Resident Short Reviews
Angiolymphoid Hyperplasia With Eosinophilia
Ruifeng Guo, MD, PhD; Alde Carlo P. Gavino, MD
 Angiolymphoid hyperplasia with eosinophilia (ALHE),
also named epithelioid hemangioma (EH), is an inflamed
vascular tumefaction of uncertain pathogenesis, charac-
terized by proliferation of histiocytoid endothelial cells
with prominent lymphocytic and eosinophilic infiltration.
Although considered a benign condition, it may recur in up
to one-third of cases in the absence of complete surgical
excision. The pathogenesis of ALHE/EH is still controver-
sial. However, reaction to trauma and arteriovenous
shunting are considered relevant. Histologically, ALHE/
EH may be differentiated from other vascular neoplasms by
its several unique characteristics including prominent
proliferation of plump endothelial cells, and accompanying
eosinophilic and lymphocytic inflammation, often with
formation of lymphoid follicles. Surgery is the mainstay of
treatment and various other treatment strategies have been
used with varying results.
(Arch Pathol Lab Med. 2015;139:683–686; doi: 10.5858/
arpa.2013-0334-RS)
T he term angiolymphoid hyperplasia with eosinophilia
(ALHE) was coined by Wells and Whimster1 in 1969
to describe a distinct neoplasm characterized by a florid
proliferation of blood vessels lined by plump endothelial
cells and admixed with a dense inflammatory infiltrate of
lymphocytes, eosinophils, and mast cells. They presented 9
cases found in asymptomatic young adults, 7 of whom had
blood eosinophilia. All cases involved the head and neck
region and were located primarily in the subcutis. The
lesions were solitary or multiple, and ranged in size from 1
to 10 cm in diameter. Although recurrence after excision was
observed in some, all cases followed a benign course.
Owing to the uncertainty regarding the nature of this
entity, the term epithelioid hemangioma (EH) was introduced
by Weiss and Enzinger2 in 1982, as they believed the lesion
was neoplastic and wanted to clearly separate the lesion
from the malignant vascular tumor, epithelioid hemangio-
endothelioma. Although other names have been given to
ALHE/EH, such as histiocytoid hemangioma, angiomatous
nodule, pseudopyogenic granuloma, and inflammatory
Accepted for publication March 24, 2014.
From the Department of Pathology, University of Oklahoma
Health Sciences Center, Oklahoma City (Dr Guo); and the
Department of Dermatology, University of Texas Southwestern-
Austin, Austin (Dr Gavino).
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Alde Carlo P. Gavino, MD, Department of Dermatology,
University of Texas Southwestern-Austin, 601 E 15th St, CEC 2.443,
Austin, Texas 78701 (e-mail: apgavino@seton.org).
Arch Pathol Lab Med—Vol 139, May 2015
angiomatous nodule,3,4 angiolymphoid hyperplasia with eo-
sinophilia and epithelioid hemangioma remain the current
unanimously accepted terms for this entity.
Since 1969, numerous case reports and small series of
ALHE/EH have appeared in the literature. The 2 largest
series comprising 212 cases represent comprehensive
analyses of the tumor’s clinical and histopathologic fea-
tures.3,4 We review herein what we currently know of the
clinicopathologic features, differential diagnosis, and treat-
ment of ALHE/EH, as they pertain to the practice of
pathology.
CLINICAL FEATURES
Angiolymphoid hyperplasia with eosinophilia/EH most
commonly presents in young to middle-aged adults as single
or multiple, nondescript, flesh- to plum-colored papules or
nodules, ranging in size from a few to several centimeters.1,3,4
This entity is a dermal and/or subcutaneous process.
Although the head and neck region is most commonly
involved, the trunk, extremities, hands, penis, oral mucosa,
and colon may rarely be affected.1,3–7 There appears to be a
predilection for women, although some have reported a male
preponderance.1,3,4 However, the male sex bias in 2 of the
studies from the former Armed Forces Institute of Patholo-
gy2,3 is attributable to the large number of cases from military
and Veterans Health Administration hospitals, where the
patient population is predominantly male. Indeed, Olsen and
Helwig3 found that 62% of the civilian cases in their study
involved females. The length of time from onset of lesions to
initial medical consultation has ranged from a few months to
many years. There are usually no associated symptoms.
However, owing mainly to the vascular nature of the lesions,
tenderness, pulsation, pruritus, or bleeding, either spontane-
ously or after minor trauma, may occur in some patients.1,3,4
Peripheral blood eosinophilia and regional lymphadenopathy
may also be present.1,3,4
PATHOGENESIS
The etiology of ALHE/EH is currently unknown. Various
hypotheses have been put forth, including a reactive
process,3,4,8,9 a neoplastic process,7,10,11 and infectious
mechanisms with possible association with human immu-
nodeficiency virus12; however, none have proven to be
conclusive or definitive.
The characteristic inflammatory infiltrate in ALHE/EH
appears to be a key component of this disease; however,
its role in the etiology of ALHE/EH needs further
clarification. Response of the endothelial cells to prolif-
erative stimuli generated by the accompanying inflam-
matory cells and immunologic allergic reaction may
Angiolymphoid Hyperplasia With Eosinophilia—Guo & Gavino 683

Figure 1. Proliferation of blood vessels, lymphoid follicles, and
abundant eosinophils set in a fibrous stroma (hematoxylin-eosin,
original magnification 34).
Figure 2. a, Proliferation of vessels lined by ‘‘hobnailed’’ plump
endothelial cells. b, Pseudolumen formation secondary to discrete
endothelial cytoplasmic vacuoles (hematoxylin-eosin, original magnifi-
cation 320 [a and b]).
account for the vascular proliferation.3,9 Arteriovenous
shunting,3,8 local trauma,4,9 and elevated serum estrogen
levels3,13 are probably important contributing factors in
ALHE/EH as well.
684 Arch Pathol Lab Med—Vol 139, May 2015
Interestingly, a case of dermal ALHE/EH was found to
harbor a mutation in the TEK gene, which encodes the
endothelial cell tyrosine kinase receptor Tie-2, indicating
that certain molecular alterations might be contributory to
the pathogenesis of this entity.14 A larger-scale study will be
necessary to further elucidate the molecular pathomecha-
nisms underlying ALHE/EH.
Although considered a benign tumefaction, ALHE/HE has
been associated with various lymphoproliferative condi-
tions, supporting the contention made by some that ALHE/
EH, in some cases, may represent a monoclonal T-cell
process.10,11 A few cases of ALHE/EH were found to have
concurrent follicular mucinosis.15 However, this association
is rather nonspecific, and a definitive association between
ALHE/EH and mycosis fungoides has yet to be reported.
Interestingly, peripheral T-cell lymphoma has been reported
to develop in a patient with ALHE/EH.16 There are also
cases of ALHE/EH in which T-cell receptor gene (TCR)
rearrangement and monoclonality have been detected.10,11
For example, in 1 of the aforementioned case reports, the
patient had both peripheral T-cell lymphoma (axillary node)
and ALHE/HE (temporal nodule), and the same monoclonal
TCR gene rearrangement was detected in both lesions.11
HISTOPATHOLOGY
Central to the histology of ALHE/EH is the proliferation of
blood vessels of varying sizes lined by plump endothelial
cells.1,3,4 These histiocytoid endothelial cells are enlarged,
with abundant eosinophilic or clear cytoplasm and large
vesicular nuclei (Figure 1). The cells are mostly cuboidal
with occasional ‘‘hobnailing’’ (Figure 2, a), which is related
to the presence of cytoplasmic vacuoles in these cells,
causing cytoplasmic protrusion into lumina (Figure 2, b).
The endothelial and inflammatory cells in ALHE/EH are
typically bland. Mitoses are rare, if at all present. A case that
contained multinucleated giant cells has been reported but
the significance of this finding is not known.17
Inflammation is the second defining characteristic of
ALHE/EH.1,3,4 Lymphocytes and varying amounts of eosin-
ophils diffusely surround and may infiltrate the blood
vessels (Figures 1 and 2). The lymphocytes may be diffusely
present or may form distinct follicles with germinal centers.
It should be noted that approximately 20% of the patients
have blood eosinophilia without elevation of immunoglob-
ulin E (IgE) levels.3 An accompanying fibrous stromal
reaction is generally present.
Depending on the age of the lesion, the vascular or
inflammatory component may predominate. In early or
actively growing ALHE/EH, the vascular component pre-
dominates, whereas in late stages of the disease lympho-
cytes become more prominent. The vessels in early ALHE/
EH are immature with prominent epithelioid endothelial
cells, whereas in the later stage when the lymphoid infiltrate
predominates, the endothelial cells lining the maturing
vessels become smaller and less epithelioid.3,4
Angiolymphoid hyperplasia with eosinophilia/EH is typ-
ically an intradermal or subcutaneous process, with primary
or secondary involvement of the latter being more
common.1,3,4 Peculiar to the subcutaneous form of ALHE/
EH is the florid proliferation of large epithelioid endothelial
cells that may become so exuberant as to form solid
intraluminal nodules or clusters. Thus, subcutaneous ALHE/
EH may be treacherous and challenging to diagnose in that
these masses may obscure the vascular nature of the lesion.
Angiolymphoid Hyperplasia With Eosinophilia—Guo & Gavino
By contrast, dermal ALHE/EH tends to be less circum-
scribed, smaller, and composed of more mature open
vessels lined by smaller, less epithelioid endothelial cells.1,3,4
DIFFERENTIAL DIAGNOSIS
The histologic features of ALHE/EH are relatively distinct.
The major differential diagnosis lies between ALHE/EH and
Kimura disease. In the past, ALHE/EH and Kimura disease
were thought to be the same entity. It has been found,
however, that ALHE/EH is actually clinically and patholog-
ically distinct from Kimura disease. The typical presentation
of Kimura disease is that of a large subcutaneous mass in the
periauricular or submandibular region of a young Asian
male.18 Moreover, Kimura disease is a systemic immune-
mediated process that commonly presents with lymphade-
nopathy, eosinophilia, increased serum levels of IgE, and
may be associated with renal disease.19 Histologically, florid
lymphoid follicles with germinal center formation, eosino-
philic infiltrates, eosinophilic microabscesses, and eosino-
philic folliculolysis are salient features of Kimura disease. In
addition, the process does not have the histiocytoid/
epithelioid cells that are characteristic of ALHE/EH.18,20
Angiolymphoid hyperplasia with eosinophilia/EH must
also be differentiated from angiosarcoma, particularly the
latter’s epithelioid variant, and from epithelioid hemangio-
endothelioma. Angiosarcoma is distinguished from ALHE/
EH by its unmistakable atypical appearance with nuclear
hyperchromasia, pleomorphism and brisk mitotic activity,
and the prominent formation of anastomosing vascular
channels.3,21 Epithelioid hemangioendothelioma, on the
other hand, is differentiated from ALHE/EH by the presence
of vacuolated endothelial cells growing singly or in linear
streaks or cords separated by a myxohyaline stroma, and
lack of lymphoid or eosinophilic inflammatory infiltra-
tion.1,3,4
Clinically, the nodule of ALHE/EH can be very similar to
that of Kaposi sarcoma and pyogenic granuloma. However,
the distinctions of histopathologic features among the above
entities are usually dramatic. Kaposi sarcoma is composed of
fusiform cells and slitlike vascular spaces that stain positively
with human herpes virus-8 (HHV-8).3,22 Pyogenic granulo-
ma consists of tight aggregates of capillary-sized vessels that
grow in a lobulated fashion in a fibromyxoid (granulation
tissue–like) stroma.3,4,22,23
TREATMENT AND PROGNOSIS
Surgical excision is the treatment of choice and when
completely excised, ALHE/EH rarely recurs.3,4,22,24 One-third
of cases that are incompletely excised do recur, either at the
same site or distant from it, but still typically along the
course of the affected vessel.3,4,24 Other types of procedures,
such as Mohs micrographic surgery,25 pulsed-dye laser,26
carbon dioxide laser,27 and cryosurgery,28 have been applied
and reported. Medical treatment of ALHE/EH with conven-
tional intralesional corticosteroids and irradiation is gener-
ally not very effective.29,30 New regimens have been
extensively investigated and have shown promising results,
including topical imiquimod, tacrolimus, isotretinoin, and
interferon a-2a.31–34
Concerning the prognosis of ALHE/EH, it tends to persist
for years without regressing spontaneously except for
occasional cases, which makes surgical or medical interven-
tion necessary in most cases.3,4,24
Arch Pathol Lab Med—Vol 139, May 2015
CONCLUSION
Angiolymphoid hyperplasia with eosinophilia/EH is an
uncommon idiopathic lesion characterized by proliferation
of histiocytoid endothelial cells with lymphoid and eosin-
ophilic inflammatory infiltration. Histologically, it shows
some overlapping features with several other types of
dermatologic vascular lesions, especially Kimura disease,
and the pathologic differential diagnosis for this condition is
important. Clinically, ALHE/EH follows a benign clinical
course, with no metastases reported thus far, and with only
one-third of cases recurring when incompletely excised.
Multiple other treatments have been applied for ALHE/EH
with undetermined effects.
We would like to sincerely thank Elizebeth Gillies, MD, for
providing the sample case we used, and for helping with the critical
revision of this manuscript.
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Angiolymphoid Hyperplasia With Eosinophilia—Guo & Gavino
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