirus 6, human
herpesvirus 7, Epstein-Barr virus and cytomegalovirus in the aetiol- ogy of pityriasis rosea. J Eur
Acad Dermatol Venereol. 2009;23(1):16-21.

6. Drago F, Ranieri E, Malaguti F, et al. Human herpesvi- rus 7 in patients with pityriasis rosea.
Dermatology. 1997;195(4):374-378.

7. Chuang T-Y, Ilstrup DM, Perry H, et al. Pityriasis rosea in Rochester, Minnesota, 1969 to 1978. J
Am Acad Dermatol. 1982;7(1):80-89.

8. Nanda A, Al-Hasawi F, Alsaleh QA. A prospective survey of pediatric dermatology clinic patients
in Kuwait: an analysis of 10,000 cases. Pediatr Dermato

pathophysiology, risk factors, and therapeutic management. Dermatol Surg. 2009;35(2):171–81.

12. Dong X, Mao S, Wen H. Upregulation of proinfammatory genes in skin lesions may be the cause of
keloid formation. Biomed Rep. 2013;1(6):833–6.

6. Khan MA, Bashir MM, Khan FA. Intralesional triamcinolone alone and in combination with 5-
fluorouracil for the treatment of keloid and hypertrophic scars. J Pak Med Assoc. 2014;64(9):1003–7.

13. Gupta S, Sharma VK. Standard guidelines of care: keloids and hypertrophic scars. Indian J Dermatol
Venereol Leprol. 2011;77(1):94-100.

7. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids:
Pathomechanisms and current and

14. Darougheh A, Asilian A, Shariati F. Intralesional triamcinolone alone or in combination with 5-

fluorouracil for the treatment of keloid and hypertrophic scars. Clin Exp Dermatol. 2009;34(1):219–23.

15. Kranendonk S, Obagi S. An algorithmic approach 40 International Journal of Integrated Health Sciences.
2017;5(1):36–41

11. Edriss AS, Smrcka V. Therapy of keloid and hypertrophic scars:a review. Eur J Plast Surg.
2011;34(5):425–36.

Jono Hadi Agusni, Eva Krishna Sutedja, et al.

Kartamihardja AHS. Comparison of the effectiveness of phosphorus 32 application and 10 mg/cc

triamcinolone acetonide intralesional injection on keloid. IJIHS. 2016;4(1):26–31.

tohypertrophicscarsandkeloids:maximizing nonsurgical options. J Cosmet Dermatol. 2011;24(1):28–39.

16. Indrayati H, Agusni JH, Soedarwoto A,

B
is more striking in darkly pigmented skin. In Caucasians, IGH may favor those with brown eyes and
brown hair. An apparent female pre- dominance is probably the result of heightened perception of
a cosmetic problem.

98
The typical IGH lesion is a circumscribed, sharply deined, asymp- tomatic porcelain white macule .
The lesions are usually 0.5–6 mm in diameter and often delineated by the skin furrows;
occasionally, lesions are up to 2.5 cm in size (Fig. 66.31). Once present, they do not change in size
or coalesce; their surface is smooth but not atrophic. Spontaneous repigmentation has not been
reported. Hairs within the lesions usually retain their pigment. In most patients, there are multi- ple
lesions on the extensor forearms and shins; the remainder of the extremities can be affected, but
rarely the face.

The most consistent histologic features of IGH are a lattening of the dermal–epidermal junction,
moderate to marked reduction or focal absence of melanin granules in the basal and suprabasal
layers, and a basket-weave hyperkeratosis. There is a moderate to relatively marked reduction in
the number of DOPA-positive epidermal melanocytes (10–50% compared with normal skin), but
these cells are never totally absent. At the ultrastructural level, some melanocytes have normal
melanogenic activity, while others lack mature melanosomes. The

1045

66

Vitiligo and Other Disorders of Hypopigmentation

SECTION

10
Fig. 66.34 Progressive macular hypomelanosis. Note the coalescence
of the non-scaly hypopigmented macules on the center of the back.
DISORDERS ASSOCIATED WITH PREMATURE GRAYING OF
SCALP HAIR
• Piebaldism
• Waardenburg syndrome
• Vitiligo
• Sudden whitening of hair
• Hereditary premature canities
• “Bird-headed”dwarism
• Progeria
• Werner syndrome
• Ataxia telangiectasia
• Rothmund–Thomson syndrome
• Fisch syndrome
• Myotonic dystrophy
• Prolidase deiciency (also in Table 66.11) • Oasthouse disease
1046

Fig. 66.32 Disseminated hypopigmented keratoses. Over 200 guttate minimally elevated
hypopigmented papules developed after several months of

PUVA therapy. Histologically, there was no evidence of verruca plana. Courtesy, Jean L Bolognia, MD

Fig. 66.33 Clear cell papulosis. Multiple hypopigmented, barely elevated lat-topped papules
and macules in the suprapubic area and on the abdomen along the “milk lines” in a 2-year-old boy.
Histologically , these lesions are characterized by large clear cells in the lower epidermis that have
a pattern of immunohistochemical staining similar to clear cells of Toker and extramammary
Paget’s disease. Courtesy, Julie V Schafer, MD.

keratinocytes show marked variation in their content of melanin, which may be absent or markedly
decreased.

The diagnosis of IGH is usually made clinically; the differential diagnosis of guttate leukoderma is
shown in Table 66.7 and includes achromic verrucae plana, pityriasis lichenoides chronica,
disseminated hypopigmented keratoses that follow PUVA therapy (Fig. 66.32) and clear cell
papulosis (Fig. 66.33). Although lesions of atrophie blanche favor the distal shins and ankles, these
porcelain white scars are usually depressed and encircled by papular telangiectasias. The cause of
IGH is unknown, but sun exposure probably plays a role.

Cryotherapy with liquid nitrogen has been described as a possible therapy for IGH. As sunlight is
most likely a precipitating factor, use of sunscreens and physical barriers should be recommended.

Vagabond’s Leukomelanoderma
This skin disorder occurs in older persons in whom dietary deiciency is combined with lack of
cleanliness and heavy infestation with

Table 66.10 Disorders associated with premature graying of scalp hair.

Pediculus humanus var. corporis. These patients have small macules of hypomelanosis (related to
scratching) superimposed on a background of diffuse hypermelanosis, especially of the wrists,
axillae, groin, inner thighs and posterior neck.

Progressive Macular Hypomelanosis

Progressive macular hypomelanosis (PMH) is a fairly common skin disorder, observed more
frequently in young women with darkly pig- mented skin who originate from or reside in tropical
climates. The disorder is characterized by poorly deined, nummular, non-scaly hypopigmented
macules and small patches on the trunk, with rare extension onto the proximal extremities or head
99
and neck region; con- luence of lesions may occur centrally (Fig. 66.34) . Another variant of PMH
features large circular lesions. There is no associated pruritus or preceding inlammation, and
patients are sometimes misdiagnosed as having residual hypopigmentation related to pityriasis
versicolor. Histologically, there is decreased pigment in the epidermis and a normal-appearing
dermis. Electron microscopy demonstrates a shift from large melanosomes in uninvolved skin to
small aggregated membrane-bound melanosomes in hypopigmented skin. Propionibac- terium
acnes residing within hair follicles may play a role in PMH. One proposed treatment regimen
consists of topical 1% clindamycin and 5% benzoyl peroxide plus UVA irradiation (three times per
week for 12 weeks).

Hair Hypomelanosis
Poliosis refers to a circumscribed hypomelanosis of hair (see Table 66.4), whereas canities implies
a more generalized depigmentation of hair. Graying of hair, localized or generalized, is
characterized by an admixture of normally pigmented, hypomelanotic and amelanotic hairs.
Whitening of hair is the endpoint of canities and graying of hair. The graying and whitening of
100,101
human hair that occurs with aging is due to defective maintenance of melanocyte stem cells .
A number of genetic disorders are associated with premature graying of hair (Table 66.10), while
there are both hereditary and acquired causes of diffuse hypomelanosis of hair (Table 66.11). In
Chédiak- Higashi, Griscelli and Elejalde syndromes, the scalp hairs have a silvery hue due to
pigment clumping.

PIGMENTARY DISORDERS

CHAPTER

DISORDERS ASSOCIATED WITH DIFFUSE HYPOMELANOSIS OF SCALP HAIR

 Fanconi syndrome
 Book syndrome
 Down syndrome
 Hallerman–Streif syndrome
 Treacher–Collins syndrome
 Prolidase deiciency (also in Table 66.10)
 Hyperthyroidism
 Chronic protein loss or deiciency (e.g. due to kwashiorkor, nephrosis, ulcerative colitis,
malabsorption)
 Vitamin B12 deiciency
 Tyrosine kinase inhibitors
 Antimalarials (chloroquine > hydroxychloroquine)

Table 66.11 Disorders associated with difuse hypomelanosis of scalp hair. See also Figure
66.11.

Leukodermas without Hypomelanosis

Woronof’s ring

Woronoff’s ring is a blanched halo of fairly uniform width surrounding psoriatic lesions after
phototherapy or topical treatments. There is an element of vasoconstriction, but it is uncertain
whether there is any decrease in pigmentation.

Nevus anemicus

Nevus anemicus (see Ch. 106) presents as a pale area of variable size (often 3–6 cm) with an
irregular, “broken up” outline. It is usually unilateral and located on the trunk. Present since birth,
the lesion is most commonly detected later in life, and it is most noticeable when there is
surrounding vasodilation due to heat or emotional stress. On diascopy, the lesion becomes
indistinguishable from surrounding skin. Histologically, there are no abnormalities in the
melanocytes or melanin content. Nevus anemicus is caused by decreased blood low through the
capillaries in the dermal papillae, due to a localized hypersensitivity of the blood vessels to
catecholamines.

Cutaneous edema and anemia

Cutaneous edema and anemia also produce lightening of the skin and mucous membranes. In the
case of anemia, it is due to decreased hemoglobin levels in the skin.

Angiospastic macules (Bier spots)

Pale mac