Journal of Interdisciplinary Histopathology

www.scopmed.org

Original Research DOI: 10.5455/jihp.20161208123939

Clinicopathological correlation
in diagnosis of Hansen’s disease:
A histopathologist’s perspective
Reshma Gopal Kini, Hemangini Choudhury

ABSTRACT
Department of Objectives: Hansen’s disease follows a chronic course and though curable causes considerable degree of
Pathology, Father Muller disability and deformity. Key to managing leprosy is its early diagnosis and treatment with multidrug regimen.
Medical College, Histopathological evaluation of skin biopsies plays crucial role in the correct diagnosis of clinically ambiguous
Mangalore, Karnataka, cases. Moreover, classifying lesions by the Ridley-Jopling (RJ) system gives personalized information about
India the immunological status of the individual and also aids in placing the patient in the correct treatment category.
Materials and Methods: Skin biopsies obtained from newly diagnosed cases of leprosy were included.
Paraffin-embedded sections stained with hematoxylin-eosin and Fite-Faraco were evaluated for features
Address for correspondence:
Dr. Reshma Gopal Kini,
confirming leprosy and further categorized as per the RJ system. Sensitivity, specificity, and concordance
Department of Pathology, rates were studied. Results: A total of 93 cases were studied after excluding those which had a component
Father Muller Medical of reaction. Among the clinically suspected cases, 93% of the biopsies were positive for leprosy. Sensitivity
College, Kankanady, of clinical diagnosis ranged from 60% for borderline (BB) to 100% for histoid leprosy. Specificity ranged from
Mangalore - 575 002, 84.5% for borderline tuberculoid (BT) to 100% for neuritic leprosy. The agreement between histopathological
Karnataka, India. and clinical diagnosis was more than 90% in all the subclasses except for BT which showed agreement in about
Phone: +91-9986287395. E-
82% of the cases. Two of the cases were categorized into multibacillary type of leprosy-based histopathological
mail: drreshmakini@gmail.
com
evaluation. Conclusion: Confirmation of leprosy by the examination of skin biopsy before starting the patient
on long-term multidrug therapy is invaluable. Experience of the leprologists and adherence to histopathological
criteria as per the RJ classification yield excellent concordance rates.
Received: July 17, 2016
Accepted: October 14, 2016
Published: December 31, 2016 KEY WORDS: Histopathology, leprosy, Ridley-Jopling classification

INTRODUCTION prevalence by correlating the clinical and the histopathological

features [4,5].
Hansen’s disease is a chronic infectious condition affecting
principally the skin and peripheral nerves [1]. In the absence MATERIALS AND METHODS
of the classic involvement of the peripheral nerves, the clinical
manifestations of leprosy are diverse and can mimic a host of Settings and Design
other skin disorders. With decreasing prevalence of the disease
in the current post-elimination era, the opportunities to study This study is a descriptive, hospital-based retrospective study.
this enigmatic disease are fewer whereas the need to sustain a
high level of diagnostic expertise is absolutely necessary. The Skin biopsies obtained from patients clinically diagnosed as
consequence of untreated or undertreated leprosy is not only leprosy in the OPD and leprosy clinic of our institute between
the permanent and debilitating deformity suffered by these January 2012 and November 2015 were included in the study.
patients but also the risk posed by these individuals who act as The study was initiated after obtaining ethical clearance from
reservoir for infection in the community. At this juncture, the the Ethics Committee of our institution.
histopathological examination of skin biopsies for diagnosis of
leprosy and for the categorization of clinically suspected cases Slides stained with hematoxylin and eosin and Fite-Faraco were
plays a pivotal role [2,3]. evaluated for features representing/indicative of leprosy. Cases
positive for Hansen’s disease were evaluated for the presence or
Hence, we aimed to evaluate the histopathological features absence of granulomas, type of cells comprising the granulomas,
of cases diagnosed as leprosy on clinical examination and also nature of the histiocytes - whether foamy/epithelioid, presence
to assess the applicability of the Ridley-Jopling (RJ) system of epidermal involvement, evidence of neural involvement/
of classification in the current era of decreasing disease destruction, presence location and density of lymphocytes, type

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Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease

and number of giant cells, and bacillary index. Based on these, Table 1: Distribution of cases in individual categories based on
the biopsies were categorized into five classes of RJ classification clinical and histopathologic criteria
system as tuberculoid (TT) leprosy, borderline tuberculoid (BT) Type of leprosy Clinical diagnosis Histopathological diagnosis
leprosy, mid-borderline leprosy (BB), borderline lepromatous TT 18 16
(BL), and lepromatous leprosy (LL) [4,5]. BT 33 30
BB 3 5
Data were analyzed by: BL 12 9
LL 5 7
i. Comparing the histopathological diagnoses with the clinical Histoid 8 6
impression. Neuritic 1 1
ii. Calculating the accuracy, sensitivity, specificity, and positive
and negative predicted values of clinical categorization for IL 13 12
Not leprosy - 7
individual subclasses. Total 93 93
iii. Evaluating the concordance of histopathological and clinical
TT: Tuberculoid, BT: Borderline tuberculoid, BB: Borderline,
diagnosis for each of the classes.
BL: Borderline lepromatous, LL: Lepromatous leprosy, IL: Indeterminate

Concordance in cases of indeterminate, histoid leprosy, and

neuritic leprosy were also studied. Table 2: Histopathological diagnosis of clinically classified
lesions
Clinical Histopathological diagnoses
RESULT diagnosis
Clinical TT BT BB BL LL Neuritic Histoid Indeterminate Negative
A total of 93 cases were included in the study. The majority of
(n-number
the patients were males (60.2%). of cases)

TT-18 11 3 1 3
The age of the patients ranged from 7 to 72 years. Of the BT-33 4 22 1 2 2 2
93 cases diagnosed clinically, 7 were negative for features of BB-3 3
leprosy. The distribution of cases into individual subclasses by BL-12 5 7
LL-5 4 1
clinical and histopathological criteria is presented in Table 1 Neuritic1 1
and Figures1 and 2. Histioid-8 2 6
IL13 1 1 10 1
BT cases were the largest in number. The borderline groups Total-93 16 30 5 9 7 1 6 12 7

together constituted more than 50% of the cases. The TT: Tuberculoid, BT: Borderline tuberculoid, BB: Borderline,
histopathological diagnosis of the clinically categorized cases BL: Borderline lepromatous, LL: Lepromatous leprosy, IL: Indeterminate
with the sensitivity, specificity, and concordance is shown in leprosy
Tables 2 and 3.
Table 3: Sensitivity, specificity, positive predictive value,
Clinical diagnosis of TT was based on the presence of one or negative predictive value, and agreement of clinical diagnosis
very few well-demarcated hypoanesthetic patches of slightly for individual subclasses

raised plaques in asymmetrical distribution with neural Type of Sn (%) Sp (%) PPV (%) NPV (%) Agreement
thickening adjacent to the skin abnormalities. We identified leprosy

classic tuberculoid granulomas composed of epithelioid [Figure 4c and d]. Three cases had bacillary index of 1 and one
histiocytes with numerous well-developed Langhans’ type of had surprisingly high load 4. Neural involvement by granulomas
giant cells and dense lymphocytic infiltrate in 11 of the 18 cases considered a classic feature of BT was seen in 57.1% of the cases.
[Figure 3a and b]. Bacillary index was uniformly 0 in all the cases Rest of the cases showed either absence of dermal nerves in the
of TT. Dermal fibrinoid necrosis, periadnexal, and perineural biopsy or only lymphocytic infiltrate around the nerve bundles
lymphocytes were additional points. of which two cases showed no granulomas.

Cases classified as BT type differed from cases of TT by the

presence of greater number of lesions slightly ill-defined
though with equal or more loss of sensations [Figure 4a and b].
Histopathologically BT lesions showed significantly less number
of giant cells as well as lymphocytes in comparison with TT

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 Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease

TT 68.75 91.46 61.11 93.75 92.4

BT 73.3 84.51 66.67 88.24 82
BB 60 100 100 97.83 97.8
BL 77.78 94.19 58.33 97.59 92.6
LL 66.67 98.88 80 97.78 96.8
Histoid 100 97.7 75 100 93.8
IL 83.33 96.39 76.9 97.5 94.7
Neuritic 100 100 100 100 100
TT: Tuberculoid, BT: Borderline tuberculoid, BB: Borderline,
BL: Borderline lepromatous, LL: Lepromatous leprosy, IL: Indeterminate
leprosy

Cases that showed several ill-defined skin lesions with mild loss
of sensation and involvement of several nerves were classified
into BB of mid-borderline type. There was 100% concordance
between the clinical and histopathological diagnosis in BB.

Histopathological hallmark of BB lesions was the total absence

of the Langhans’ type of giant cells and scant number of

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Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease

a b

Figure 1: Distribution of cases by clinical criteria

c d
Figure 4: (a and b) A patient with clinical diagnosis of borderline
tuberculoid showing two well-defined erythematous dry scaly plaques
over the left arm and right elbow (a and b, respectively). The mark over
the lesion on the left arm represents the site from which the biopsy was
later taken, (c) histopathology revealed well-developed granulomas not
involving the epidermis. A few Langhans’ type of histiocytic giant cells
and lymphocytes can be discerned. Hematoxylin and eosin Original
magnification ×100, (d) classic tuberculoid granulomas comprised
exclusively of well-developed epithelioid histiocytes with lymphocytes
not forming a mantle. Hematoxylin and eosin. Original magnification
×400

Figure 2: Distribution of cases by histopathological criteria

BL cases were diagnosed based on the presence of several

asymmetrically distributed lesions ranging from mere macules
a b
Figure 3: (a) Histopathology of 3a showing well-formed granulomas
with many Langhans’ giant cells eroding into the epidermis from below.
Note the loss of melanocytes at the site of erosion in comparison with
the adjacent uninvolved epidermis representing the clinically
perceivable hypopigmentation. Hematoxylin and eosin. Original
magnification ×100, (b) histopathology of tuberculoid showing
granuloma composed of epithelioid histiocytes, lymphocytes, and
well-developed Langhans’ type of giant cell. Hematoxylin and eosin
original magnification ×400

lymphocytes [Figure 5a]. The proportion of epithelioid cells

within the granulomas was less as compared to BT, the cells
being replaced by foamy macrophages [Figure 5b].

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 Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease

a b
Figure 5: (a) Skin biopsy in borderline showing periadnexal granulomas
with scant lymphoid cells. Note the absence of giant cells which helps
in distinguishing it from a borderline tuberculoid lesion H and E

composed of the so-called immature epithelioid cells, histiocytes, and

scant lymphocytes. H and E original magnification ×400

to patches to plaques to nodules [Figure 6a] cases with similar

lesions, but more shiny and distributed in symmetrical pattern
were categorized into LL [Figure 7]. Cases of LL showed classic
morphology with very high bacillary index [Figure 8].

Seven out of twelve cases of clinically diagnosed cases of BB

revealed the presence of granulomas comprised predominantly
of foamy macrophages with scattered epithelioid cells.
Granulomas were present in 66% of the cases. One case showed
epidermal involvement by granulomas. However, the nature of
the histiocytes and bacillary index of 2 helped in classifying it
into BB as opposed to TT which classically shows epidermal
involvement. The lymphoid infiltrate was rather more dense

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Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease

Indeterminate cases numbered 11, of which 9 were clinically

diagnosed as IL and 2 as BT.

The definitive diagnosis of IL depended on the presence of acid-

fast bacilli with nerve lesion. Histopathologically, a diagnosis of
leprosy was also even in the absence of bacilli when perineural/
periadnexal lymphocytic infiltrates were present in the biopsy,
especially in patients from endemic regions [Figure 9].
than in BB [Figure 6b]. The rest of the five cases showed features
consistent with those of BT.

Figure 6: Patient clinically diagnosed as borderline lepromatous

showing asymmetrically distributed papules and nodules over the left
flank, (b) granulomas composed of macrophages and showing only
occasional epithelioid cells. There is a denser infiltrate of lymphoid
cells throughout the granuloma as compared to borderline (Figure 5b)
hematoxylin and eosin original magnification ×400

a b

c d
Figure 7: (a) Classical case of lepromatous leprosy leprosy showing
infiltration of skin of forehead with madarosis, (b) patient had depressed
nasal bridge and mild ear lobe infiltration, (c and d) numerous plaques
and papules distributed symmetrically over the trunk and both upper limbs

a b
Figure 8: (a) Lepromatous leprosy granuloma composed of histiocytes,
many of them showing vacuolated cytoplasm. Granulomas lack
lymphoid infiltrate representing the second trough after borderline in
the degree of lymphoid population. Hematoxylin and eosin original
magnification ×400, (b) Fite stain revealed a bacillary index of 6.
Original magnification ×1000

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 Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease

We encountered 7 cases of clinically diagnosed histoid leprosy,

of which 5 were LL and 3 were histoid histopathologically.
Histopathology of histoid leprosy showed spindle cell
proliferation of macrophages resembling a storiform tumor.
The stain for leprae organisms showed huge clumps of bacilli
arranged like sheaves of wheat [Figure 10].

The patient diagnosed as pure neuritic leprosy had no skin

lesions as the definition demands. He had involvement of
multiple nerves in both upper and lower limbs. Histopathology
revealed the presence of foamy histiocytes and a high bacillary
load within the substance of the nerve [Figure 11].

Discussion

RJ in their seminal paper classified leprosy based on combination

of clinical and histopathological features into five categories
as TT, BT, BB, BL, and LL. The outcome of this classification
system was the categorization of the patients based on their
immunological response to leprosy. In 1982, the World Health
Organization advocated the use of two separate regimens for
the treatment of leprosy based on the RJ classification system
into paucibacillary (PB) group (including TT and BT) and
multibacillary (MB) group including (BB, BL, and LL) with
treatment being longer in the latter. The current treatment
protocol, however, depends on counting of the lesions (Less
than or equal to five lesions-PB, more than five-MB).[4-6]

It has been estimated that following of the latter protocol

has resulted in risk of undertreatment of 38-51% of the
leprosy cases, specifically in those with lesions numbering <5.
A histopathological evaluation of skin lesions in a suspected case
of leprosy is therefore very much desirable. This entails a high
level of diagnostic proficiency in the reporting pathologist on
whom the treatment might ultimately depend [6].

In our series, the accuracy of clinical diagnosis of leprosy was

92.4%. The rest of the cases were negative for leprosy. The
evidentiary information obtained which helps in ruling out
leprosy and consequently its social stigma and prolonged
treatment is in fact one of the most important indications for
performing a biopsy in a clinically suspected case of leprosy
[Table 4].

The polar forms of tuberculoid and LL comprised 25% of total

number of cases where the borderline types were the majority
and the indeterminate leprosy (IL) the least common category
of leprosy. This finding is similar to those observed by Nadkarni
and Rege [11].

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Table 4: Comparison of agreement in our study as compared

to similar studies
Present Ridley Santos Suri Sharma Shivaswamy
study et al. [4] et al. [7] et al. [8] et al. [9] et al. [10]
91.7% 68.3% 84.8% 75.5% 53.5% 74.7%

a Type 1 reaction that can occur once treatment is initiated in

the latter category of patients [18,19].

When in doubt, we have observed the presence of epidermal

erosion to be a very useful characteristic in distinguishing TT
from BT as this feature excludes the latter [Figure 3].

BT
Figure 9: Perineural lymphocytic infiltrate is a clue to leprosy in The advantage of distinguishing TT and BT histopathologically
otherwise indeterminate cases. Hematoxylin and eosin. Original is in the fact that it alerts the treating clinician to possibility of
magnification ×400

a b

c
Figure 10: (a) Skin biopsy from one of the nodules from a case of
histoid leprosy reveals a well-defined Grenz zone beneath which
there are sheets of histiocytes the spindle shape of which can just be
discerned. Hematoxylin and eosin (H and E) original magnification
×40, (b) section showing aggregates of spindle-shaped histiocytes H
and E original magnification ×400, (c) Fite stain reveals acid-fast bacilli
in classical sheaves of wheat arrangement. Original magnification
×1000

Tuberculoid Leprosy

The concordance between clinical and histopathological

diagnosis for TT (92.4%) was on the higher side as compared to
other similar studies where the concordance rates ranged from
around 24% to nearly 95% [Table 5]. The histopathological
diagnosis of TT is rather more straightforward than the other
categories owing to being one of the polar forms.

Three of the cases diagnosed clinically as TT were categorized

histopathologically into the BT. This shift of one group is
understandable as the clinical and histopathological features
of TT and BT overlap. The majority of TT and BT have <5
lesion, and since treatment would depend on the status of the
slit skin smears, this was considered to be a minor discrepancy.

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 Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease

As in other studies, BT constituted a major chunk in our

study [16]. Concordance for BT in our study was the least when
compared to that in other categories. This is a unique feature
as other similar studies have obtained the better concordance
rates in BT than in other categories [11,12,17].

We observed minor discrepancy (shift of one group on either

side) in 4 cases (3 TT and 1 BB) and major discrepancy in six
cases (2 LL, 2 IL, and 2 negative).

Histopathological examination in these discrepant cases was

invaluable. It helped in ruling out leprosy in two suspected
cases. Two of the cases with histopathological features of LL had
lesions of only the plaque type and were <5 in number. These
patients would under the current protocol be categorized under
the PB regimen. Histopathological findings, however, aided in
the correct classification of these patients both of whom are
currently undergoing the MB regimen.

The concordance rate for the mid-borderline leprosy (BB) in

our study was the highest (97.8%). This is in contrast to the
other studies which quote either the least concordance in this
category [9] or a concordance among the lowest [14,11]. This
could be explained by the fact that we received only three cases
clinically suspected and histologically conforming to the diagnosis
of BB whereas the others had substantially more number.

The concordance rates of BL (92.6%) are comparable with those

of Nadkarni and Rege [11]. However, when compared to other
studies, it is significantly higher [12,16].

When compared to the rates in other categories, however,

concordance rate is lower. It is known the borderline categories
(BT, BB, and BL) are immunologically unstable. Among the
three, BB is the least stable. Shifting of the cases from one
category to another is common. It does not follow, however,
that the histopathological findings will correspond exactly to
the category at a given point of time as the morphology can
precede or succeed the clinically observable changes so much
so that the features of each of these classes can be present in
different biopsies in a single patient and also in serial sections of
biopsies of the same lesion. Hence, discrepancy in the borderline
categories is not only observed but also to be expected [18,19].

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Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease

Table 5: Concordance rates for TT, BT BB, BL, LL, and IL in our study in comparison with other studies
Leprosy class Present study Jerath and Bhatia Nadkarni and Kar et al. [14] Kalla Moorthy Manandhar Shivaswamy
Desai [12] et al. [13] Rege [11] et al. [15] et al. [16] et al. [17] et al. [10]
TT (%) 92.4 74.5 50 97 87.5 76.7 46.15 24 56
BT (%) 82 64.7 77 95 60.9 44.2 66.6 63.15 64.1
BB (%) 97.8 53.8 25 89 54.5 37 50 0 50
BL (%) 92.6 28.5 43 87 53.8 43.7 70 57.4 73.3
LL (%) 96.8 61.5 91 98 71.4 75.6 80 57.1 84.2
IL (%) 93.8 88.8 35 - 81.2 20 0 50
BB: Borderline, BL: Borderline lepromatous, LL: Lepromatous leprosy, IL: Indeterminate leprosy
histiocytes and a high bacillary load, our case would belong to
the LL group [22].

a b

c
Figure 11: (a) Nerve biopsy from a case of neuritic leprosy showing
mildly edematous nerve. With infiltration of foamy histiocytes within
the nerve (arrow), (b) high power view of the nerve with collection
of histiocytes having vacuolated cytoplasm. Hematoxylin and eosin
original magnification ×400, (c) globi of lepra bacilli seen within the
foamy cells. Original magnification ×1000

IL was identified by RJ as those cases in which the

histopathological and clinical features are sufficient for diagnosis
of leprosy but not for classification of the type as it was an
early and transitory stage of leprosy found in persons, whose
immunological status was yet to be determined [5,20,21].

We received 13 clinically diagnosed cases of IL, of which

12 were confirmed to be leprosy with 10 of them categorized
into IL and one each into BT and BB. The proportion of cases
diagnosed is similar to those observed by Nadkarni and Rege
and Sharma et al. [9,11]. In two of the cases of BT, we failed to
find granulomas, but histopathological features suggestive of
leprosy were present. This further emphasizes the asynchrony
of the temporal relationship between the clinical and the
histopathological features of leprosy which requires a careful
clinical and histopathological correlation to avoid overlooking
the subtle features indicative of leprosy.

The original definition of pure neuritic leprosy required the

absence of skin lesions along with involvement is of single or
multiple nerves with sensory loss in the areas of distribution
of the nerves. Studies on the histopathology of leprosy have
demonstrated features suggestive of all the categories as defined
in the RJ classification. With the exclusive presence of foamy

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 Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease Kini and Choudhury: A histopathologist’s perspective in Hansen’s disease

Histopathological examination of skin biopsy is recommended

in all clinically suspected cases of leprosy for accurate diagnosis
as well as to avoid undertreatment of cases of MB especially
in the current post-elimination era. Borderline cases represent
majority of the lesions of leprosy and must receive special
consideration due to their unstable immunologic status. The
high rates of concordance in our study are indicative of the
continuing expertise of our clinical colleagues and a good
clinicohistological correlation with strict adherence to diagnostic
criteria.

ACKNOWLEDGMENTS

We would like to acknowledge with gratitude Dr. Ramesh M.

Bhat, Professor, Department of Dermatology, Father Muller
Medical College for providing us with the clinical photographs.

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