Resident’s Acantholysis revisited: Back to basics

Page

Divya Seshadri, Sendhil Kumaran M., Amrinder J. Kanwar

Department of Dermatology, ABSTRACT

PGIMER, Chandigarh, India
Acantholysis means loss of coherence between epidermal cells due to the breakdown of
Address for correspondence: intercellular bridges. It is an important pathogenetic mechanism underlying various bullous
Dr. M. Sendhil Kumaran, disorders, particularly the pemphigus group, as well as many non-blistering disorders.
Department of Dermatology,
Venerology and Leprology,
Although a well-known concept, the student often has to refer to many sources to comprehend
PGIMER, Chandigarh, India. acantholysis completely. Thorough knowledge of this topic helps in clinching many diagnoses.
E-mail: The etiopathogenesis, classification, clinical signs, and laboratory demonstration of
[email protected] acantholysis are discussed in detail to help students build clear concepts. We have focused
on various distinguishing points in different disorders for an easy grasp of the topic.

Key words: Acantholysis, Nikolsky’s sign, primary, secondary

INTRODUCTION space of desmosomes includes two chief glycoproteins;

the desmogleins (Dsg) and desmocollins, which
The term acantholysis, coined by Auspitz in 1881, in conjunction with the cytoplasmic counterparts
is derived from the Greek words akantha, meaning plakoglobin and plakophilin, bring about the complex
a thorn or prickle, and lysis, i.e. loosening.[1,2] intercellular attachment.[6] Experiments in the recent
Acantholysis is defined as the loss of coherence past have partially elucidated the multiple triggers,
between epidermal cells due to the breakdown of their targets, and steps involved in acantholysis.
intercellular bridges.[3,4] The cells remain intact but are
no longer attached to each other; they tend to acquire There are a number of triggering factors, which can
the smallest possible surface area and become rounded commence the cascade of acantholysis [Table 1].
up, resulting in intra-epidermal clefts, vesicles and Acantholysis is initially characterized by separation of
bullae. Acantholysis is the primary pathological the inter-desmosomal regions followed by splitting and
change occurring in pemphigus and its variants and disappearance of desmosomes, forming intercellular
other conditions like Hailey-Hailey disease (HHD).[5]
gaps. These intercellular gaps result in fluid influx
This article presents acantholysis in a nutshell,
from the dermis leading to cavity formation, which
catering to the needs of the dermatology student.
may be suprabasal, mid-epidermal, or subcorneal in
location. The acantholytic cells remain metabolically
Pathogenesis and classification of acantholysis
active for some time and retain their capacity for
Desmosomal cadherins are the primary pathological
DNA synthesis. Degeneration and cell death represent
targets in the pemphigus group of disorders and some
secondary phenomena.[4]
conditions like bullous impetigo. The intercellular

Another important molecule in the pathogenesis

Access this article online
of acantholysis is syndecan-1, a heparan sulfate
Quick Response Code: Website:
proteoglycan on the keratinocyte membrane, which
www.ijdvl.com
functions in intercellular adhesion. Absent or markedly
DOI:
decreased syndecan-1 expression by acantholytic
10.4103/0378-6323.104688
keratinocytes has been reported in biopsies of
PMID:
pemphigus, Grover’s disease, and herpes simplex.[9]
*****
Keratinocytes from spongiotic dermatitis showed a

How to cite this article: Seshadri D, Kumaran MS, Kanwar AJ. Acantholysis revisited: Back to basics. Indian J Dermatol Venereol Leprol
2013;79:120-6.
Received: April, 2012. Accepted: July, 2012. Source of Support: Nil. Conflict of Interest: None declared.

120 Indian Journal of Dermatology, Venereology, and Leprology | January-February 2013 | Vol 79 | Issue 1
Seshadri, et al. Acantholysis revisited

diffuse mild decrease in syndecan expression while which leads to dissociation of adhesion molecules and
keratinocytes from bullous pemphigoid showed no also initiates apoptosis. Subsequently, tonofilaments
loss of expression.[9] Syndecan expression was also collapse and keratinocytes shrink with sloughing of
decreased in acantholytic squamous cell carcinoma.[10] desmosomes, which elicits an autoimmune response.
Finally, anti-Dsg antibodies bind to their targets
Classification of acantholysis precluding formation of new intercellular junctions.[14]
Acantholysis has been broadly classified as primary or The linking of the apoptotic pathways to basal cell
secondary [Table 2]. shrinkage and suprabasal acantholysis has been
termed apoptolysis.[15]
Primary acantholysis: Dissociation and disintegration
of desmosomes leads to the separation of keratinocytes; In HHD, acantholysis results from a genetically
either due to direct injury to desmosomes or due to determined defect, resulting in desmosomal
hereditary defects in their construction.[11] Thus, in instability, in combination with exogenous factors like
these diseases, acantholysis is the primary event bacterial toxins, trauma, or maceration.[4] A mutation
leading to the formation of intra-epidermal cavities in ATP2C1 gene disturbs keratinocyte differentiation,
and hence the manifestations of the disease. Primary proliferation and adhesion, which in combination
acantholysis is of prime pathogenetic relevance in with other triggers, results in the separation of keratin
diseases of the pemphigus group. filaments from desmosomal plaques. The keratin
filaments aggregate in the perinuclear area as whorls
Mechanism of acantholysis in pemphigus: It is an leading to widespread partial acantholysis.[8] A similar
enigmatic process, and newer aspects are continually phenomenon plays a role in Darier’s disease.
being discovered. The major auto-antibodies in
pemphigus target Dsg-1 (PF and PV) and Dsg-3 (PV). Few authors include bullous impetigo and
The conventional concept is that PV IgG binds to staphylococcal scalded-skin syndrome (SSSS) under
Dsgs resulting in stearic hindrance, interference with primary acantholysis.[4] Melish and Glasgow showed
desmosomal cadherin trans-interactions and loss of that Exotoxin (ET) produced by Staphylococcus aureus
intercellular adhesion. The Dsg compensation theory
explains the different level of blistering in PV and PF.
Table 2: Causes of primary and secondary acantholysis
Plasminogen activation in lesional epidermis is also
Primary acantholysis Secondary acantholysis
believed to contribute to acantholysis.[7] However,
Pemphigus vulgaris and Herpes simplex virus infections
recent immuno-electron studies demonstrate that its variants Herpes zoster
desmosomes remain intact till the late stages of Pemphigus foliaceus and Condyloma acuminatum
acantholysis when they are cleaved behind the its variants
Tinea corporis
desmosomal plaque, due to shearing forces produced Hailey-Hailey disease
BT leprosy
by collapsing cells.[12] Hence, the pivotal role of anti- Darier’s disease
Epidermolytic hyperkeratosis
Dsg antibodies in pemphigus is being questioned.[13] Transient acantholytic
Epidermolysis bullosa (EB)
dermatosis (Grover’s
In addition to Dsgs, pemphigus auto-antibodies disease) Lethal acantholytic EB
recognize numerous other antigens. In a recently- Bullous impetigo Acantholytic Dowling-Meara type of
described model [Figure 1], the proposed initial step is EB simplex
Staphylococcal scalded
skin syndrome (SSSS) Mal de Meleda type of PPK
the binding of antibodies to peripheral myelin protein
Galli-Galli disease
(PERP) and/or cellular acetylcholine receptor (AChR),
Solar keratoses
Acantholytic acanthoma
Table 1: Triggers of acantholysis[7,8] Adenoid squamous cell carcinoma
Autoimmunity Sweating Basal cell carcinoma
Drugs Ionizing radiation Keratoacanthoma
Infections Friction Melanocytic naevi
Food Maceration Dermatofibromas
Burns Trauma Elastolytic granuloma
Genetics Contact dermatitis Pityriasis rubra pilaris
Heat Infestations like scabies Psoriasis
UV rays; especially UV-B Leukocytoclastic vasculitis

Indian Journal of Dermatology, Venereology, and Leprology | January-February 2013 | Vol 79 | Issue 1 121
Seshadri, et al. Acantholysis revisited

causes bullous impetigo and SSSS. ET results in loss acantholysis has been reported in numerous other
of cohesion between keratinocytes by cleaving Dsg1, conditions ranging from BT leprosy to melanocytic
as confirmed experimentally.[16] Its amino acid make- naevi [Table 2].[3,21-24]
up is analogous to that of chymotrypsin-like serine
proteases.[17] Biochemical acantholysis: The term describes a
special type of primary acantholysis brought about
Secondary acantholysis: The acantholysis is secondary without antibody mediation.[25] Drugs and food items
to alteration or damage to keratinocytes by various of the thiol or phenol groups can trigger pemphigus
factors.[5] In other words, keratinocytes are injured through this mechanism. The proposed mechanisms
first followed by subsequent disintegration of for thiol-induced acantholysis include direct
desmosomes.[11] This includes secondary shedding biochemical effect by formation of thiol–cysteine
of keratinocytes from the walls of established intra- bonds disturbing cell adhesion, protease activation,
epidermal blisters developing due to other causes.[4] and immunological reaction with the formation
Secondary acantholysis can occur in a wide variety of a neo-antigen. Possible mechanisms of phenol-
of benign and malignant skin diseases. One example induced acantholysis include induction of IL-1
of secondary acantholysis is the dissociation of cells and TNF- release from keratinocytes, which result
in herpes simplex and herpes zoster lesions. Others in the dysregulation of proteases like plasminogen
include epidermolytic hyperkeratosis, solar keratoses, activator.[26]
acantholytic acanthoma, and adenoid squamous cell
carcinoma.[5] Acantholysis can be a prominent finding Sites of acantholysis
in certain variants of epidermolysis bullosa (EB) and The site of acantholysis in a given condition helps in
is the defining feature of the Galli-Galli variant of the diagnosis, especially in blistering disorders. In PF
Dowling Degos disease.[18-20] Incidental focal secondary and pemphigus erythematosus, acantholysis is usually

Figure 1: Current concepts of acantholysis in pemphigus[14]

122 Indian Journal of Dermatology, Venereology, and Leprology | January-February 2013 | Vol 79 | Issue 1
Seshadri, et al. Acantholysis revisited

confined to the sub-corneal layer due to involvement of as Nikolsky’s)[34] The sign is elicited by applying
Dsg1, which is distributed predominantly in the upper tangential pressure with a finger or thumb to the
epidermis. In PV, the clefting occurs in the suprabasal affected skin, peri-lesional skin, or normal skin in
epidermis due to involvement of Dsg3, predominantly patients with suspected pemphigus [Figure 2]. It is
expressed in the lower epidermis. In HHD, although termed positive if there is extension of the blister
acantholysis is often focal or incomplete, it tends to and/or removal of epidermis in the rubbed area.[35]
affect the entire epidermal thickness [Table 3]. “Marginal Nikolsky's sign” describes the extension of
the erosion on the surrounding normal-appearing skin
Clinical signs associated with acantholysis by rubbing the skin surrounding existing lesions while
“Direct Nikolsky's sign” is the induction of an erosion
a) Nikolsky's sign on normal-appearing skin, distant from the lesions.[36]
Uzun and Durdu tested the utility of Nikolsky’s sign in
The Russian dermatologist Pyotr Vasiliyevich 123 pemphigus cases and found it to be a moderately
Nikolskiy first described this sign. (Although his sensitive but highly specific diagnostic tool. The
name was spelt Nikolskiy, the sign is better known marginal Nikolsky's sign was more sensitive (69%),

Table 3: Characteristics of acantholysis in different disorders

Disease Site of acantholysis Light microscopic appearance of acantholytic cells Associated findings
Pemphigus Suprabasal Typical Tzanck cells in large numbers either singly or Lack of significant surrounding
vulgaris as loosely adherent clumps[27] inflammation
+/- Sertoli’s rosettes, streptocytes[28]
Pemphigus Suprabasal Abundant Tzanck cells[29] Large numbers of inflammatory
vegetans cells; particularly eosinophils[29]
Pemphigus Subcorneal Moderate numbers of acantholytic cells[27] Cells have hyalinized cytoplasm ,
foliaceus and corresponding to dyskeratosis seen
erythematosus on histopathology[27]
Hailey-Hailey Full-thickness of Abundant rounded acantholytic cells with single, round No inflammatory cells.
disease epidermis hypertrophic nucleus with one or two prominent, viable Dilapidated brick wall appearance
nucleoli and mourning-edge of cytoplasm[30,31] of epidermis on histopathology[8]
Darier’s disease Mainly upper Corps ronds and grains (dyskeratotic acantholytic Suprabasal lacunae on
epidermis cells)[29] histopathology[32]
SSSS Subcorneal Few dyskeratotic acantholytic cells[27] Few inflammatory cells[27]
Bullous impetigo Subcorneal Dyskeratotic acantholytic cells in moderate to large Abundant neutrophils; gram positive
numbers[27] cocci[27]
Herpes simplex / Bases of intra- Acantholytic Balloon cells - single cells and Plenty of neutrophils; necrotic cells
zoster epidermal vesicles multinucleate giant cells. (Swollen keratinocytes with in older lesions[33]
homogenous eosinophilic cytoplasm with large nuclei
often containing inclusion bodies)[33]

a b
Figure 2: (a) Eliciting Nikolsky's sign on perilesional skin. Note the tangential pressure, (b) Eliciting Nikolsky's sign, peeling of skin
revealing moist erosion

Indian Journal of Dermatology, Venereology, and Leprology | January-February 2013 | Vol 79 | Issue 1 123
Seshadri, et al. Acantholysis revisited

while the direct Nikolsky's sign was more specific b) Bulla spread sign (Asboe-Hansen sign)
(100%) to diagnose pemphigus.[37]
Described originally by Wilhelm Lutz, it is the
The underlying pathophysiology of this sign is the enlargement of an intact blister by the application
acantholysis occurring in affected areas as well of mechanical pressure on its roof [Figure 3]. If one
as in areas with intact, normal-appearing skin.[34] carefully presses upon the blister, it enlarges towards its
Microscopic Nikolsky’s sign is the subclinical periphery due to the mechanical pressure of the blister
counterpart of Nikolsky’s sign. Tangential pressure fluid.[36] In PV, the blister extension has a sharp angle,
on apparently normal skin, exerted as in eliciting whereas in BP, the advanced border is rounded.[36]
clinical Nikolsky’s sign, produces the classical
Laboratory investigations to demonstrate acantholysis
microscopic changes of PV or PF in the epidermis that
Acantholytic cells are easily demonstrated using a side-
can be visualized on skin biopsy. Hameed and Khan
lab cytologic smear (Tzanck smear). Introduced by
demonstrated a positive microscopic Nikolsky's sign in
Arnault Tzanck, this is a simple technique to analyze
73.9% of pemphigus patients who were biopsied after
vesiculobullous diseases. The base of an unroofed
applying tangential pressure. There were no changes
blister is gently scraped; the material obtained is
in the biopsies of healthy controls. This technique
gently smeared onto a clean glass slide, allowed to air
could be of value in areas where immunofluorescence dry and stained with Giemsa.[40]
is not readily available.[38] Nikolsky’s sign is usually
positive in diseases with epidermal acantholysis and Light microscopic changes in acantholysis
typically negative in diseases with dermo-epidermal A typical acantholytic cell of PV as seen in a Tzanck
separation,[34] thus helping to distinguish pemphigus smear is called a ‘Tzanck cell’ [Figures 4 and 5]. It
from bullous pemphigoid (BP).[35] is a rounded keratinocyte with a hypertrophic or
dysmorphic nucleus, hazy or absent nucleoli, increased
Nikolsky’s sign is further characterized as “wet” nuclear to cytoplasmic ratio due to the loss of normal
Nikolsky’s, in which a moist, glistening, eroded base intercellular cohesion and abundant eosinophilic to
is seen after pressure is exerted on the skin; and basophilic cytoplasm. The staining is more intensely
“dry” Nikolsky’s, in which the base of eroded skin is basophilic near the cell membrane (‘mourning edge’)
dry. In active PV, a wet sign is expected, whereas the because of cytoplasmic condensation at the periphery,
dry sign indicates re-epithelialization beneath a PV resulting in a perinuclear halo.[27,40] Other findings, not
blister or may suggest PF and hence a higher level of pathognomonic to pemphigus but frequently detectable,
blister formation.[35] In “Nikolsky’s phenomenon,” the are Sertoli’s rosettes and ‘streptocytes.’ Sertoli’s rosettes
superficial epidermis is felt to move over the deeper are composed of a central necrobiotic keratinocyte with
layers, and instead of immediate erosion formation a surrounding leukocyte rosette. A ‘streptocyte’ is a
as in Nikolsky’s sign, a blister develops after some chain of leukocytes, joined by a filamentous, glue-like
time.[39] substance. Sertoli’s rosettes and ‘streptocytes’ can be

False Nikolsky’s sign or Sheklakov’s sign is positive

in sub-epidermal blistering disorders. It involves
pulling the peripheral remnant roof of a ruptured
blister, thereby extending the erosion on the
surrounding normal skin. The erosions thus induced
are limited in size, lack the tendency to extend
spontaneously, and heal rapidly. Pseudo-Nikolsky’s
sign is positive in Stevens-Johnson syndrome, toxic
epidermal necrolysis and in some cases of burns and
bullous ichthyosiform erythroderma. However, it
can be elicited only on the affected or erythematous
areas. Here, the underlying mechanism is necrosis
of epidermal cells and not acantholysis as in true
Nikolsky’s sign.[39] Figure 3: Eliciting Bulla spread sign. Note the vertical pressure.

124 Indian Journal of Dermatology, Venereology, and Leprology | January-February 2013 | Vol 79 | Issue 1
Seshadri, et al. Acantholysis revisited

Figure 4: Tzanck smear of pemphigus vulgaris showing abundant Figure 5: High power view of Tzanck cells in pemphigus vulgaris.
acantholytic cells. (Giemsa stain, 10) Note the perinuclear halo visible in the marked cell. (Giemsa
stain, 40)

Figure 6: Tzanck smear showing secondary acantholysis in

Herpes simplex. The yellow arrow points to a single acantholytic Figure 7: High power view of secondary acantholysis in Herpes
cell; the red arrow indicates a MNG. (Giemsa stain, 10) simplex. Few MNGs are also seen. (Giemsa stain, 40)

observed in herpes zoster and the pemphigoid group, finding acantholytic cells in Tzanck smears for PV is
respectively.[30] The presence of typical Tzanck cells in reported to be 100% and 43.4%, respectively.[41]
large numbers, either discretely or as loosely adherent
clumps, without significant surrounding inflammation CONCLUSION
substantiates the diagnosis of pemphigus.[27,28]
Acantholysis is a key phenomenon in various
Although acantholysis does occur in a variety of skin diseases. Complete knowledge regarding
conditions, subtle differences in the appearance its pathogenesis, location, associated signs, and
of acantholytic cells, site of involvement, and the demonstration is of profound importance for
associated findings aid us in clinching the diagnosis dermatology students and is an invaluable aid in
[Table 3]. For example, Tzanck smears from bullous arriving at a proper diagnosis, which this article has
impetigo show abundant neutrophils along with tried to address.
acantholytic cells in contrast to a bland picture in
PV. It is worthwhile to mention here that in herpes ACKNOWLEDGEMENT
simplex and zoster, the acantholytic cells either occur
as a single cell or as multinucleated giant cells (MNGs) We would like to acknowledge Dr. Uma Nahar Saikia,
[Figures 6 and 7]. The sensitivity and specificity of Additional Professor, Department of Pathology, PGIMER,

Indian Journal of Dermatology, Venereology, and Leprology | January-February 2013 | Vol 79 | Issue 1 125
Seshadri, et al. Acantholysis revisited

Chandigarh for providing the Tzanck smear photographs. epidermolysis bullosa simplex: A reappraisal of acantholysis in
the newborn. Eur J Dermatol 2011;21:966-71.
19. McGrath JA, Bolling MC, Jonkman MF. Lethal acantholytic
REFERENCES epidermolysis bullosa. Dermatol Clin 2010;28:131-5.
20. Sprecher E, Indelman M, Khamaysi Z, Lugassy J, Petronius D,
1. Hurst HG. Pemphigus and pemphigoid: Some current concepts. Bergman R. Galli-Galli disease is an acantholytic variant of
Can Med Assoc J 1970;103:1279-82. Dowling-Degos disease. Br J Dermatol 2007;156:572-4.
2. Calonje E, Brenn T, Lazar A, McKee PH, editors. Acantholytic 21. Joshi R. Incidental Hailey-Hailey like acantholysis in a lesion
disorders. Mckee’s Pathology of the Skin. Philadelphia: of borderline tuberculoid leprosy. Indian Dermatol Online J
Saunders Elsevier; 2012. 2011;2:109-10.
3. Young S, Jee SH, Chang CH. Mal de Meleda with incidental 22. Yamamoto T. Incidental acantholysis of the overlying epidermis
acantholysis - a case report with histopathological and of dermatofibroma. J Eur Acad Dermatol Venereol 2009;23:
ultrastructural studies. Dermatol Sinica 1997;15:87-92. 735-6.
4. Mihm MC, Kibbi AG, Klaus Wolff. Basic pathologic reactions 23. Hashimoto K, Fedoronko L. Pityriasis rubra pilaris with
of the skin. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest B, acantholysis and lichenoid histology. Am J Dermatopathol
Paller AS, Leffell DJ, editors. Fitzpatrick’s Dermatology In 1999;21:491-3.
General Medicine. 7th ed. New York: McGraw-Hill; 2008. p. 45-7. 24. Sebastian A, Koff AB, Goldberg LJ. PRP with subcorneal
5. Calonje E. Histopathology of the skin: general principles. In: acantholysis: Case report and review. J Cutan Pathol 2010;37:
Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s 99-101.
textbook of dermatology. 8th ed. Chichester: Wiley-Blackwell; 25. Ruocco V, Pisani M, de Angelis E, Lombardi ML. Biochemical
2010. p. 10.1-43. acantholysis provoked by thiol drugs. Arch Dermatol
6. Bruckner-Tuderman L, Stanley JR. Epidermal and epidermal- 1990;126:965-6.
dermal cohesion. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest 26. Brenner S, Srebrnik A, Goldberg I. Pemphigus can be induced
BA, Paller AS, Leffell DJ, editors. Fitzpatrick’s Dermatology by topical phenol as well as by foods and drugs that contain
In General Medicine. 7th ed. New York: McGraw-Hill; 2008. phenols or thiols. J Cosmet Dermatol 2003;2:161-5.
p. 447-59. 27. Barr RJ. Cutaneous cytology. J Am Acad Dermatol 1984;10:163-80.
7. Wojnarowska F, Venning VA. Imunobullous Diseases. In: Burns T, 28. Durdu M, Seçkin D, Baba M. The Tzanck smear test: Rediscovery
Breathnach S, Cox N, Griffiths C, editors. Rook’s textbook of of a practical diagnostic tool. Skinmed 2011;9:23-32.
dermatology. 8th ed. Chichester: Wiley-Blackwell; 2010. p. 40.3-19. 29. Gupta LK, Singhi MK. Tzanck smear: A useful diagnostic tool.
8. Fine JD, Burge SM. Genetic Blistering Diseases. In: Burns Indian J Dermatol Venereol Leprol 2005;71:295-9.
T, Breathnach S, Cox N, Griffiths C, editors. Rook’s textbook 30. Ruocco E, Brunetti G, Del Vecchio M, Ruocco V. The practical
of dermatology. 8th ed. Chichester: Wiley-Blackwell; 2010. use of cytology for diagnosis in dermatology. J Eur Acad
p. 39.32-7. Dermatol Venereol 2011;25:125-9.
9. Bayer-Garner I, Dilday B, Sanderson R, Smoller B. Acantholysis 31. Ruocco V, Ruocco E. Tzanck smear, an old test for the new
and spongiosis are associated with loss of syndecan-1 millennium: When and how. Int J Dermatol 1999;38:830-4.
expression. J Cutan Pathol 2001;28:135-9. 32. Hovnanian A. Acantholytic disorders of the skin: Darier-
10. Bayer-Garner IB, Smoller BR. The expression of syndecan-1 White disease, Acrokeratosis Verruciformis, Grover disease
is preferentially reduced compared with that of E-cadherin and Hailey-Hailey disease. In: Wolff K, Goldsmith LA, Katz
in acantholytic squamous cell carcinoma. J Cutan Pathol SI, Gilchrest BA, Paller AS, Leffell DJ, editors. Fitzpatrick’s
2001;28:83-9. Dermatology In General Medicine. 7th ed. New York: McGraw-
11. Brehmer-Andersson E, editor. Dermatopathology. Berlin: Hill; 2008. p. 432-6.
Springer-Verlag; 2006. 33. Xu X, Erickson LA, Elder DE. Diseases caused by viruses. In:
12. Diercks GF, Pas HH, Jonkman MF. The ultrastructure of acantholysis Elder DE, Elenitsas R, Johnson BL, George F Murphy, editors.
in pemphigus vulgaris. Br J Dermatol 2009;160:460-1. Lever’s Histopathology of the Skin. 9th ed. Philadelphia:
13. Amagai M, Ahmed AR, Kitajima Y, Bystryn JC, Milner Y, Lippincott Williams and Wilkins; 2005. p. 652-7.
Gniadecki R, et al. Are desmoglein autoantibodies essential 34. Channual J, Wu JJ. The Nikolskiy sign. Arch Dermatol
for the immunopathogenesis of pemphigus vulgaris, or just 2008;144:1140.
“witnesses of disease”? Exp Dermatol 2006;15:815-31. 35. Urbano FL. Nikolsky’s Sign in Autoimmune Skin Disorders.
14. Grando SA. Pemphigus autoimmunity: hypotheses and Hosp Physician 2001;37:23-4.
realities. Autoimmunity 2012;45:7-35. 36. Grando SA, Grando AA, Glukhenky BT, Doguzov V, Nguyen
15. Grando SA, Bystryn JC, Chernyavsky AI, Frusić-Zlotkin M, VT, Holubar K. History and clinical significance of mechanical
Gniadecki R, Lotti R, et al. Apoptolysis: A novel mechanism symptoms in blistering dermatoses: A reappraisal. J Am Acad
of skin blistering in pemphigus vulgaris linking the apoptotic Dermatol 2003;48:86-92.
pathways to basal cell shrinkage and suprabasal acantholysis. 37. Uzun S, Durdu M. The specificity and sensitivity of Nikolskiy
Exp Dermatol 2009;18:764-70. sign in the diagnosis of pemphigus. J Am Acad Dermatol
16. Payne AS, Hanakawa Y, Amagai M, Stanley JR. Desmosomes 2006;54:411-5.
and disease: pemphigus and bullous impetigo. Curr Opin Cell 38. Hameed A, Khan AA. Microscopic Nikolsky’s sign. Clin Exp
Biol 2004;16:536-43. Dermatol 1999;24:312-4.
17. Vath GM, Earhart CA, Rago JV, Kim MH, Bohach GA, Schlievert 39. Sachdev D. Sign of Nikolskiy and related signs. Indian J
PM, et al. The structure of the superantigen exfoliative toxin A Dermatol Venereol Leprol 2003;69:243-4.
suggests a novel regulation as a serine protease. Biochemistry 40. Kelly B, Shimoni T. Reintroducing the Tzanck smear. Am J Clin
1997;36:1559-66. Dermatol 2009;10:141-52.
18. Darwich E, Vicente A, Bolling MC, González-Enseñat MA, 41. Durdu M, Baba M, Seçkin D. The value of Tzanck smear test
Cusi V, Fortuny C, et al. Extensive acantholysis as the major in diagnosis of erosive, vesicular, bullous, and pustular skin
histological feature of a severe case of Dowling Meara- lesions. J Am Acad Dermatol 2008;59:958-64.

126 Indian Journal of Dermatology, Venereology, and Leprology | January-February 2013 | Vol 79 | Issue 1