ORIGINAL ARTICLE

Metastasizing Benign Cutaneous Fibrous Histiocytoma

A Clinicopathologic Analysis of 16 Cases
Leona A. Doyle, MD and Christopher D.M. Fletcher, MD, FRCPath

Abstract: Cutaneous brous histiocytoma (FH) is considered a

benign tumor; however, certain types of FH have been shown to
have a tendency for local recurrence, and there are rare reported
cases of metastasis. In this study, 16 cases of morphologically
benign FH with locoregional or distant metastasis were identied in consult les. Pathologic features of primary, recurrent,
and metastatic tumors, as well as clinical outcome, were evaluated. Nine were male and 7 were female patients; mean age was
42 years (range, 3 to 68 y). Primary tumors arose on the leg in 5
patients, buttock in 1, trunk in 3, shoulder in 3, neck in 2, and
nger in 1. The primary site in 1 case was unknown. Fifteen
primary tumors available for review involved the dermis; 6 extended into the supercial subcutis. Tumor size ranged from 1 to
5 cm (median 3.2 cm). Histologically, primary tumors showed
characteristic features of FH, being composed in most cases of a
polymorphous population of bland spindle and histiocytoid cells
in a mixed storiform and fascicular growth pattern with admixed foam cells, multinucleate cells, and inammatory cells
in varying proportions. Histologic variants included 11 cellular
(2 with mixed atypical and cellular features), 2 aneurysmal, 1
atypical, and 1 epithelioid type. All tumors showed entrapment
of hyalinized collagen bundles. Mitotic activity ranged from <1
to 13/10 HPF. Focal necrosis was seen in 1 primary tumor. Ten
patients had local tumor recurrence; 4 patients had multiple
local recurrences. Time to rst recurrence ranged from 6 weeks
to 13 years. The local recurrences of 1 tumor showed increased
cytologic atypia, but recurrences were otherwise morphologically similar to primary tumors. Metastases occurred 0 to 180
months after diagnosis (median 17 mo) and involved the lungs
(12 patients), lymph nodes (8), soft tissues (6), and liver (1). Five
patients developed multiple satellite nodules in the region of the
primary tumor. Metastases were morphologically similar to the
primary tumors. So far, 6 patients died of disease, with a median
time to death of 64 months (range, 10 to 168 mo). Four patients
are alive with metastatic disease. Two patients are disease free at
last follow-up, and 1 patient died of unrelated disease. MetaFrom the Department of Pathology, Brigham and Womens Hospital,
Harvard Medical School, Boston, MA.
Presented in part at the 101st Annual United States and Canadian
Academy of Pathology Meeting, Vancouver, BC, March 17 to 23,
2012.
Conicts of Interest and Source of Funding: The authors have disclosed
that they have no signicant relationships with, or nancial interest
in, any commercial companies pertaining to this article.
Correspondence: Christopher D.M. Fletcher, MD, FRCPath, Department of Pathology, Brigham and Womens Hospital, 75 Francis
Street, Boston, MA 02115 (e-mail: cetcher@partners.org).
Copyright r 2013 by Lippincott Williams & Wilkins

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stasis of morphologically benign cutaneous FH is an extremely

rare but clinically aggressive event. Primary tumors tend to be
large and cellular, but aggressive behavior cannot be predicted
on morphologic grounds alone; however, early or frequent local
recurrence may warrant closer clinical follow-up.
Key Words: soft tissue, tumor, metastasis, brous histiocytoma,
dermatobroma, sarcoma
(Am J Surg Pathol 2013;37:484495)

enign brous histiocytoma (FH), also known as dermatobroma, is one of the most common soft tissue
tumors of the skin. Cutaneous FH arises in the reticular
dermis but may quite often extend into the supercial
subcutis and typically occurs on the extremities of young
to middle-aged adults.1 In its classic form, cutaneous FH
is composed of mononuclear spindle-shaped or histiocytoid cells arranged in a storiform pattern, with or without
fascicles, and with entrapped collagen bundles at the edge
of the lesion. The stroma is typically variably collagenous
or hyalinized, and variable numbers of admixed chronic
inammatory cells, multinucleate giant cells, and foamy
histiocytes are usually present.2 The papillary dermis is
often spared, resulting in a grenz zone between the lesion
and the overlying epidermis, which is frequently hyperplastic.3 Several morphologic variants of cutaneous FH are
well established, some of which also have distinctive clinical features, including cellular,4 aneurysmal,5,6 atypical,7
clear cell,8 lipidized,9 and epithelioid10,11 types. Although
generally considered a benign tumor, the cellular, aneurysmal, and atypical variants of cutaneous FH have a signicant tendency for local recurrence, with a recurrence
rate of approximately 20% for each of these variants.47
Furthermore, extremely rarely, cutaneous FH can give rise
to metastatic disease. At least 16 well-documented cases of
cutaneous FH with metastasis have been described in the
literature over the last 22 years, mostly as single-case reports. This highly unusual event in cutaneous FH is much
rarer than metastasis of deep brous histiocytoma,
which is a variant of FH that occurs exclusively in deep
soft tissues and has a distinctive morphologic appearance
and a small but signicant risk of metastasis, occurring in
5% in a study of 69 cases.12
The aim of this study was to investigate this unusual
and rare occurrence by studying the clinical and pathologic features of a series of patients with morphologically
benign cutaneous FH that developed metastases.
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MATERIALS AND METHODS

Sixteen cases of morphologically benign cutaneous FH with locoregional or distant metastases were
identied in the consultation les of 1 of the authors
(C.D.M.F.), diagnosed over a 20-year period. Three of
these cases have been reported previously.5,7,13 In each
case hematoxylin and eosin-stained, and in some cases
immunoperoxidase slides, were also available for study.
Diagnostic criteria for FH included the presence of a
predominantly dermal tumor composed of a polymorphous population of mononuclear spindle-shaped or
histiocytoid cells in a fascicular and/or storiform growth
pattern with entrapment of hyaline collagen bundles at
the edges, or features of the histologic variants of FH,
including cellular, aneurysmal, atypical, and epithelioid
types. Morphologic features evaluated in primary, recurrent, and metastatic tumors included cellularity,
pleomorphism, atypia, growth pattern, stromal composition, mitotic rate, necrosis, and vascular invasion. Mitotic rate was expressed as the number of mitoses in 10
consecutive high-power elds (HPF) in the most mitotic
areas (1 HPF area = 0.18 mm2).
All previously performed immunohistochemical
stains were reviewed in each case. The Envision Plus detection system (Dako, Carpinteria, CA) was used for all
antibodies. Immunohistochemical analysis was performed
on unstained slides (4-mm-thick formalin-xed paranembedded tissue sections) using the avidin-biotin-peroxidase technique. The antibodies, clones, dilutions,
pretreatment conditions, and sources were as follows:
CD34 (QBEnd10; 1:400; Dako), SMA (1A4; 1:20,000;
Sigma, St Louis, MO), desmin (D33; 1:500; Dako),
S100 (polyclonal; 1:3000; Dako), and pancytokeratin
(MNF116; 1:700; 10 min protease pretreatment; Dako).
In addition, 5 primary tumors were evaluated for expression of p16INK4a (MTM Laboratories, Westborough,
MA; clone E6H4; 1:2). Appropriate positive and negative
controls were used throughout.
Clinical information was obtained from medical
records and from the referring pathologists, and additional clinical follow-up data were available for 14
patients.

RESULTS
Clinical Findings
The clinical ndings are summarized in Table 1.
There were 9 male and 7 female patients in the study
group. Patient age at the time of presentation ranged
from 3 to 68 years, with a mean age of 42 years. Apart
from 1 pediatric patient, all patients were adults (Z23 y).
Primary tumors arose on the lower leg in 3 patients, thigh
in 2, buttock in 1, trunk (back) in 3, shoulder region in 3,
neck in 2, and nger in 1. The primary site was uncertain
for 1 patient (patient 12), who presented with bilateral
axillary masses and lung nodules. Although originally it
was thought that axilla represented the primary tumor
site, clinically and radiologically the axillary masses were
deep and appeared most consistent with lymph nodes.
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Metastasizing Benign Cutaneous Fibrous Histiocytoma

The patient was lost to follow-up soon after biopsies of

the axillary nodes and lung nodules were performed, and
no clear or detailed information regarding a primary cutaneous lesion was available. All other patients presented
initially with a solitary cutaneous lesion. Three tumors
were described as slow growing. The primary tumors
were relatively large, with a median size of 3.2 cm (range,
1 to 5 cm). All patients underwent excision of the primary
tumors; 1 patient underwent toe amputation. Three patients had an incisional biopsy before excision. In 2 cases,
a history of a prior tumor at the same anatomic site was
obtained after further clinical investigation. For those 2
cases the earlier tumors were not available for review.
Follow-up data were available in 14 cases (median
duration 82 mo; range, 10 to 264 mo). Local recurrence
was frequent; 10 tumors (62.5%) recurred locally. The
time to rst recurrence ranged from 6 weeks to 13 years
(median 20.5 mo). Four patients had multiple local recurrences; 1 patient had 2 recurrences, 2 had 3 recurrences, and 1 had 7 recurrences. All 4 tumors that
recurred multiple times were the cellular variant.
All 16 patients developed metastatic disease. Metastases were rst detected 0 to 180 months after the primary diagnosis (median 17 mo). One patient (patient 12)
had metastatic disease detected at the time of initial presentation. The most common metastatic site was lung
(n = 12), followed by lymph nodes (n = 8), soft tissues
(n = 6), and liver (n = 1). Nine patients developed
metastases at >1 site. Five patients developed discrete
discontiguous satellite nodules in the region of the primary tumor, spanning areas up to 15 cm, which were interpreted as representing soft tissue metastases. In 4 cases
the soft tissue deposits occurred at distant sites. Lung
metastases in 2 patients appeared cystic by imaging.
The patient with metastatic disease to liver had a solitary
liver mass.

Histologic FindingsPrimary Tumors

Histologically, the primary tumors showed characteristic features of FH, being composed in most cases of a
polymorphous population of bland spindle and histiocytoid cells with vesicular nuclei and inconspicuous or small
nucleoli, in a mixed fascicular and storiform growth
pattern. All primary tumors involved the dermis, with 6
extending into supercial subcutis. All showed at least
focal entrapment of collagen bundles at the tumor edges
(Fig. 1). Epidermal hyperplasia was present in 6 cases. A
grenz zone was present in 8 cases. Eleven tumors showed
increased cellularity compared with ordinary FH, often
with a predominance of spindle cells, typical of the cellular variant of FH (Fig. 1). Two of these cases also
showed combined features of the atypical variant of FH,
having scattered tumor cells with nuclear pleomorphism
and hyperchromasia. One case showed classic FH features with small numbers of admixed atypical cells, consistent with atypical FH. Otherwise the primary tumors
showed minimal nuclear pleomorphism and cytologic
atypia. Two tumors showed marked stromal hemorrhage
and cystically dilated blood-lled spaces, consistent with
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TABLE 1. Clinicopathologic Features of 16 Metastasizing Cutaneous FHs

Time to
First
Primary Size Histologic
Local
Recurrence
Case Age Sex
Site
(cm)
Type
Recurrence
(mo)
1

42

Neck

NK Aneurysmal

Yes, 2

24

Metastatic Sites

Time to
Metastasis
(mo)

Lymph node
(cervical-1/51
nodes)

24

Soft tissue (necksatellite nodules)

Lung (5 cm, cystic)

24

250

30

Shoulder

1.8

Epithelioid

No

NA

33

Back

Cellular &
atypical

No

NA

Lung (multiple,
bilateral nodules)

24

63

Leg
(lower)

Cellular

Yes, 3

36

Lymph node
(inguinal)

96

Lung (large
unilateral mass)
Soft tissue (satellite
nodules &
preauricular)
Lymph nodes
(axillary-5/10)
Lung (multiple,
bilateral nodules)
Lung (multiple,
bilateral, up to
1.2 cm, nodular
and cystic)
Soft tissue
(supraclavicular)
Lung (multiple
nodules, up to
0.7 cm RUL,
RML, RLL)
Liver
Lung (multiple,
bilateral nodules,
up to 1 cm)

132

41

Shoulder

Aneurysmal

Yes

17

55

Toe

Atypical

Yes

36

62

Back

3.5

Cellular

Yes

11

Radiation therapy after DOD, 165

wedge resection of
lung metastases but
had progressive lung
disease
Adriamycin and
DOD, 32
ifosfamide for 3 mo,
stopped due to
disease progression
Postoperative
DOD, 168
chemotherapy after
rst recurrence

132

Inguinal
lymphadenectomy

74

Axillary node dissection NED, 182

95

Surgical resection of
lung metastases
Adriamycin and
ifosfamide

60

17

17
3

Neck

Cellular

No

NA

56

Finger

2.5

Cellular

Yes

1.5

Soft tissue (hand,

satellite nodules)

3.5

10

Lower leg NK

Cellular

Yes

11

23

Shoulder

Cellular

No

NA

Lymph nodes
(inguinal; 4/5
nodes)
Lung (bilateral lung
nodules)
Axillary &
supraclavicular
lymphadenopathy, presumed
metastases
clinically

AWD, 132

Local radiation therapy DOD, 23

after rst recurrence
Gemcitabine; disease
progression

17

38

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AWD, 264

Surgical resection of
lung metastases

NK

Radiation therapy to
primary site after
second local
recurrence

246

Soft tissue opposite

shoulder
Lung (multiple,
bilateral, up to
0.3 cm)

Adjuvant/
Additional
Treatment

Disease
Status
[Follow-up
Duration
(mo)]

Sorafenib for 5 mo,

stopped due to
progressive disease
and toxicity
Surgical resection of
primary, recurrent
and satellite tumors
Inguinal
lymphadenectomy

<1y

NK (biopsy only of 1
lung lesion)

AWD, 68

DUC, 17
(myocardial
infarction)
NED
NA
AWD,E12

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TABLE 1. (continued)
Time to
First
Primary Size Histologic
Local
Recurrence
Case Age Sex
Site
(cm)
Type
Recurrence
(mo)
12

51

M Uncertain NK

13

68

14

25

Leg
(upper)
Buttock

NA

NA

NA

Cellular

No

NA

NK

Cellular

Yes, 7

24

Metastatic Sites
Lung (multiple,
bilateral nodules,
up to 2.7 cm)
Lymph nodes
(bilateral axillary,
up to 4.3 cm)
Lung (multiple),
pleura, chest wall
Lymph nodes
(inguinal)

Time to
Metastasis
(mo)
0

NA (biopsies only)

NA

NK

DOD, 10

72

Chemotherapy &
radiation therapy
after 4th local
recurrence

DOD, 96

Soft tissue (legssatellite nodules,

arms, perineum,
chest wall)
Skin

15

16

31

50

Back
(upper)

Thigh

NK

NK

Cellular &
atypical

Cellular

Yes

Yes, 3

12

156

Intra-abdominal
Lung
Soft tissue (4-5
satellite nodules
from primary
scar site to
shoulder)
Lymph nodes
(axillary, 1/21)
Lymph nodes
(inguinal, 4/14)

Adjuvant/
Additional
Treatment

Disease
Status
[Follow-up
Duration
(mo)]

Additional
chemotherapy after
development of soft
tissue mets
84
12

Radiation therapy after NED, 63

resection of nodal
and soft tissue
metastases

19
180

No

NED, 186

AWD indicates alive with disease; DOD, died of disease; DUC, dead of unrelated causes; NA, not applicable/not available; NED, no evidence of disease; NK, not
known.

the aneurysmal variant of FH (Fig. 2). One tumor showed

features of the epithelioid variant of cutaneous FH,
consisting of a mixed storiform and sheet-like proliferation of epithelioid cells with moderate amounts of
palely eosinophilic cytoplasm, which was often eccentrically located and with frequent binucleate forms as usually seen in this tumor type (Fig. 3). All tumors had
admixed inammatory cells, predominantly lymphocytes
and plasma cells, to varying degrees. In 4 tumors the inammatory inltrate was prominent, but in the remainder
it was sparse or mild. Eight primary tumors had admixed
multinucleate cells (Fig. 4) and 4 had prominent foamy
histiocytes. The tumor stroma was variably hyalinized or
collagenous, and, as mentioned above, aneurysmal
change was present in 2 cases. Focal central necrosis was
present in 1 case (patient 10). Mitotic activity ranged from
<1 to up to 13 per 10 HPF in 1 case, with a median of 4
mitoses per 10 HPF. Vascular invasion was not identied
in any of the primary tumors.
Tumor cells showed focal or multifocal SMA positivity in 5 of 8 cases, focal desmin positivity in 2 of 6
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cases and focal CD34 positivity in 1 of 9 cases. Tumor

cells were consistently negative for S100 and pancytokeratin. p16INK4a was positive in tumor cells in 2 of 7
primary tumors examined, 1 diusely and 1 in a multifocal distribution, with similar patterns of p16 expression
seen in the corresponding metastatic lesions of these 2
primaries.

Histologic FindingsRecurrent and Metastatic

Tumors
Material was available for review for the local recurrences in 5 of the 10 cases with documented recurrence. Primary tumors and recurrent tumors were
morphologically similar, being composed of a tumor cell
population indistinguishable from that seen in the corresponding primary tumor and having similar growth patterns (Fig. 5). Of the recurrent tumors, 7 were of the
cellular type, 2 were aneurysmal, and 1 was atypical. In 1
case (patient 14) the recurrent tumors showed increased
cytologic atypia, progressively developing features of a
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FIGURE 1. Cellular FH (neck, patient 8) with mild overlying epidermal hyperplasia, a Grenz zone (A) and entrapped hyaline
collagen bundles at the edges (B). The growth pattern is mixed fascicular and storiform (C), and the lesional cells are bland,
spindled, and histiocytoid with admixed foam cells (D).

pleomorphic sarcoma. The third local recurrence of 1

patient showed aneurysmal change, necrosis, and increased mitotic activity compared with earlier tumor resections (patient 16, Fig. 6). Otherwise, mitotic rates were
similar to those seen in the corresponding primary tumors: mitotic activity in recurrent tumors ranged from 1
to 20 per 10 HPF, with a median of 5 per 10 HPF.
Lymphovascular invasion was not identied in any of the
recurrences.
Material from 1 or more metastatic tumors was
reviewed for all 16 cases. In all cases the metastatic tumors were morphologically similar to the primary tumors, having similar cytomorphologic features and a
similar stroma to the corresponding primary tumor
(Figs. 27). Necrosis was present in the center of metastatic tumor deposits in the chest wall of 1 patient (patient
13); no necrosis was seen in the remaining cases with lung
metastases. In 2 cases, tumor within the lung was present
as multiple small nodules in a peribronchial distribution
(patients 2 and 6) (Fig. 2). Otherwise the lung metastases
consisted of well-circumscribed discrete nodules of tumor
within lung parenchyma (Fig. 3). Lymph node metastases

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were composed in all cases of tumor morphologically

similar to that in the primary tumors (Fig. 6). Mitotic
activity in the metastatic tumors ranged from 1 to 24 per
10 HPF, with a median of 3 mitoses per 10 HPF. In 1 case,
metastatic tumor in a lymph node showed focal necrosis
and increased cytologic atypia and mitotic activity compared with the primary tumor (patient 16, Fig. 6), but
otherwise the mitotic rates in the metastatic tumors were
similar to those in the corresponding primary tumors.
Lymphovascular invasion was not identified in any of the
metastatic tumors.
Immunohistochemical analysis was performed on 4
metastatic lung tumors and 1 metastatic tumor within a
lymph node. Tumor cells showed multifocal SMA positivity in 2 of 5 cases, both of which involved the lungs.
Tumor cells were consistently negative for S100, CD34,
and pancytokeratin.

Follow-up and Treatment

Additional clinical follow-up information was
available for 14 patients. So far, 6 patients (3 male and 3
female patients) have died of disease, with a median time
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Metastasizing Benign Cutaneous Fibrous Histiocytoma

FIGURE 2. Aneurysmal cutaneous FH (shoulder, patient 5) with dilated blood-filled spaces (A). Biopsy of an axillary lymph node
with bland histiocytoid tumor cells associated with prominent stromal hemorrhage, hemosiderin deposition, and cholesterol clefts
(B). Lung metastases in this patient were solid and cystic (C), and the tumor was morphologically similar to the primary
aneurysmal FH (D).

to death of 64 months (range, 10 to 168 mo) after the

primary diagnosis. Four patients are alive with stable
metastatic disease at last follow-up, 12, 68, 132, and 264
months after initial presentation, and 14, 65, 72, and 240
months after rst metastasis. One patient remains disease
free 7 years after resection of nodal and lung metastases, 1
was disease-free at last follow-up 63 months after resection of nodal metastases, and another is disease free 6
months after resection of nodal metastases. One patient
who developed multiple discontiguous soft tissue tumor
nodules extending proximally from the primary site on a
nger died of unrelated causes 17 months after initial
presentation.
Five patients received chemotherapy: adriamycin and
ifosfamide in 2 cases (patients 3 and 6), gemcitabine in 1
(patient 7), and sorafenib in 1 (patient 8). Chemotherapy
type was unknown for 1 patient (patient 4). Four of
the 5 patients had disease progression on chemotherapy;
3 ultimately died of disease, and 2 are alive with disease at
last follow-up. Two patients received radiation therapy for
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metastatic disease: patient 2 after resection of lung metastases and patient 15 after soft tissue and nodal metastases
(patient 15). Two patients received radiation therapy for
locally recurrent disease (patients 1 and 7). One patient
received both chemotherapy and radiation therapy but died
due to slowly progressive disease 96 months after primary
diagnosis (patient 14).

DISCUSSION
In this report, the clinical and pathologic features of
16 patients with morphologically benign cutaneous FH
that metastasized are described. The primary tumors
showed characteristic features of the cellular, atypical,
aneurysmal, or epithelioid histologic subtypes, the cellular variant being the most commonly encountered (11
of 16 cases). The primary tumors tended to be somewhat
large, with an average size of 3.2 cm but were otherwise
indistinguishable from conventional cutaneous FH
and, as such, lacked any histologic features that might
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FIGURE 3. Epithelioid cutaneous FH (shoulder, patient 2) with peripheral entrapment of hyaline collagen bundles (A). Tumor cells
have epithelioid cytomorphology with frequent binucleate forms (B). A subpleural lung nodule (C) in the same patient demonstrates almost identical tumor cell morphology (D) to that in the primary tumor.

have suggested the potential for aggressive clinical

behavior. In fact, the reason for consultation in the majority of cases was to conrm an original diagnosis of
cutaneous FH in the face of morphologically similar
metastatic tumors. Focal necrosis was present in 1 primary tumor; however, necrosis in large or cellular FH is
not an uncommon nding and does not predict clinical
behavior.4 Mitotic activity was variable among primary
tumors, ranging from <1 to up to 13 mitoses per 10 HPF,
and apart from 1 case that showed a marked increase
in mitotic activity with each recurrence and in a subsequent lymph node metastasis, mitotic activity was
similar among primary, recurrent, and metastatic tumors.
However, it is also well documented that mitotic activity
in FH does not predict behavior, and many cases of FH
that do not recur or metastasize will have readily identiable mitoses and even atypical mitoses.4,7 Three cases in
the current study had features of the atypical variant of
FHthat is, scattered pleomorphic cells with hyperchromatic nuclei in a background of classic features of
FH. In a prior study of 59 cases of atypical FH, 2 tumors

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metastasized, and both of these cases are included in the

current study, but this likely represents a significant
overestimate of frequency due to referral bias in this
predominantly consultation-based series.7 In fact, it is
essentially impossible to make any realistic estimate of the
frequency of this phenomenon.
This unusual and unpredictable phenomenon has
resulted in some controversy in the literature regarding
these lesions. Some have proposed that the diagnosis of
FH is incompatible, by denition, with the presence of
metastases and that all these cases should be diagnosed as
sarcoma.14 However, given that the tumors in the
current study were, at the time of diagnosis, morphologically indistinguishable from otherwise conventional
cutaneous FHs that do not pursue an aggressive clinical
course, identication of these lesions as anything other
than cutaneous FH using currently accepted diagnostic
classication schemes is, for all intents and purpose, not
possible at the current time. Some referring pathologists
had attempted to rationalize by reassessing the primary
skin tumors after the development of metastases and
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Metastasizing Benign Cutaneous Fibrous Histiocytoma

FIGURE 4. Cellular FH (back, patient 7) with a mixed fascicular and storiform growth pattern. Multinucleate giant cells were
noted in other areas (A). Needle biopsy of a supraclavicular soft tissue metastasis that developed 1 year after the primary diagnosis
consists of a bland histiocytoid tumor morphologically similar to the primary and also has prominent multinucleate giant cells (B).
The liver tumor also showed a similar storiform proliferation of bland histiocytoid cells (C and D).

interpreting these tumors as other entities, such as dermatobrosarcoma protuberans (DFSP), so-called angiomatoid malignant brous histiocytoma (AMFH), or
unclassied dermal sarcomathat is, a cutaneous tumor
that may fall into the morphologic differential diagnosis
with FH and have recognized metastatic potential. All
cases in this series lacked the monotonous population of
more basophilic spindle cells with high nuclear/cytoplasmic ratio of DFSP. Furthermore, although occasional
cases extended into the superficial subcutis as often happens in FH, none showed the characteristic honeycomb
pattern of invasion into the subcutis or the compact
storiform growth pattern seen in DFSP. AMFH most
commonly arises in superficial subcutaneous tissue, is well
circumscribed, often with a peripheral lymphoid cuff, and
is composed of a monotonous population of tumor cells
with a uniform spindled or oval cytomorphology. The
large dilated pseudovascular spaces of AMFH may mimic
aneurysmal FH, but the above features, in addition to the
presence of one of the characteristic translocations of this
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tumor type, [t(12;16), t(12; 22), or t(2; 22)], help support a

diagnosis of AMFH.15,16 The diagnosis of unclassified
dermal sarcoma may be considered in the evaluation of
these cases, in part because cellular cutaneous FH, at least
before it was recognized as a variant of FH, was often
interpreted as a dermal sarcoma of some type. Primary
dermal sarcomas (not otherwise specified) usually arise in
sun-damaged skin, show diffuse atypia, are poorly circumscribed, and have a predominantly fascicular growth
pattern. They also frequently show tumor necrosis and
vascular or perineurial invasion.17 Features of FH such as
entrapped hyaline collagen, a polymorphous population
of tumor cells, and admixed inflammatory cells are usually lacking.
The exceptional occurrence of metastasis from tumors that almost always have a benign clinical course and
that lack any overt features of malignancy is a poorly
understood, yet well recognized, phenomenon not limited
to cutaneous FH. Other tumors that may demonstrate
similar behavior include so-called benign metastasizing
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FIGURE 5. Cellular FH arising on a finger (patient 9) (A). The tumor recurred locally 6 weeks after initial excision, and the
reexcision also shows classic features of cellular FH (B). Multiple discontiguous nodules developed proximal to the primary tumor,
2 of which are shown here and are morphologically indistinguishable from the primary tumor (C and D).

leiomyoma,18,19 pleomorphic adenoma/mixed tumor of

the salivary gland,20,21 diuse-type giant cell tumor,22 and
giant cell tumor of the bone.23 Aggressive behavior in these
tumors is usually not predicted because of their bland
morphologic appearances, nor can they be distinguished
histologically from their far more common clinically benign counterparts. Metastasis of these tumors is therefore
an unexpected, but not unrecognized, event.
At least 16 cases of metastasizing cutaneous FH
have previously been well documented, mostly as singlecase reports, over the last 21 years, 3 of which are also
included in the current studycase 1,5 case 2,7,13 and case
147 (Table 2). Notably, after some of these cases had been
published, the World Health Organization revised the
definition of a benign soft tissue tumor, noting that
exceedingly rarely, a morphologically benign lesion may
give rise to distant metastases and that this is entirely
unpredictable on the basis of conventional histologic examination.31 Similar to the findings in this series, other
reports describing metastases of cutaneous FH have
demonstrated classic features of FH or its variant histo-

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logic subtypes in the primary lesions, which lacked morphologic features that may have predicted adverse
outcome and which showed correspondingly similar
morphology in the metastases. In these cases, the primary
tumors included ordinary FH24,28,30 as well as the cellular,13,2529 aneurysmal5,26 or atypical7,26 variants, and,
similar to the current study, the most common metastatic
sites were the lungs and lymph nodes. Lung metastases
were frequently cystic and were originally mistaken as
primary lung tumors because of this.24 Again, similar to
our findings, the interval to metastases in the prior reports was extremely wide, ranging from as short as 4
months26 to up to 23 years from the time of excision of a
cellular FH in 1 case.27 In the current study, the interval
to first metastasis ranged from 0 to 180 months.
Metastasis of histologically benign cutaneous FH
is a clinically aggressive event with substantial morbidity
and mortality. In this series, local recurrence also
occurred in 10 patients, 4 of whom had multiple recurrences. Six patients have so far died of disease, and the
clinical course in these patients was variable with some
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Metastasizing Benign Cutaneous Fibrous Histiocytoma

FIGURE 6. Cellular FH (thigh, patient 16) with admixed foamy histiocytes and lymphocytes (A). The local recurrence shows
increased mitotic activity (B; arrows) compared with the initial tumor. The inguinal lymph node metastasis shows typical features
of cellular FH and some dilated blood-filled spaces (C). The cytomorphology of the metastatic tumor is bland, spindled, and
histiocytoid, similar to the initial lesion, with conspicuous mitoses (D).

patients having rapidly progressive disease, whereas others

had a protracted and indolent course. Complete resection
of metastatic disease appeared to be associated with a better
outcome. Despite the lack of reliable morphologic features
in primary tumors to identify the potential for aggressive
behavior, there are several clinical features that may provoke closer clinical follow-up. The recurrence rate for ordinary FH, even when incompletely excised, is <2%,2
whereas the atypical, aneurysmal, and cellular variants have
recurrence rates of up to 20% each; in addition, multiple
recurrences of cutaneous FH are exceptional. In this series,
however, local recurrence occurred in 62% of patients, and
4 patients developed multiple documented local recurrences: 3 patients had 2 to 3 recurrences, and 1 patient had
7. Similarly, in previous reports of metastasizing FH, 4
patients had multiple local recurrences,2528 whereas another 3 had 1 local recurrence.25,28,32 These ndings, together with the fact that the primary tumors tended to be
large and more often of the cellular variant, suggest that
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2013 Lippincott Williams & Wilkins

close clinical follow-up may be warranted for patients with

either multiple recurrences of cutaneous FH, or large, cellular cutaneous FH, as these patients may be at greater risk
of developing metastasis.
Drawing parallels with modern concepts of tumorigenesis, this unusual phenomenon presumably reects the acquisition of a rare additional genetic hit,
which enables these tumors to metastasize. Molecular
comparisons of this clinically distinct group of cutaneous
FH with conventional FH may possibly shed some light
on the underlying pathogenetic mechanisms, which confer
metastatic potential in these tumors. Although it is not
possible to estimate the true frequency of metastasis in the
biased setting of consultation material, given the small
numbers of reported cases in total, metastasis of cutaneous FH should be regarded as a biologically fascinating
but highly exceptional event, which most certainly should
not be used as grounds for labeling all histologically
comparable primary lesions as malignant.
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FIGURE 7. Metastatic tumor in the lung from the primary tumor shown in Figure 1; note the similar storiform and fascicular
growth pattern (A) and cytomorphology (B) to that seen in the primary tumor. The metastatic tumor also contained admixed
foam cells.

TABLE 2. Summary of Previously Reported Cases of Metastasizing Cutaneous FHs

References
Joseph et al24

No. Cases Histologic Type(s)

1/?2

Calonje and Fletcher5*

Colome-Grimmer and Evans25

1
2

Guillou et al26

De Hertogh et al13*
Kaddu et al7*

1
2

Osborn et al27

Bisceglia et al28

Gu et al29
Szumera-Cieckiewicz and
Ptaszynski30

1
1

Ordinary
NK
Aneurysmal
Cellular
Cellular
Aneurysmal/
atypical
Cellular
Cellular
Cellular
Atypical/cellular
Atypical
Cellular
Cellular
Ordinary
Cellular
Cellular
Ordinary

Local
Recurrence

Metastatic Site(s)

Outcome

Yes
NK
Yes, multiple
Yes, multiple
Yes
No

Lung
Lung
Lymph node
Lung, lymph nodes
Lung, lymph nodes
Lymph node

AWD, 22 y
AWD, 2 y
Case 1 of present study
NED, 9 y
AWD, 15 y
Mets, 19 y

No
Yes, multiple
No
No
Yes
Yes, multiple
NK
Yes, multiple
Yes
No
No

Lymph node
Lymph node
Lung
Lung
Lymph nodes, soft tissues
Lung
Lung
Lymph nodes
Lymph nodes
Lung
Lymph nodes

Mets, 4 mo; NED, 14 y

Mets, 20 mo; NED, 36 mo
Case 3 of present study
Case 3 of present study
Case 15 of present study
AWD, 4 y
NK
NED, 5 y (11 mo after mets)
NED, 12 y (12 mo after mets)
NK
NED, 3 y (1 y after mets)

*Cases (3) included in the current study.

AWD indicates alive with disease; DOD, died of disease; NA, not applicable/not available; NED, no evidence of disease; NK, not known.

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ACKNOWLEDGMENTS
The authors thank the following pathologists who
kindly contributed case materials and clinical follow-up
information when available: B. Loftus, Amsterdam, The
Netherlands; M-L.F. van Velthuysen, Amsterdam, The
Netherlands; B. Boyce, Rochester, NY; J.Z. Sickel, Rochester, NY; R.E. Nakhleh, Jacksonville, FL; R. Sciot,
Leuven, Belgium; K. Hara, Nagakute-cho, Aichi-gun, Aichiken, Japan; R.F.M. Schapers, Venlo, The Netherlands;
A.P. de Bruine, Venlo, The Netherlands; O. Ben-Izhak,
Haifa, Israel; L.K. Yacoub, Methuen, MA; H. Bai, Methuen, MA; A.L. Uzieblo, Royal Oak, MI; M. Roh, Ann
Arbor, MI; S. Dudley-Walker, Hattiesburg, MS; R.H.
Byrd, Tulsa, OK; N. Saxena, Peoria, IL; T. Zhang, West
Palm Beach, FL; A. van Lenders, Rotterdam, The Netherlands; A. Mackay, Chester, UK; D. Eakins, Norfolk, UK;
R. Cawley, Portland, ME; A. Nahal, Montreal, Canada.
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