DOI: 10.1111/cup.

13807

COVER QUIZLET

Susan Pei, Andrew S. Fischer, Heather Milbar, Brian C. Capell, Rosalie Elenitsas, Adam I. Rubin
Figures 1 and 2 are depicted on the journal cover.

FIGURE 3. FIGURE 4.

FIGURE 5. FIGURE 6.

FIGURE 3

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J Cutan Pathol. 2020;1–4. wileyonlinelibrary.com/journal/cup © 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd 1
2 PEI ET AL.
Perforating and granulomatous exogenous ochronosis
Susan Pei MD1 | Andrew S. Fischer MD1
Brian C. Capell MD, PhD1 | Rosalie Elenitsas1
1
Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
2
Section of Pediatric Dermatology, Children’s Hospital of Philadelphia, Philadelphia, PA
3
Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
Correspondence
Adam I. Rubin, MD, Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Email: adam.rubin@pennmedicine.upenn.edu
K E Y W O R D S : ochronosis, exogenous, exogenous ochronosis, perforating, granulomatous
1 | I N T RO DU CT I O N
Exogenous ochronosis (EO) is a cutaneous disorder induced by cosmetic
application of skin lightening agents, most commonly hydroquinone.1
The pathogenesis is secondary to inhibition of local activity of
homogentisic acid oxidase by hydroquinone, leading to accumulation of
homogentisic acid that polymerizes to form ochronotic pigment in the
skin. Clinically, EO presents as bluish-gray, hyperpigmented macules or
papules over bony prominences, especially the face, neck, back and
extensor surfaces. The clinical severity of EO is classified into three
stages. Stage I presents as erythema and mild pigmentation of the face
and neck. Stage II presents with progression to hyperpigmentation,
black colloid milia, and atrophy with appearance of “caviar-like” papules.
Stage III includes papulonodules with or without surrounding inflamma-
tion. Biopsy of EO shows yellow-brown, curvilinear “banana-shaped”
ochronotic fibers in the dermis. With increasing clinical severity, histo-
pathology may also show formation of colloid milium and a mixed
inflammatory infiltrate including plasma cells, histiocytes and multi-
nucleate giant cells. Granulomatous ochronosis is rare, with only
16 cases reported since 1979.2 Perforating EO is even more infrequent
and, although it has been reported previously, only two cases provided
3
detailed description. Here we present a case of strikingly severe EO
exhibiting the rare features of both granulomatous inflammation and
perforation of the ochronotic collagen fibers.
2 | CASE REPORT
A 60-year-old female presented for a facial rash with swelling and
pruritus. She attempted self-treatment of the rash with 90-proof alco-
hol, exacerbating the rash. She reported possible contact of her face
with cleaning sprays from her workplace. She denied exposures to
any new facial products or intake of new medications. Her physical
exam demonstrated erythematous and bluish-gray hyperpigmented
patches with superimposed grouped, yellow, crusted papules
scattered on her face (Figure 1A,B). Several scaly papules were dome
| Heather Milbar MD, MPH1 |
| Adam I. Rubin MD1,2,3
shaped and demonstrated small, crateriform central crust (Figure 1C).
She also had periorbital edema. Her initial diagnosis was favored to be
irritant contact dermatitis with associated secondary bacterial superin-
fection. She was treated for bacterial superinfection with doxycycline,
and a topical steroid for irritant contact dermatitis. On follow up ten
days later, she had persistent erythematous and hyperpigmented pat-
ches, with superimposed yellow, crusted papules and new pustules on
the face, though her facial edema improved. Therefore, a punch
biopsy of a crusted papule was performed.
The biopsy demonstrated epidermal hyperplasia with areas of
prominent pseudoepitheliomatous hyperplasia (PEH) (Figure 2). A
broad, tortuous channel was connected to the overlying hyperplastic
epidermis (Figure 3). Within the channel were hyperkeratotic keratin
and yellow-brown, irregularly shaped, fragmented fibers consistent
with ochronotic fibers, which demonstrated perforation through the
epidermis (Figure 4). In the dermis, there were broad areas of
ochronosis with brown, pigmented collagen fibers, some of which
were associated with a granulomatous infiltrate with multinucleate
giant cells, some engulfing ochronotic fibers (Figures 5 and 6). The
deep dermis demonstrated a mild mixed inflammatory infiltrate and
did not contain granulomas away from the ochronotic fibers. Grocott’s
methenamine silver and Fite stains did not show infectious organisms.
Polarization did not show refractile foreign material.
Based on the biopsy findings of ochronosis, further questioning of
the patient revealed that she had been applying an over-the-counter
cream marketed for “lightening and blemish removal” on the packaging
and labelled to contain 0.05% betamethasone diproprionate to her
face for several years. We speculate that the cream may have also
contained hydroquinone, as it is one of the most common skin lighten-
ing agents. However, we also considered the possibility of other caus-
ative agents of EO that can be found in topical preparations, including
resorcinol, phenol, mercury and picric acid.1 Notably, we also consid-
ered the possibility that her workplace cleaning agents may contain
phenols, which upon inappropriate exposure may cause EO. In addi-
tion, the patient did not have a history of quinine use, an antimalarial
reported to cause EO.1
PEI ET AL. 3

A diagnosis of severe (Stage III), perforating and granulomatous

EO was made. As the clinicopathologic differential diagnosis included
sarcoidosis, a workup to evaluate for sarcoidosis was performed,
which include a chest radiograph, angiotensin-converting enzyme
(ACE), c-reactive protein (CRP), erythrocyte sedimentation rate (ESR)
laboratory values, and a referral to ophthalmology. The workup was
negative for sarcoidosis. Based on a case report of tetracycline treat-
ment for sarcoid-like ochronosis secondary to hydroquinone,4 the
patient was restarted on doxycycline 100 mg twice a day for 14 days.
She was also urged to stop using the aforementioned lightening cream
as well as to take precautions to avoid inappropriate exposure to her
cleaning agents at work. Subsequently, the patient reported that the
papules on her face resolved and her facial hyperpigmentation dimin-
ished, and she declined further treatment or follow up.
3 | DISCUSSION
F I G U R E 3 A broad, tortuous channel connected to the overlying
hyperplastic epidermis (H&E, 60×)
F I G U R E 4 Hyperkeratotic keratin and yellow-brown, irregularly
shaped, fragmented fibers consistent with ochronotic fibers
demonstrating perforation through the epidermis (H&E, 150×)
F I G U R E 5 Ochronotic fibers associated with a granulomatous
infiltrate with many multinucleated giant cells, some engulfing
ochronotic fibers (H&E, 260×)
F I G U R E 6 Higher power view of brown, pigmented ochronotic
fibers (H&E, 400×)
rim, and a central hypopigmented area. The ochronotic zone showed
yellow-brown, thickened ochronotic collagen bundles. The elevated
rim demonstrated a granulomatous infiltrate in the upper and mid der-
mis consisting of macrophages, epithelioid cells, giant calls, lympho-
cytes and well-formed granulomas with occasional small foci of
eosinophilic necrosis. The central zone showed absence of elastosis

Doliotti and Leibowitz reported the first four cases of granulomatous

ochronosis in which the histopathologic findings were of sarcoid-like
granulomas in a focal distribution surrounding ochronotic material in
the dermis.2 Multinucleate giant cells engulfing ochronotic fibers were
a prominent feature. In 3 of the 4 cases, epithelioid cells, histiocytes,
plasma cells, occasional neutrophils, and a few lymphocytes sur-
rounded the sarcoidal granulomas. The authors noted that the granu-
lomatous reaction was an extremely “clean” one, which they
interpreted to indicate a direct response to the abnormal pigmented
brown material. It was not reported whether these patients had
sarcoidosis.
Later reports indicated that granulomatous EO may be a manifes-
tation of sarcoidosis. Jacyk described six black women with annular
granulomatous lesions developing within areas of EO.5 Three of the
patients had proven systemic sarcoidosis. Only 1 patient had skin
lesions outside of the area of EO, but it was not reported whether this
patient had systemic sarcoidosis or cutaneous lesions only. Histopath-
ologic findings from the 3 patients without evidence of systemic sar-
coidosis corresponded to the three morphological zones seen in the F I G U R E 2 Epidermal hyperplasia with areas of prominent
annular lesions clinically: a surrounding ochronotic zone, an elevated pseudoepitheliomatous hyperplasia (H&E, 15×)

F I G U R E 1 (A, B) Heaped papules with yellow crust on a background of erythema and bluish-grey hyperpigmented patches around the
eyebrows and on upper cutaneous lip. (C) A group of scaly, dome shaped papules demonstrating small, crateriform central crust
4 PEI ET AL.
and ochronotic fibers, vasodilation and mild fibrosis. Moche et al addi-
tionally reported cases of two black women with systemic sarcoidosis
and cutaneous annular sarcoidosis which developed on a background
of EO.6 Biopsy findings from both patients showed sarcoidal granulo-
mas associated with ochronotic fibers. In addition, the histopathologic
features of granulomatous EO share similarities with those seen in
actinic granuloma (AG). AG-like change in EO has been reported in a
patient who presented with annular lesions on a background of severe
EO.7 Of note, in AG, elastophagocytosis is a prominent feature, which
is absent in actinic granuloma-like EO. In contrast, in granulomatous
EO, phagocytosis of ochronotic fibers is seen.
Interestingly, comparison of the histopathologic findings of the
annular EO lesions in patients with and without systemic sarcoidosis
showed only minor differences.5 In patients with systemic sarcoidosis,
the zonal pattern on histopathology was less defined. There was more
extensive granuloma formation, which may extend into the area
corresponding to the clinically atrophic center. Finally, eosinophilic
necrosis within granulomas was more pronounced. However, there
was no difference in either the composition of the granulomatous
infiltrate or the degree of ochrophagocytosis. Both Jacyk and Moche
et al raised the question of whether the granulomatous findings in EO
arise solely in response to the altered ochronotic fibers or are associ-
ated with another pathologic process such as sarcoidosis, given the
role of foreign bodies in cutaneous sarcoidosis.5,6,8 Importantly, these
cases demonstrate that sarcoidal granulomas developing on a back-
ground of EO could be a presentation of sarcoidosis, therefore full
systemic evaluation for systemic sarcoidosis should be performed.
Our patient’s biopsy also demonstrated the rarely reported histo-
pathologic feature of perforation (or transepidermal elimination) of
ochronotic fibers, initially reported but not fully described in two of
48 biopsies of EO.9 Later, Jordaan and Niekerk described in more
detail the histopathology of perforation of ochronotic fibers in two
black patients with severe papular ochronosis.3 The first patient had
well circumscribed, slightly scaly papules showing mild central depres-
sion. The second patient demonstrated papules without epidermal
change. Histopathology in both cases showed transfollicular elimina-
tion of ochronotic fibers. In addition, the first patient’s biopsy showed
gross epidermal hyperplasia together with a lichenoid infiltrate with
focal vacuolar alteration, and ochronotic fibers inserting within adja-
cent keratinocytes in the epidermis. Transepidermal elimination of
ochronotic material was also noted but not described in detail in a
series of 6 patients.5 Notably, our case contributes to the literature
excellent clinicopathologic correlation of perforating ochronosis. Our
patient presented clinically with multiple scaly papules showing
central crateriform crust, which directly correlates to the PEH and tor-
tuous epidermal channel containing perforating ochronotic fibers seen
on histopathology.
EO has been reported to develop gradually over 6 months to
3 years or longer from use of topical cosmetic lightening agents such
as hydroquinone.10 It typically occurs in a symmetric distribution over
osseous surfaces such as the zygomatic regions. As mentioned above,
the clinical severity of EO is classified into three stages. In Stage I,
there is erythema and mild hyperpigmentation which may be indistin-
guishable from melasma. In Stage II, there is progressive hyper-
pigmentation with pigmented colloid milium and atrophy. In Stage III,
papulonodular lesions develops. Histopathologic findings are corre-
lated with increasing clinical severity, showing formation of colloid
milium and a mixed inflammatory infiltrate including plasma cells, his-
tiocytes and multinucleate giant cells as EO progresses.1
In sum, we present a case of severe EO highlighting the rare his-
topathologic findings of granulomatous inflammation and perforation
of ochronotic fibers. The combination of these two striking histopath-
ologic findings is unusual. Clinicopathologic correlation shows how
the pathologic features of granulomatous inflammation and perfora-
tion of ochronotic fibers associated with PEH manifest in the skin.
Dermatologists and dermatopathologists should be aware of the
sarcoidal-like granulomas that can be seen in EO, as it is important to
alert the submitting clinician to the association of systemic sarcoidosis
with granulomatous EO.
OR CID
Susan Pei https://orcid.org/0000-0001-9267-9484
Andrew S. Fischer https://orcid.org/0000-0003-0996-0553
Adam I. Rubin https://orcid.org/0000-0002-9273-1817
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How to cite this article: Pei S, Fischer AS, Milbar H, Capell BC,
Elenitsas R, Rubin AI. Perforating and granulomatous
exogenous ochronosis. J Cutan Pathol. 2020;1–4. https://doi.
org/10.1111/cup.13807