Efficacy of Vinblastine and Prednisone in Multicentric Reticulohistiocytosis With Onset in InfancyVijay Kumar Jha, MD, a Ravindra Kumar, MD, b Abhijeet Kunwar, MS, c Ankur Singh, MD, b Mahendra Kumar, MD, a Mohan Kumar, MD, a Rajniti Prasad, MDb

Departments of aPathology, bPediatrics, and cOrthopedics,

Institute of Medical Sciences, Banaras Hindu University,

Uttar Pradesh, India

Dr Jha made provisional pathological diagnosis

of multicentric reticulohistiocytosis, and

conceptualized and designed the study; Dr

Mahendra Kumar compiled data, drafted the initial

manuscript, and approved the fi nal manuscript

to be submitted; Dr Mohan Kumar fi nalized the

pathological diagnosis, and reviewed and approved

the manuscript submission; Dr Ravindra Kumar

obtained detailed clinical history of the patient

along with treatment history and response;

Dr Singh compiled clinical data and treatment

response; Mr Kunwar provided opinion regarding

joint deformities and helped to make the fi nal

diagnosis of multicentric reticulohistiocytosis;

and Dr Prasad fi nalized clinical and treatment

history, provided follow-up details and response

to treatment, and reviewed and approved the

manuscript for submission.

DOI: 10.1542/peds.2015-2118

Accepted for publication Feb 23, 2016

Address correspondence to Mahendra Kumar,

MD, Department of Pathology, Institute of

Medical Sciences, Banaras Hindu University,

Varanasi, Pin-231001, Uttar Pradesh, India. E-mail:

drbindmahendra@gmail.com

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,

1098-4275).

Copyright © 2016 by the American Academy of

Pediatrics

FINANCIAL DISCLOSURE: The authors have

indicated they have no fi nancial relationships

relevant to this article to disclose.

Multicentric reticulohistiocytosis

(MRH) is an unusual systemic

inflammatory disorder of unknown

etiology, affecting skin, mucosa,

and joints; however, in some cases

visceral organs also may be involved.

Clinically, patients present with

cutaneous papulo-nodular lesions

and progressive symmetric and

erosive arthritis.1 Review of literature

showed ∼13 cases of childhood MRH,

including the present study, defining

its rarity in childhood.1, 2 To the best

of our knowledge, the present case

is the youngest in the literature with

onset of disease in infancy. MRH is

often misdiagnosed due to its rarity

and overlapping clinical and histologic

features. Characteristic histologic

findings include infiltration of

histiocytes and multinucleated giant

cells with a homogeneous eosinophilic

ground glass cytoplasm.1–4 Early

diagnosis and immediate treatment

are important to prevent irreversible

joint deformity. There is no definite

treatment protocol for MRH, and

various drugs have been attempted

with inconsistent results.1, 3 We tried

vinblastine and prednisone in this

case with good response, which has

not been attempted before.

CLINICAL HISTORY

A 3.5-year-old girl presented with

red-colored skin lesions with elevated

margins on the left lower neck along

with pain and swelling of multiple

fingers since 3 months of age. Skin

lesions started as a small swelling

measuring 1.5 × 1.5 cm at the left

lower side of neck at 3 months of age,

which gradually increased in size

abstractMulticentric reticulohistiocytosis (MRH) is a rare histiocytic proliferative

disorder of uncertain etiology, characterized by mucocutaneous

papulonodular lesions and progressive, symmetric erosive arthritis.

MRH can coexist with various autoimmune disorders, tuberculosis, and

malignancy. It usually occurs in the elderly and is very rare in children.

This is probably the first case in which disease manifestation appeared in

infancy in the form of skin lesions. The patient had recurrent ulceration of

cutaneous lesions, which is unusual in MRH. Early diagnosis and aggressive

treatment are essential to prevent progressive irreversible course and

development of arthritis mutilans. Various drugs, such as steroids,

nonsteroidal anti-inflammatory drugs, immunosuppressants, interleukin

inhibitors, and tumor necrosis factor-α antagonist, have been tried with

variable responses. The present case responded well to vinblastine and

steroid, which have not been reported previously. Here, we document a

case of MRH with early onset in infancy along with role of vinblastine and

prednisone in its treatment.

CASE REPORTPEDIATRICS Volume 137 , number 6 , June 2016 :e 20152118

To cite: Jha VK, Kumar R, Kunwar A, et al. Effi cacy

of Vinblastine and Prednisone in Multicentric

Reticulohistiocytosis With Onset in Infancy.

Pediatrics. 2016;137(6):e20152118

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JHA et al

and later developed a discharging

sinus that healed over the next 3

months, leaving behind a red-colored

scaly scab with nodular margin.

Skin lesions gradually increased

in size, involving the lower neck

and shoulder area with itching (Fig

1A). At 2 years of age, the child also

developed a similar lesion at the

lateral side of the left upper arm

and at the base of nose. In addition

to skin manifestations, the patient

also developed pain and swelling

of the right index finger at the age

of 7 months, which progressed to

involve the right middle finger and

left index finger during the course

of the next month. Fingers became

sausage shaped with multiple small

nodules (Fig 1 B and C), which

displayed recurrent ulceration and

healing leading to a small yellowish

scar during a period of 3 to 4 days.

Mainly metacarpophalangeal joints

and proximal interphalangeal (PIP)

joints were involved with joint laxity

and increased range of movement.

Later, at the age of 14 months, she

also developed painful swelling over

bilateral first metatarso-phalangeal

joints of feet. There was no

associated malignancy, autoimmune

disorder, hypercholesterolemia, or

significant family history.

Physical examination revealed

moderate pallor, generalized

lymphadenopathy, hepatomegaly of

size 5.5 cm, and mild splenomegaly

(1 cm below left costal margin).

Blood investigation revealed anemia

(hemoglobin 7.7g/dL), leukocytosis

(total leukocyte count 23 600/cmm)

with normal distribution of cells, and

raised erythrocyte sedimentation

rate (70 mm in first hour). Peripheral

blood smear demonstrated moderate

anisopoikilocytosis with presence

of microcytic hypochromic cells;

however, there were no blasts or

atypical cells. Her renal function, liver

function tests, and lipid profile were

within normal range. Mantoux test,

rheumatoid factor, C-reactive protein,

and collagen profile were negative.

Radiographs of both hands showed

lytic lesions with sclerotic margin in

the left second and fifth phalanges,

and right second and third phalanges

(Fig 1D). The patient was very ill

with progressive multiple skin

lesions, swelling of fingers and toes

with severe arthralgia, and bacterial

infection, for which the patient was

admitted to the hospital.

Fine needle aspiration cytology from

bony lesions revealed numerous

histiocytes with vesicular nuclei and

many multinucleated giant cells with

abundant homogeneous eosinophilic

cytoplasm. There was no associated

cytologic feature of Langerhans cell

histiocytosis (LCH); however, in view

of clinical and radiologic findings, the

possibility of LCH was suggested.

Histopathological Findings

Skin biopsy showed dense infiltrates

of mononuclear cells and many

multinucleated giant cells in the

dermis extending into subcutaneous

fat (Fig 2A). Mononuclear cells and

giant cells had round to oval vesicular

nuclei with moderate to abundant

fine granular eosinophilic “ground

glass” cytoplasm (Fig 2B). Overlying

epidermis was focally ulcerated.

Xanthogranulomatous changes,

Touton giant cells, necrosis, and

Langerhans cells were not seen. Ziehl

Neelsen stain and periodic acid-Schiff

stain did not reveal any organism.

Mononuclear cells and giant cells

were strongly positive for CD68 (Fig

2C) and negative for CD1a, S100,

CD20, CK (Pan CK), and CD34 (Fig 2

C and D).

In view of the possibility of LCH on

cytology, the patient was started on

vinblastine (6 mg/m2 once a week

for 6 weeks) and prednisolone

(40 mg/m2 daily for 6 weeks). This

combination of drugs is safe in

the pediatric population, and the

patient exhibited significant clinical

improvement, so we continued the

same drugs even after confirmation

of MRH on histopathology. Clinical

improvement was evident after 4

to 6 weeks of therapy. Skin lesions

showed relatively early response

as compared with bony lesions. The

patient developed systemic fungal

(Candida) infection after 2 months

and responded well to antifungal

therapy. After 6 weeks, we continued

e2

FIGURE 1A, Large scaly red skin lesion with elevated margins, along with, B, C, sausage-shaped swelling of fi ngers. D, Radiograph of hand shows lytic lesion with sclerotic margin of phalanges.

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PEDIATRICS Volume 137 , number 6 , June 2016

vinblastine (6 mg/m2 every 3 weeks)

and prednisone (40 mg/m2 daily

for 5 days at every 3 weeks) with

target of total duration of 6 months

of therapy. Recent follow-up of the

patient showed resolving skin lesions

with healing of ulcerated margin

(Fig 3A) and reduced joint swelling

(Fig 3B); however, radiology of the

hands revealed persistence of bony

lesions (Fig 3C). No fresh cutaneous

lesion appeared. Splenomegaly,

hepatomegaly, and lymphadenopathy

subsided. Erythrocyte sedimentation

rate became normal and hemoglobin

improved (9.6 g/dL). Liver function

tests, renal function test (RFT), and

other biochemical and hematologic

profiles became normal. The patient

did not develop hematologic or any

other toxicity.

DISCUSSION

MRH is a rare multisystem histiocytic

disorder, typically characterized

by chronic, destructive, disfiguring

polyarthritis and cutaneous nodules.

Exact pathogenesis is unknown;

however, a few theories suggest

inflammatory and others suggest

proliferative disorder.1–3 It usually

affects individuals in the fourth

decade of life and is very rare in

children.2–4 To the best of our

knowledge, ∼13 pediatric cases have

been reported (Table 1), our case

being the youngest of all with the

earliest presentation at the age of

3 months.1, 5, 6 MRH predominately

affects female individuals, both in the

adult and pediatric populations. In

adults, the male-to-female ratio is 1:2

to 3 and in the pediatric population,

12 of 13 reported cases are girls.1, 2, 6–17

Irrespective of age groups, this disease

is more prevalent in white ethnicity.2, 5

MRH manifests with 2 major clinical

features, the first being polyarthritis

and the second being skin lesions.

In adults, symmetric polyarthritis

is the initial symptom in two-thirds

of patients and skin manifestations

appear after an average period of 3

years of arthritis. Cutaneous lesions

as an initial manifestation are present

in 20% of patients and simultaneous

skin and joint lesions present in

the remainder. A similar pattern of

clinical presentation is also noticed in

pediatric MRH.2, 3

Skin lesions are usually in the form

of reddish brown papules and

nodules varying in size from a few

millimeters to several centimeters,

which are usually asymptomatic.

Skin ulceration is unusual in MRH18;

however, our patient had recurrent

ulceration and healing of skin

lesions. Both adult and pediatric

MRH have similar kinds of cutaneous

manifestations with respect to type

and distribution of lesions.

Cervical spondylitis may be a

manifestation in approximately

e3

FIGURE 2Panel of photomicrographs of skin biopsy shows mononuclear and multinucleated histiocytic giant cells extending throughout the dermis (A, hematoxylin-eosin stain, ×100) and their ground glass eosinophilic cytoplasm (B, hematoxylin-eosin stain, × 200). Immunohistochemistry highlights strong positivity for CD68 (C, ×200) and negativity for CD1a (D) in mononuclear and multinucleated giant cells.

FIGURE 3Panel of photographs demonstrating response to vinblastine and steroid. A, Skin lesions are resolving with healed ulcerated margins. B, Joint swelling is reduced. C, Radiology of hands revealed persistence of lytic bony lesions.

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JHA et al e4

TABL

E 1

Su

mm

ary

of 1

3 C

hild

hoo

d M

RH

Rep

orte

d in

Lit

erat

ure

SN

Ref

eren

ceAg

e/

Gen

der

Init

ial L

esio

ns

and

Pre

sen

tati

onC

uta

neo

us

Lesi

onB

ony

Lesi

ons

and

Joi

nt

Lesi

ons

Asso

ciat

ed

Dis

ease

s

Trea

tmen

t

1.M

elto

n a

nd

Irb

y

(197

2)7

16 y

/FAr

thri

tis

Per

iun

gual

red

dis

h b

row

n p

apu

les

Met

acar

pop

hal

ange

al jo

ints

,

wri

sts,

elb

ows,

sh

ould

ers,

knee

, an

d a

nkl

es

Non

eN

one;

Sel

f-lim

itin

g

2.S

togm

an e

t al

(197

5)8

10 y

/F—

Nod

ula

r le

sion

s m

ain

ly p

eriu

ngu

al in

volv

ing

seco

nd

to

fou

rth

fi n

gers

of

bot

h h

and

s

Eros

ive

arth

riti

s in

volv

ing

DIP

and

PIP

join

ts, b

ilate

ral k

nee

swel

ling

and

eff

usi

on

Non

e—

3.M

ign

one

et a

l

(197

9)9

7 y/

FAr

thri

tis,

fev

er, r

ash

Ras

h o

n e

xten

sor

asp

ect

of f

orea

rm a

nd

han

ds

Acu

te in

fl am

mat

ion

of

PIP

an

d

DIP

join

ts

Non

eAs

pir

in

4.S

cute

llari

et

al

(198

6)10

18 y

/FAr

thri

tis

Mu

ltip

le n

odu

les

on h

and

s, e

ar, f

oreh

ead

,

scal

p, a

nd

nas

al r

im

Eros

ive

arth

riti

s of

th

e P

IP a

nd

DIP

join

ts

Non

eN

one

5.O

md

al e

t al

(198

8)11

9 y/

FS

kin

lesi

on w

ith

itch

ing

at fi

nge

r ti

ps

Mu

ltip

le p

apu

les

and

nod

ule

s on

fi n

ger

tip

s

and

fro

nt

of t

hig

h

Arth

riti

s of

DIP

, PIP

, wri

st, k

nee

,

elb

ow, a

nd

an

kles

Non

eS

elf-

limit

ing

6.R

aph

ael e

t al

(198

9)12

14 y

/FAr

thri

tis

and

cu

tan

eou

s n

odu

les

Mu

ltip

le p

eriu

ngu

al v

erru

cou

s n

odu

les

and

dee

per

nod

ule

s al

ong

ten

don

sh

eath

Elb

ows,

wri

sts,

kn

ees,

an

d D

IP

wit

h jo

int

effu

sion

, no

eros

ion

seen

Non

eAs

pir

in

7.Ku

ram

oto

et a

l

(198

9)13

16 y

/MAg

e 6:

mu

ltip

le c

uta

neo

us

nod

ule

s

on f

ace

and

tru

nk

that

res

olve

d

spon

tan

eou

sly

Age

6: fl

esh

y p

apu

les

at a

ge 6

Non

eAt

age

16

dev

elop

ed

lym

ph

oma

Pre

dn

isol

one

and

cycl

osp

orin

e w

ith

no

resp

onse

; lat

er,

chem

oth

erap

y fo

r

lym

ph

oma

Kura

mot

o et

al

(199

1)14

Age

13: i

nd

ura

tion

an

d u

lcer

atio

n o

f

left

leg

Age

13: b

and

like

scle

rosi

s ex

ten

din

g fr

om

knee

to

ankl

e

8.Fr

ied

man

an

d

Kalis

her

(19

98)15

6 y/

FM

ult

iple

pal

mar

nod

ule

s an

d s

wel

ling

of

han

ds,

kn

ees,

an

d r

igh

t an

kle

Mu

ltip

le r

edd

ish

bro

wn

pap

ule

sS

ynov

itis

of

left

wri

sts,

bot

h

knee

s, a

nd

join

ts o

f h

and

s

Non

eN

ot m

enti

oned

9.C

and

ell C

hal

om e

t

al (

1998

)16

6 y/

FJo

int

swel

ling

and

fat

igu

eP

eriu

ngu

al p

apu

les

and

nod

ule

s an

d m

ult

iple

pal

mar

nod

ule

s

Syn

ovit

is o

f m

ult

iple

join

ts: l

eft

wri

st, b

ilate

ral k

nee

s an

d

han

d jo

ints

ANA

1:64

0;

Sp

eckl

ed

pat

tern

Par

tial

res

pon

se t

o

met

hot

rexa

te a

nd

pre

dn

ison

e

10.

Hav

ill e

t al

(19

99)17

12 y

/FAg

e 7.

5: p

ain

ful s

wel

ling

of t

he

bila

tera

l

knee

, an

kles

, wri

sts,

an

d fi

nge

rs

Age

8: m

ult

iple

pap

ula

r le

sion

s on

lip

, bu

ccal

mu

cosa

, an

d p

roxi

mal

nai

l fol

ds

Eros

ion

of

the

left

fou

rth

an

d

fi ft

h, r

igh

t se

con

d a

nd

th

ird

DIP

, eff

usi

on o

f b

oth

kn

ees

Non

eR

esp

ond

ed t

o n

apro

xen

11.

Mat

iz e

t al

(20

09)6

3 y/

FP

apu

lar

skin

lesi

ons

and

art

hra

lgia

Pin

k fl

at-t

opp

ed p

apu

lar

skin

lesi

ons

on t

he

fi n

ger

nai

l mar

gin

s of

han

ds,

sca

lp, a

nd

arou

nd

th

e n

ares

Arth

ralg

ias

of w

rist

s an

d

knee

s, o

steo

pen

ia, m

ult

iple

join

t ef

fusi

ons,

an

d s

ynov

ial

thic

ken

ing

Non

eN

apro

xen

, met

hot

rexa

te,

pre

dn

ison

e, e

tan

erce

pt,

infl

ixim

ab

12.

Ols

on e

t al

(20

15)1

2 y/

FAt

2 y

: cu

tan

eou

s p

apu

lar

lesi

ons

on t

he

thig

hs,

elb

ows,

an

d k

nee

sM

ult

iple

pin

k, p

apu

lar

lesi

ons

on e

lbow

an

d

knee

s, a

nd

late

r al

so d

evel

oped

on

nos

e,

fore

hea

d, e

ars,

dor

sal h

and

s, fi

nge

rs, a

nd

knu

ckle

s

Pol

yart

hri

tis

of t

he

cerv

ical

spin

e, b

ilate

ral w

rist

s, r

igh

t

ind

ex fi

nge

r, b

ilate

ral k

nee

s,

ankl

es a

nd

su

bta

lar

join

ts,

righ

t to

e b

ony

enla

rgem

ent

Non

eN

apro

xen

, met

hot

rexa

te,

tum

or n

ecro

sis

fact

or

inh

ibit

ors,

infl

ixim

ab t

o

wh

ich

goo

d r

esp

onse

was

seen

At 5

y: m

igra

tin

g jo

int

pai

n w

ith

sw

ellin

g

13.

Pre

sen

t ca

se3

mo/

FP

apu

lon

odu

lar

cuta

neo

us

lesi

ons

in

nec

k an

d s

hou

lder

reg

ion

Sp

read

ing

cuta

neo

us

lesi

on t

hat

ulc

erat

es,

hea

ls, a

nd

new

cro

p o

f fl

esh

y n

odu

les

app

ear

Pai

nfu

l sw

ellin

g of

mu

ltip

le

bila

tera

l han

d jo

ints

an

d

bila

tera

l met

atar

sop

hal

ange

al

join

ts

Non

eIn

itia

lly c

uta

neo

us

lesi

ons

resp

ond

ed

wel

l to

pre

dn

ison

e an

d

vin

bla

stin

e fo

r 2

mo;

aft

er

that

pat

ien

t d

evel

oped

recu

rren

ce o

f cu

tan

eou

s

lesi

ons

ANA,

an

tin

ucl

ear

anti

bod

y; D

IP, d

ista

l in

terp

hal

ange

al jo

int;

F, g

irl;

M, b

oy; S

N, s

eria

l nu

mb

er; —

, no

info

rmat

ion

ava

ilab

le in

res

pec

tive

stu

dy.

by guest on April 16, 2018http://pediatrics.aappublications.org/Downloaded from

PEDIATRICS Volume 137 , number 6 , June 2016

half of adult MRH cases; however,

in childhood MRH, only 1 case with

cervical joint involvement has been

reported.3 Only 2 pediatric cases

of MRH had involvement of foot

joints, including present case (Table

1). Many of the adult MRH cases

show association with autoimmune

disorders, 3–5, 7 tuberculosis, and

various malignancies (breast,

cervix, stomach, hematologic

malignancies, melanoma, lung and

colonic carcinoma).3, 4, 18 In contrast

to adult MRH, childhood MRH cases

usually do not show association

with autoimmune disorder and

malignancy; however, 1 case of

lymphoma and 1 case of autoimmune

disorder have been reported in

pediatric MRH.14, 16

Regarding involvement of other organs,

adult MRH may involve myocardium,

pericardium, and pleura. There are a

few case reports suggesting association

of MRH with trigeminal neuropathy,

central retinal vein thrombosis, and

fracture of femoral neck. Systemic

involvement has not been reported in

childhood MRH.2, 3

There is lack of a sufficient number

of MRH cases for clinical trial, so

there is no standardized treatment

protocol.1, 3 MRH has a variable

disease course. Some of the

patients have self-limiting disease,

and others have unpredictable

relapses and remissions or

progressive disease with joint

deformity. Nonsteroidal anti-

inflammatory drugs, corticosteroids,

cyclophosphamide, azathioprine,

methotrexate, chlorambucil, and

leflunomide have been used with

variable responses.3, 4, 19 Some recent

studies have demonstrated good

response with anti–tumor necrosis

factor-α (etanercept, infliximab),

anti–interleukin-1 (anakinra)

and interleukin-6 antagonists

(tocilizumab) both in adult and

pediatric cases.1, 20 Considering the

possibility of LCH on fine needle

aspiration cytology, we prescribed

vinblastine and prednisolone to our

patient and she responded well to

this regimen with significant clinical

improvement. In view of good

response and safety of these drugs

in childhood, we put the patient on

the same drugs. The organomegaly

resolved and most of the biochemical

and hematologic parameters became

near normal until recent follow-up. In

the present case, good response with

vinblastine and prednisone signifies

their role in treatment of childhood

MRH. This observation may help in

understanding of pathogenesis of

MRH; however, studies with large

sample sizes are required.

CONCLUSIONS

Childhood MRH is extremely rare,

although it should be considered

in patients presenting with erosive

arthritis and mucocutaneous

lesions. A high degree of clinical

suspicion, meticulous clinical

examination, radiologic correlation,

and histopathological examination

are essential to confirm the diagnosis

of MRH. Treatment with vinblastine

and steroid (prednisone) may be an

effective and safe alternative for the

treatment of childhood MRH.

e5

ABBREVIATIONS

LCH:  Langerhans cell

histiocytosis

MRH:  multicentric

reticulohistiocytosis

PIP:  proximal interphalangeal

joints

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.

REFERENCES

1. Olson J, Mann JA, White K, Cartwright

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DOI: 10.1542/peds.2015-2118 originally published online May 19, 2016; 2016;137;Pediatrics 

Kumar, Mohan Kumar and Rajniti PrasadVijay Kumar Jha, Ravindra Kumar, Abhijeet Kunwar, Ankur Singh, Mahendra

Onset in InfancyEfficacy of Vinblastine and Prednisone in Multicentric Reticulohistiocytosis With

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Kumar, Mohan Kumar and Rajniti PrasadVijay Kumar Jha, Ravindra Kumar, Abhijeet Kunwar, Ankur Singh, Mahendra

Onset in InfancyEfficacy of Vinblastine and Prednisone in Multicentric Reticulohistiocytosis With

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