Histopathology 2010, 56, 133147. DOI: 10.1111/j.1365-2559.2009.03454.

REVIEW

Sebaceous neoplasia and the MuirTorre syndrome: important

connections with clinical implications
Sara C Shalin, Stephen Lyle,1 Eduardo Calonje2 & Alexander J F Lazar3
Department of Pathology, Baylor College of Medicine, Houston, TX, 1Department of Cancer Biology, University of
Massachusetts Medical Center, Worcester, MA, USA, 2St Johns Institute of Dermatology, St Thomas Hospital, London,
UK, and 3Departments of Pathology and Dermatology, Section of Dermatopathology, The University of Texas M. D.
Anderson Cancer Center, Houston, TX, USA

Shalin S C, Lyle S, Calonje E & Lazar A J F

(2010) Histopathology 56, 133147

Sebaceous neoplasia and the MuirTorre syndrome: important connections with clinical
implications
Sebaceous neoplasia comprises a spectrum ranging
from benign to malignant. Proper histological identification is important for treatment, prognosis and
potential association with the MuirTorre syndrome
(MTS). Our increased understanding of the significance
and pathogenesis of these tumours has led to improved

risk stratification, screening recommendations, and

treatment of patients with an initial presentation of a
sebaceous tumour. This review focuses on the diagnostic and histological features of sebaceous lesions,
the MTS, and recent insights into the molecular
pathogenesis of sebaceous tumours.

Keywords: mismatch repair deficiency, MuirTorre syndrome, sebaceoma, sebaceous adenoma, sebaceous
carcinoma, sebaceous hyperplasia
Abbreviations: CK, cytokeratin; EMA, epithelial membrane antigen; HNPCC, hereditary non-polyposis colorectal
carcinoma; Lef-1, lymphocyte enhancing factor 1; MSI, microsatellite instability; MTS, MuirTorre syndrome

Sebaceous glands
Sebaceous glands are associated with the hair follicle,
arising at the junction of the inferior portion of the
follicle infundibulum and the isthmus. Normal sebaceous glands are composed of lobular acini lined on the
periphery by a thin layer of flattened to cuboidal
basaloid, or germinative, cells with scant cytoplasm
(Figure 1A). The inner portions of sebaceous glands are
composed of mature sebocytes cells with a centrallylocated, often scalloped or indented nucleus and
multivacuolated cytoplasm due to the accumulation
of lipid secretions.1 Sebaceous glands, found in higher
concentrations on the head and neck region, are
Address for correspondence: Alexander Lazar, MD, PhD, The
University of Texas M. D. Anderson Cancer Center, 1515 Holcombe
Blvd- Unit 85, Houston, TX 77030-5009, USA.
e-mail: alazar@mdanderson.org
 2010 The Authors. Journal compilation  2010 Blackwell Publishing Limited.

responsible for the production of sebum, a lipid-rich

secretion with a variety of postulated functions.2,3
These structures are androgen-sensitive and typically
become more prominent during puberty.4 Developing
sebaceous glands have been shown to variably express
cytokeratin (CK) 15, which marks potential multipotent stem cells of the pilosebaceous unit and more
recently has been shown to be present within sebaceous neoplasms as well.5,6

Ectopic sebaceous glands

Although most often associated with hair follicles,
ectopic sebaceous glands arising independent of follicular structures are well described. These lesions may
arise as small 13-mm yellow-to-white papules occurring on mucosal surfaces, namely the lips and genital
regions, where they are referred to as Fordyce spots.

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S C Shalin et al.

Figure 1. A, Benign sebaceous lobules are bounded by a doublelayered rim of small basaloid epithelial cells. B, Sebaceous hyperplasia
reveals multiple prominent sebaceous lobules surrounding a central
dell. The normal follicle and sebaceous lobules on the left illustrate
that the lobules in sebaceous hyperplasia are more superficial.

Similar lesions on the female breast are called Montgomery tubercles. These are common enough at these
sites in the population that they can be considered
variants of normal. Ectopic sebaceous glands arising in
a variety of more unusual locations, including the
oesophagus, vagina, cervix, thymus and penis, have
been the subject of numerous case reports.712 These
generally appear to be of no consequence.

Sebaceous hyperplasia
Sebaceous hyperplasia is the benign overabundance of
normal-appearing sebaceous lobules. Clinically, these
lesions are small, usually <5 mm in greatest dimension. They are generally flesh-coloured papules, usually
with a central depression or umbilication. Their clinical
appearance, along with their predilection for the face, is
the basis for periodic clinical confusion with basal cell
carcinoma. Histological examination of these lesions
reveals superficial sebaceous lobules surrounding a

centrally dilated pore or follicular structure, the correlate of the central umbilication (Figure 1B).13 Sebaceous lobules are increased in number but not
dramatically in size, occupy a more superficial position
in the dermis, but have only two layers of peripherally
located basaloid or germinative cells. Treatment of
sebaceous hyperplasia is not required, but may be
achieved with conservative excision if it becomes a
cosmetic issue or clinically confused with a more
concerning lesion.
The development of sebaceous hyperplasia has
been associated with immunosuppression, specifically
noted in renal transplant patients treated with
cyclosporin.1416 Although the pathogenesis of sebaceous hyperplasia is not well understood and its
origin as either a reactive or neoplastic process is not
well established, possible contributing factors include
androgenic stimulation, ultraviolet radiation, and
immunosuppression.14 Unlike many of the entities
discussed subsequently, sebaceous hyperplasia does
not appear to be definitively linked to MuirTorre
syndrome (MTS). Deficits in mismatch repair genes, a
frequent finding in cases of MTS, are generally not
identified in cases of sebaceous hyperplasia.17,18 Case
reports documenting an association between sebaceous hyperplasia and internal malignancy are found
within the literature;19 however, these reports may
simply reflect the underlying frequency of this diagnosis within the general population.

Sebaceous adenoma
Sebaceous adenomas are benign sebaceous tumours
that clinically appear as tan, pink, or yellow nodules
or papules, usually about 5 mm in greatest dimension.
Like most sebaceous proliferations, these tumours
typically arise on the head and neck regions of older
individuals, although occurrence in many other locations has been documented.2022 Sebaceous adenomas
maintain a lobular and organoid architecture, and
often show connection with or replacement of the
overlying squamous epithelium (Figure 2A). There is
an expansion and increased prominence of the
peripherally located basaloid cells compared with
sebaceous hyperplasia (Figure 2).23 This increase in
the number of germinative cells is a key discriminator
between the categories of sebaceous hyperplasia and
sebaceous adenomas or sebaceomas. Sebaceous adenomas show variably expanded basaloid cells, with
more than the normal two cell layers seen in normal
sebaceous glands and sebaceous hyperplasia, but by
convention are <50% of the tumour cell volume
(>50% basaloid cell content is seen in sebaceoma).

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Sebaceous neoplasms and MuirTorre syndrome

135

Figure 2. A, Sebaceous adenoma with multilobular architecture and a smooth base. B, Higher power of a sebaceous adenoma reveals
an expanded peripheral basaloid component. C, The expansion of the basaloid component can be more subtle in sebaceous adenoma
and is often accompanied by an increased prominence and number of the basaloid cells. D, The cellularity of sebaceous adenomas ranges
from more peripheral germinative basaloid cells to more central mature sebocytes with crenulated nuclei.

Sebaceous adenomas thus also maintain a prominent

population of mature sebocytes often concentrated in
the central portion of the neoplasm, making their
sebaceous differentiation conspicuous in most cases
and imparting an organoid quality to the tumour.
Noticeable cytological atypia or significantly increased
mitotic rate should prompt a re-evaluation of
the diagnosis, as these features are generally
minimal.2325 These tumours are well-circumscribed
and often lobular.
Clinically, sebaceous adenomas may be mistaken for
basal cell carcinoma. Histologically, the differential
diagnosis of sebaceous adenoma includes other lesions
with clear cytoplasm, including clear cell variations of
eccrine, melanocytic, keratinocytic or xanthomatous
lesions, as well as metastatic lesions such as renal cell

carcinoma, or perhaps other lesions with sebaceous

differentiation. The characteristic bubbly or multivacuolated cytoplasm and crenated nuclei of mature
sebocytes coupled with the germinative cells should
be helpful features on histological examination
(Figure 2D), but immunohistochemical staining may
be helpful for particularly difficult lesions (discussed
further below).
Sebaceous adenomas are felt to be benign lesions,
yet common practice is complete extirpation by
conservative excision. The established association
between sebaceous adenoma and MTS deserves reference within issued pathology reports so that
patients can be appropriately evaluated for possible
additional syndrome findings as more fully presented
below.

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S C Shalin et al.

Sebaceoma
Clinically, sebaceomas appear similar to sebaceous
adenomas, although perhaps slightly larger in size,
ranging from 5 to 10 mm in greatest diameter with a
fleshy yellow to orange colour. Similar to other
sebaceous tumours, these lesions typically arise in the
head and neck region.26,27
The histology of sebaceoma differs from that of
sebaceous adenoma in that the germinative, basaloid
cells predominate over the mature sebocytes, with
>50% of the tumour cells being basaloid (Figure 3).
Furthermore, sebaceomas typically lose the organoid
quality seen in sebaceous adenomas, resulting in a
seemingly haphazard placement of mature sebocytes
without the sense of central maturation usually
encountered in adenomas. Mature sebocytes may be
focal and scarce (Figure 3B). Sebaceomas can rest
entirely within the dermis or display overlying connec-

tion to the epidermis. Ductal structures and squamous

differentiation may also be present.28 Despite the loss of
organoid quality, these lesions generally maintain
circumscription and symmetry.28 Mitotic figures may
be present within the basaloid cells, but the lesions
maintain an overall well-circumscribed architecture
without significant cytological atypia. More recently,
cytological atypia and prominent mitoses, including
atypical forms, have been suggested to occur rarely in
sebaceous neoplasms that are otherwise characteristic
of benign sebaceomas, although this has been accompanied with controversy.24,25 Of note, sebaceomas (and
sebaceous lesions in general) do not display peripheral
pallisading of basaloid nuclei or the retraction from the
surrounding stroma that is present in basal cell
carcinomas, which may aid in distinguishing these
lesions.2729 In addition, various histological patterns
have been described within the spectrum of sebaceomas, including carcinoid-like, rippled and reticulated
patterns.3032
Sebaceomas are generally treated by conservative
excision. Like sebaceous adenomas, sebaceomas are
considered part of the spectrum of MTS. Clinically and
histologically, sebaceomas have overlap with sebaceous
adenomas and together form the benign end of the
spectrum of sebaceous neoplasia associated with the
MTS. While the many similarities between these two
tumours suggest that they could be conceptualized as a
continuum of sebaceous neoplasia, it is appropriate to
distinguish sebaceoma because the higher basaloid
content can cause confusion with non-sebaceous
tumours such as basal cell carcinoma and also sebaceous carcinoma in certain instances.

Other sebaceous lesions and terminology

B

Figure 3. A, Sebaceomas are well-circumscribed and composed

primarily of basaloid cells. B, The mature sebaceous component in
sebaceoma can be rather focal.

Numerous additional terms have been introduced into

the literature, which may encompass various sebaceous neoplasms. These terms, including sebaceous
epithelioma and sebomatricoma, have variably
included sebaceous adenomas, sebaceomas, and nonsebaceous tumours such as basal cell carcinoma with
sebaceous differentiation. In addition to a lack of welldefined diagnostic features for these lesions, there has
been disagreement and confusion regarding malignant
potential, particularly in the case of sebaceous epithelioma.3335 Furthermore, these broad terms do not
clearly distinguish the sebaceous tumours most likely
to be associated with the MTS.35 These terms do have
some limited degree of support within the literature,
but the terms sebaceous adenoma and sebaceoma as
defined above will encompass the vast majority of
benign sebaceous lesions encountered, although the

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Sebaceous neoplasms and MuirTorre syndrome

histological spectrum certainly admits to variation.

Conceptually, one could certainly view sebaceomas as
cellular sebaceous adenomas given their similar
clinical contexts and significance. However, sebaceoma
is a well-defined entity and it recognizes lesions with
prominent basaloid features and sometimes more
prominent mitoses as benign and markers of the MTS.
Other rare sebaceous neoplasms include superficial
epithelioma with sebaceous differentiation and mantleoma. Superficial epithelioma with sebaceous differentiation is rarely described, but a recent report
suggests that it may be more common than previously
thought.35,36 It is a benign entity composed of a platelike epidermal growth with thickened, anastamosing
rete ridges and interposing lobules of basaloid cells and
mature sebocytes.36,37 Mantleoma is described as an
often incidental benign folliculocentric tumour with
sebaceous differentiation that is thought to replicate
the follicular mantle.38 Fibrofolliculomas and trichodiscomas, benign tumours seen in BirtHoggDube
syndrome, are considered by some to show mantle
differentiation as well, and may represent overlap with
mantleoma.39 Perhaps due to their rarity, neither
superficial epithelioma with sebaceous differentiation
nor mantleoma has a well-defined relationship with
MTS, although one patient with superficial epithelioma
with sebaceous differentiation reported an internal
malignancy.36

Sebaceous carcinoma
Sebaceous carcinomas are traditionally segregated into
two categories: periocular and extraocular. The distinction is important, as malignant sebaceous tumours
are more likely to occur in the periocular region (as
opposed to adenomas or sebaceomas), and these appear
to be less often associated with MTS than their
extraocular counterparts.40

Periocular sebaceous carcinoma

Sebaceous carcinomas of the periocular region can
arise in association with meibomian glands, glands of
Zeis, or other sebaceous glands of the eyelid. These
tumours comprise approximately three-quarters of all
sebaceous carcinomas, arising between the sixth and
eighth decades of life with an equal gender distribution
in the contemporary literature.4143 They are the
second or third most common eyelid malignancies
after basal cell carcinoma (and squamous cell carcinoma), depending on the published series.44,45 A
recent large retrospective study on the epidemiological
factors of sebaceous carcinoma noted a decreased

137

incidence in persons with black skin.40 Clinically,

sebaceous carcinoma may appear as a painless,
rounded nodule, more often on the upper eyelid and
usually without ulceration (Figure 4A). Periocular
sebaceous carcinoma may be mistaken clinically for
an inflammatory condition such as chalazion or
blepharoconjuntivitis, resulting in delay in diagnosis.
Misdiagnosis as a more indolent malignancy such as
squamous or basal cell carcinoma can lead to suboptimal initial clinical management.41,46,47 A tigroid
appearance of the conjunctiva near the eyelid margin,
due to excreted lipid material from sebaceous ducts,
may alert the clinician to the possibility of a sebaceous
carcinoma.42 Metastatic spread to lymph nodes is not
uncommon, and mortality has been reported up to
20%.48 More recent retrospective studies indicate
considerably lower mortality, perhaps owing to earlier
recognition allowing application of more effective local
excision.41,42
Histologically, periocular sebaceous carcinomas often
demonstrate an infiltrative architectural pattern within
the dermis and extension into the superficial skeletal
muscle and subcutis of the eyelid. The tumour cells are
enlarged and sometimes pleomorphic basaloid cells with
hyperchromatic nuclei and frequent mitotic figures,
some of which may be atypical (Figure 4). Depending
on the degree of differentiation, sebaceous carcinomas
may show obvious or only focal mature sebocytes.49
Intraepithelial or pagetoid spread is a frequent feature
that is rarely encountered in extraocular cases
(Figure 4C). In interpreting small biopsy specimens,
it should be noted that benign sebaceous neoplasms are
not common in the periocular region, and the identification of sebaceous differentiation in such a lesion
should prompt strong consideration of malignancy.26

Extraocular sebaceous carcinoma

Extraocular sebaceous carcinoma is less common than
its periocular counterpart, generally still arising in the
head and neck region, although other sites, including
the nipple, thorax, back, and penis, have been
reported.41,5052 Like periocular sebaceous carcinoma,
extraocular carcinoma can be an aggressive malignancy, with varying reports as to the incidence of
metastasis and mortality.23,41,52 The rarity of this
tumour and likely referral bias in published series has
complicated assignment of its aggressiveness.
Clinically, these lesions may be similar to the periocular carcinomas, presenting as an erythematous nodule
or papule with or without ulceration. While many of
these lesions have both poorly circumscribed architecture and significant atypia, including pleomorphic,

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S C Shalin et al.

Figure 4. A, Periocular sebaceous carcinoma involving the lower eyelid. B, Full-thickness eyelid excision revealing sebaceous carcinoma
involving the cutaneous portion of the eyelid (upper right). The mucosal surface is below. C, Periocular sebaceous carcinoma with pagetoid
involvement of the overlying epithelium. D, Strong, nuclear p53 expression detected by immunohistochemistry in a periocular sebaceous
carcinoma. Clinical photograph courtesy of Dr Bita Esmaeli, UT-M. D. Anderson Cancer Center, Houston, TX, USA.

enlarged basaloid cells, frequent and atypical mitoses,

and foci of necrosis, some lesions display only one or the
other feature (Figure 5A). The presence of either an
infiltrative growth pattern or extreme cytological atypia
should prompt the diagnosis of malignancy.24,26
Mature sebocytes may be only focally noted and the
nuclei often lack the distinctly crenulated features seen
in mature sebocytes (Figure 5B, compare with
Figure 1A). Unlike periocular disease, pagetoid spread
is rare in extraocular sebaceous carcinomas.
Sebaceous carcinomas have been treated with a
wide-ranging spectrum of treatment modalities, including wide excision, adjunctive radiotherapy, and even
orbital exenteration.41,42 More recently, Mohs microsurgery has been performed on periocular sebaceous
carcinomas with the purported advantage of normal
tissue sparing and apparently favourable outcomes,
although longer follow-up is needed.47

The use of immunohistochemistry in

sebaceous neoplasia
Although the identification of unequivocal sebaceous
differentiation on routine histological examination
alone will usually suffice, there are certain circumstances when the use of immunohistochemistry may
facilitate diagnosis. Several readily available immunohistochemical stains, although non-specific, may also
be helpful in the determination of sebaceous origin.
Mature sebocytes are positive for epithelial membrane
antigen (EMA) and negative for carcinoembryonic
antigen. CK7 is generally positive in the basaloid cells
of sebaceous tumours.5,53
Sebaceous tumours, because of their intracytoplasmic lipid content, will stain with Oil Red O; however,
application requires frozen tissue, as standard histological processing eliminates lipid content.26 This stain

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Sebaceous neoplasms and MuirTorre syndrome

Figure 5. A, Extraocular sebaceous carcinoma showing scattered

pleomorphic cells. B, Sebaceous differentiation can be focal.

can be rapidly performed on perioperative frozen

sections. More recently, the use of adipophilin, a
protein associated with intracytoplasmic lipid vesicles,
has been described as useful in the identification of
sebaceous differentiation (Figure 6).5456 Because of
the contribution of androgen hormones to the activation of sebaceous glands, immunostaining against the
androgen receptor has also been reported as a method
to determine sebaceous differentiation.4 This stain may
be particularly helpful in poorly differentiated sebaceous carcinomas, which may lack staining for EMA
and other markers, but additional demonstrations of
specificity are needed.4

Figure 6. Adipophilin immunohistochemistry in a normal sebaceous

gland (A), sebaceoma (B) and periocular sebaceous carcinoma (C). It
is important to identify the individual outlines of the membranes that
surrounded the lipid globules within the cells for specificity. The
numbers of globules will vary and are often less in number in
sebaceous carcinomas with limited sebaceous differentiation.
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S C Shalin et al.

Few well-documented cases exist, but basal cell

carcinomas with sebaceous differentiation frequently
enter the differential diagnosis of sebaceous neoplasms,
particularly sebaceoma.29 Although the histological
processing artefact of tumour retraction from fibromyxoid stroma also indicates basal cell carcinoma, several
immunostains have been proposed to aid in differentiating these lesions. The use of EMA and Ber-EP4
immunostaining was investigated and found to be
useful in the distinction between these lesions. Nodular-type basal cell carcinomas were typically moderately or strongly positive for Ber-EP4 and sebaceomas
were almost always negative for this marker, while
EMA staining shows the opposite pattern of reactivity.57,58 Podoplanin (D2-40) is typically weakly and
focally positive at most in basal cell carcinomas but
positive in sebaceous lesions, particularly sebaceoma.59
CK19 has also been reported to be useful in distinguishing these lesions, with basal cell carcinomas more
often displaying strong positivity, whereas sebaceous
lesions display only focal immunopositivity.60 Most of
the studies supporting these stains are small, and
multiple stains should be used in a panel to support
rather than overrule the initial histological impression.
Within the spectrum of sebaceous tumours, tumorigenic and proliferative immunomarkers may be helpful if the malignant potential of a lesion is unclear,
although histological examination is the best standard
for this determination. One study has shown that
sebaceous hyperplasia, sebaceous adenomas, and sebaceomas tend to show low levels of p53 and Ki67
(Mib-1) positivity, while sebaceous carcinomas are
usually associated with higher levels of nuclear p53
expression and Ki67 positivity, as well as decreased
Bcl-2 expression.61 Podoplanin (D2-40) has also been
suggested as a possible marker to distinguish benign
from malignant sebaceous tumours. Sebaceomas were
found to be immunopositive for podoplanin in basaloid
cells. In contrast, most carcinomas tended to be either
negative or only focally positive, although some basaloid sebaceous carcinomas were immunopositive.59

MuirTorre syndrome and sebaceous

neoplasia
MTS refers to the independent descriptions made more
than four decades ago by Drs Muir and Torre of
sebaceous neoplasms occurring coincident with internal malignancy. We now understand this syndrome to
represent a subset of the hereditary non-polyposis
colorectal carcinoma (HNPCC) syndrome. HNPCC is an
autosomal dominant cancer predisposition syndrome

due to inheritance of a defective gene encoding a DNA

mismatch repair protein. Loss of wild-type allele leads
to genomic microsatellite instability (MSI).62,63
Although initially reported having a predisposition
solely to colorectal cancer, these patients actually show
an increased risk of various malignancies, including
endometrial, ovarian, genitourinary, and small bowel
cancers. Multiple primary tumours are common, and
patients typically present at earlier age with malignancy.62 Many of these patients demonstrate germ-line
mutations in genes encoding DNA mismatch repair
proteins MLH1 or MSH2 and, less commonly, MSH6,
MSH3, MLH3, PMS1 and PMS2. These proteins function to detect and repair errors in base pairing
occurring during DNA replication, especially in regions
of DNA (termed microsatellites) characterized by repetitive mono- or dinucleotide repeats. Consistent with the
Knudson hypothesis, mismatch repair protein mutation, when paired with a second somatic mutational
hit of the remaining functional allele, leads to
susceptibility to tumour formation. Presumably this
occurs through the accumulation of base pair mismatches and increasing genomic instability.64 The
second hit may be through somatic mutation or
methylation suppression,65 although a small report has
suggested that loss of heterozygosity by complete allele
loss is unlikely to be a common mechanism.66 Conceptually, mismatch repair genes can be considered
tumour suppressor genes.
MTS comprises a small subset (13%) of HNPCC
families and is characterized by sebaceous tumours or
perhaps keratoacanthomas preceding or existing coincidently with visceral malignancies.67 Because the
sebaceous lesions may be the presenting feature of
a patient with MTS, increasing reports are being
published regarding recommendations for patient
screening following the diagnosis of a sebaceous
tumour.17,6872 The diagnosis of a sebaceous neoplasm should prompt additional clinical and or laboratory screening. A currently accepted method to
evaluate for the functional status of mismatch repair
proteins within the sebaceous tumour is the use of
immunohistochemistry using antibodies against the
mismatch repair proteins, MSH2 and MLH1, sometimes with MSH6 as well (Figure 7).17,6872 A lack of
nuclear imunoreactivity within sebaceous tumour
cells suggests MTS and has been shown to correlate
well with high levels of MSI, as assessed by the gold
standard of polymerase chain reaction-based amplification and chromatographic or electrophoretic assessment of multiple, defined microsatellite regions of
DNA (Figure 8).7376

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Sebaceous neoplasms and MuirTorre syndrome

105

110

115

120

141

125

Normal tissue

Tumour

BAT26 locus
Figure 8. The BAT26 microsatellite shows increased variability in
a sebaceous tumour from a MuirTorre patient (lower panel)
compared with normal tissue from the same patient (upper panel).
This DNA-based test uses polymerase chain reaction amplification
of specific loci with chromatographic determination of amplicon sizes
to detect alterations in the length of the tested microsatellite.

Although all types of sebaceous neoplasms (with the

exception of strictly defined sebaceous hyperplasia)
have been the subject of reports linking them to
MTS,7780 more recent literature has attempted to
better define a genotypephenotype correlation of the
syndrome by confirming the presence of mutations in
mismatch repair gene or loss of the encoded proteins
within sebaceous neoplasms. Interestingly, in contrast
to the colorectal carcinomas of HNPCC, the sebaceous
neoplasms implicated in MTS display loss of MSH2
much more commonly than MLH1.17,71,81,82 Isolated
mutations in MSH6 are noted exceptionally,82 but MTS
has not yet been definitely linked to isolated loss of
MSH3 or PMS1. Only a subset of sebaceous neoplasms
demonstrate evidence of mismatch repair deficiency
determined by various tests, ranging from 26 to 59%
overall with obvious referral bias in the published
series.17,71,72 Interestingly, benign sebaceous lesions
(sebaceous adenomas and sebaceomas) have been
shown to have significantly higher rates of MSI than
carcinomas either extraocular or periocular.17,18,82
Moreover, several reports have now documented that
loss of mismatch repair proteins is more common in
sebaceous tumours occurring outside of the head and
neck region and may more strongly suggest
MTS.17,18,71 Strong indicators of MTS include multiple
sebaceous neoplasms, but a single cutaneous tumour
can herald the syndrome. Alternative mechanisms of
pathogenesis within the spectrum of MTS may exist,
since not all patients with sebaceous neoplasia and a
characteristic internal malignancy display MSI.
Figure 7. The sebaceous tumour (A) from this MuirTorre patient
shows nuclear expression of MLH1 (B) with loss of MSH2 (C) on
immunohistochemistry. The overlying epidermis serves as an internal
positive control.

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Dissecting the molecular pathogenesis of

sebaceous tumours

Figure 9. A, Sebaceous adenoma with cystic features. B, Sebaceous

adenoma with keratoacanthoma-like architecture. Both of these
features are thought to suggest the MuirTorre syndrome, but
more study is needed.

Additional morphological properties have been suggested to correlate with syndrome-associated sebaceous
lesions. Keratoacanthoma-like and cystic change have
both been proposed as occurring more frequently in
MTS-associated sebaceous lesions (Figure 9).83,84 However, one report did not find cystic change to be
statistically associated with sebaceous tumours demonstrating loss of mismatch repair protein expression;
additional study is needed.17 More recently, the presence
of increased intratumoral lymphocytes has been shown
to correlate with MSI, similar to the feature commonly
seen in colorectal carcinomas associated with MSI.71,85
Interestingly, mutations in the genes for mismatch
repair proteins may not be the only mechanism by
which to obtain the MTS phenotype. Mutations in the
gene MYH, inherited in an autosomal recessive manner, result in an attenuated gastrointestinal polyposis
phenotype, with patients showing an increased risk of
colorectal carcinoma and other cancers.86 The protein
product of MYH is involved in DNA base excision repair
following DNA oxidative damage. Several case reports
have now noted the presence of sebaceous neoplasms
in patients with MYH-associated polyposis syndrome,
and one paper established that these sebaceous lesions
did not exhibit MSI.8789

Efforts to understand the molecular pathogenesis of

MTS, sebaceous neoplasia, or cutaneous neoplasms in
general have resulted in several transgenic mouse
models. MSH2-deficient mice, developed as a model of
HNPCC, develop sebaceous tumours with MSI, mimicking the MTS.90 MSH6-deficient mice also are
reported to develop skin tumours, although sebaceous
differentiation was not specifically reported.91 The
mechanisms by which the genomic instability accompanying loss of mismatch repair proteins promotes
sebaceous tumorigenesis are not understood.
Other mouse models that develop sebaceous tumours
have provided additional and serendipitous insights
into the molecular pathogenesis of sebaceous tumours.
Wnt and b-catenin signalling are integral for the
proper differentiation of various tissues, and alterations
of these signalling pathways have been linked to a
variety of skin and non-cutaneous tumours.92 Cellular
b-catenin levels are tightly regulated, existing in both
cytosolic and nuclear compartments. Activation of Wnt
signalling causes translocation of b-catenin to the
nucleus, where it binds to proteins such as lymphocyte
enhancing factor 1 (Lef-1) to permit gene transcription
(Figure 10). Activating b-catenin mutations are seen in
hair follicle tumours such as pilomatrixomas, along
with up-regulation of sonic hedgehog signalling.9395
Conversely, a transgenic mouse expressing a defective
b-catenin binding site in the Lef-1 protein (with
resulting inability to activate transcription efficiently)
spontaneously developed sebaceous skin tumours.96
These Lef-1 transgenic mice show up-regulation of
Indian hedgehog protein expression (rather than sonic
hedgehog), which promotes proliferation of sebaceous
precursor cells.95 Further work by this group has
provided a model whereby levels of b-catenin drive
lineage specification during development. The subsequent correlate is that aberrations in b-catenin and
hedgehog signalling pathways may promote various
cutaneous tumour types.97 Notably, dual mutations in
the same allele of LEF1 were found in one-third of
examined human sebaceous adenomas and sebaceomas, resulting in impaired b-catenin binding and
decreased transcriptional activity (Figure 10A,B).98
Thus, this pathway is believed to be contributory to
sebaceous tumour formation, although all of the
downstream effects have not been elucidated.
The FHIT gene encodes a member of the histidine
triad proteins and appears to function as a tumour
suppressor.99 Transgenic mice heterozygous for FHIT
develop a spectrum of gastrointestinal malignancies

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Sebaceous neoplasms and MuirTorre syndrome

143

B
Wnt

E45K S61P
1

384
C

Cytoplasm
-catenin
binding domain

Frizzled

HMG DNA
binding domain

Context dependent
activation domain

C
-CATENIN

Normal development

Sebaceous
differentiation

LEF-1

Tumour promotion
(no p14ARF/p53 induction)

Default
Nucleus
Mature
epidermis

Epidermal
progenitor

LEF-1
-catenin
SHH

Sebaceous
gland

Sebocyte
progenitor

Mismatch repair
deficiency and/or
inactivating
LEF-1 mutations

? Other molecular changes

IHH
PTCH

Niche

Multi-potent,
self-renewing
stem cell
LEF-1
-catenin
SHH

Sebaceous
tumours

Tumorigenesis

Hair follicle
progenitor
Hair
follicle

Figure 10. Dual inactivating mutations in the LEF-1 transcription factor have been documented in benign sebaceous neoplasms (A) leading
to attenuation of Wnt signalling in tumour cells (B). This not only promotes sebaceous differentiation, but also inhibits p53-mediated
senescence and apoptosis. C, Cutaneous stem cells reside in a specialized tissue niche and are responsible for development and regeneration
of epithelial structures including the epidermis, follicle and sebaceous gland under the influence of various signalling pathways (left).
Mutations and resulting dysregulation of many of these same pathways appear to be involved in the generation of various cutaneous tumours
such as that illustrated for sebaceous tumours (right). SHH, sonic hedgehog; IHH, Indian hedgehog; PTCH, patched.

and sebaceous lesions when exposed to carcinogens.

Importantly, these tumours do not exhibit MSI.100 Fhit
has been linked to apoptosis, with FHIT mutations
resulting in defective programmed cell death99, and,
more recently, Fhit has been shown to exert a
repressive function on b-catenin transcriptional activity.101,102 FHIT mutations have been documented in
human periocular sebaceous carcinomas both with
and without concomitant MSI,103,104 thus providing
additional support for the complex role of b-catenin
signalling in sebaceous tumorigenesis.
No discussion of tumorigenesis is complete without
mention of p53, the original tumour suppressor and
guardian of the genome. When activated by cell
damage, p53 degradation is decreased, with resultant

increased transcriptional activation of genes that

function in cell cycle arrest and apoptosis programs.
Mutations in the DNA binding regions of p53 are
common in skin cancers, with ultraviolet irradiation
inducing predictable mutations that promote tumour
formation by the inability to halt the cell cycle or
induce apoptosis.105 Some sebaceous neoplasms, particularly carcinomas, have been shown to display
increased nuclear immunoreactivity for p53, which
can correlate with mutation and or dysregulation of
p53 signalling (Figure 4D).46,61,97,106 Conversely,
sebaceous tumours from transgenic Lef-1 mutated
mice consistently showed an absence of p53 protein
by immunohistochemical staining, which correlated
with down-regulation of the binding partner ARF.97

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144

S C Shalin et al.

These findings were hypothesized to result in tumour

promotion by preventing nuclear accumulation and
appropriate transcriptional activation of pro-apoptotic
genes by p53. Thus, p53 signalling alterations may
represent an early, primary event in a subset of
sebaceous malignancies (those with nuclear accumulation of p53), while being a downstream, secondary
effect within other sebaceous tumours (those with
inactivating LEF1 mutations).

Conclusions
Sebaceous lesions encompass a spectrum from benign,
cosmetically bothersome hyperplasias to aggressive
carcinomas. Most commonly found in the head and
neck region, these lesions are united by the presence of
some degree of sebaceous differentiation. The mature
sebocyte shows vacuolated cytoplasm and crenulated
nuclear contours, although immunohistochemistry to
identify intracytoplasmic lipid or to support sebaceous
differentiation may be helpful in challenging cases.
Accurate identification of sebaceous lesions is important, as the diagnosis may indicate MTS. Lesions
associated with MTS frequently demonstrate mutations
in genes encoding DNA mismatch repair proteins,
resulting in MSI. Although MTS-associated lesions may
be predicted by features such as tumour type (sebaceous adenoma or sebaceoma) and site (non-head or
neck location), and perhaps by morphological features
such as intratumoral lymphocytes, the identification of
any sebaceous neoplasm should prompt consideration
for screening for MTS. Periocular sebaceous carcinoma
is much less commonly associated with MTS. Immunohistochemistry to evaluate the status of mismatch
repair protein expression is increasingly used on a
routine basis on these tumours.71,72
The molecular pathogenesis of sebaceous neoplasia
is still being dissected. Alterations in Wnt b-catenin,
Indian hedgehog, and p53 signalling pathways have
been implicated, along with mutations in numerous
tumour suppressor genes such as FHIT, DNA mismatch
repair genes, and P53 itself. Further research will
elucidate additional pathways. Improved understanding of normal cutaneous developmental biology is
providing key insights into the biological basis for
these tumours, with the hope of eventually establishing new strategies for prevention and treatment
(Figure 10C).92,107,108

Acknowledgements
This work is supported by the US National Institutes
of Health (1R01CA118916, S.L. & A.J.F.L.) and the

M. D. Anderson Physician Scientist Grant (A.J.F.L.). Mz.

Kim Vu is thanked for expert aid in figure preparation.

References
1. Li M. Normal skin. In Mills SE ed. Histology for pathologist.
Philadelphia: Lippincott, Williams and Wilkins, 2007; 328.
2. Danby FW. Why we have sebaceous glands. J. Am. Acad.
Dermatol. 2005; 52; 10711072.
3. Zouboulis CC, Baron JM, Bohm M et al. Frontiers in sebaceous
gland biology and pathology. Exp. Dermatol. 2008; 17; 542
551.
4. Bayer-Garner IB, Givens V, Smoller B. Immunohistochemical
staining for androgen receptors: a sensitive marker of sebaceous differentiation. Am. J. Dermatopathol. 1999; 21; 426
431.
5. Bieniek R, Lazar AJ, Photopoulos C, Lyle S. Sebaceous tumours
contain a subpopulation of cells expressing the keratin 15 stem
cell marker. Br. J. Dermatol. 2007; 156; 378380.
6. Misago N, Narisawa Y. Cytokeratin 15 expression in neoplasms
with sebaceous differentiation. J. Cutan. Pathol. 2006; 33; 634
641.
7. Wang WP, Wang WS, Tsai YC. Multiple tiny ectopic sebaceous
glands discovered throughout entire esophageal tract. Dig. Dis.
Sci. 2009; 54; 27542757.
8. Belousova IE, Kazakov DV, Michal M. Ectopic sebaceous glands
in the vagina. Int. J. Gynecol. Pathol. 2005; 24; 193195.
9. Harada A, Tatsumi Y, Matsumoto T, Tani T, Nishida H,
Katsura K. Ectopic sebaceous glands. Gastrointest. Endosc.
2004; 60; 97.
10. Robledo MC, Vazquez JJ, Contreras-Mejuto F, Lopez-Garcia G.
Sebaceous glands and hair follicles in the cervix uteri.
Histopathology 1992; 21; 278280.
11. Wolff M, Rosai J, Wright DH. Sebaceous glands within the
thymus: report of three cases. Hum. Pathol. 1984; 15; 341
343.
12. Batistatou A, Panelos J, Zioga A, Charalabopoulos KA. Ectopic
modified sebaceous glands in human penis. Int. J. Surg. Pathol.
2006; 14; 355356.
13. Prioleau PG, Santa Cruz DJ. Sebaceous gland neoplasia.
J. Cutan. Pathol. 1984; 11; 396414.
14. Zouboulis CC, Boschnakow A. Chronological ageing and
photoageing of the human sebaceous gland. Clin. Exp. Dermatol. 2001; 26; 600607.
15. Pang SM, Chau YP. Cyclosporin-induced sebaceous hyperplasia in renal transplant patients. Ann. Acad. Med. Singapore
2005; 34; 391393.
16. de Berker DA, Taylor AE, Quinn AG, Simpson NB. Sebaceous
hyperplasia in organ transplant recipients: shared aspects of
hyperplastic and dysplastic processes? J. Am. Acad. Dermatol.
1996; 35; 696699.
17. Singh RS, Grayson W, Redston M et al. Site and tumor type
predicts DNA mismatch repair status in cutaneous sebaceous
neoplasia. Am. J. Surg. Pathol. 2008; 32; 936942.
18. Cesinaro AM, Ubiali A, Sighinolfi P, Trentini GP, Gentili F,
Facchetti F. Mismatch repair proteins expression and microsatellite instability in skin lesions with sebaceous differentiation: a
study in different clinical subgroups with and without extracutaneous cancer. Am. J. Dermatopathol. 2007; 29; 351358.
19. Spraul CW, Jakobczyk-Zmija MJ, Lang GK. Sebaceous hyperplasia of the lower eyelid. Klin. Monatsbl. Augenheilkd. 1999;
215; 319320.

 2010 The Authors. Journal compilation  2010 Blackwell Publishing Ltd, Histopathology, 56, 133147.

Sebaceous neoplasms and MuirTorre syndrome

20. Ferguson JW, Geary CP, MacAlister AD. Sebaceous cell

adenoma. Rare intra-oral occurrence of a tumour which is a
frequent marker of Torres syndrome. Pathology 1987; 19;
204208.
21. Welch KC, Papadimitriou JC, Morales R, Wolf JS. Sebaceous
adenoma of the parotid gland in a 2-year-old male. Otolaryngol.
Head Neck Surg. 2007; 136; 672673.
22. Terrell S, Wetter R, Fraga G, Kestenbaum T, Aires DJ. Penile
sebaceous adenoma. J. Am. Acad. Dermatol. 2007; 57; S42
S43.
23. Rulon DB, Helwig EB. Cutaneous sebaceous neoplasms. Cancer
1974; 33; 82102.
24. Kazakov DV, Kutzner H, Spagnolo DV, Rutten A, Mukensnabl
P, Michal M. Discordant architectural and cytological features
in cutaneous sebaceous neoplasmsa classification dilemma:
report of 5 cases. Am. J. Dermatopathol. 2009; 31; 3136.
25. Resnik KS. Classifying neoplasms with sebaceous differentiationa reviewers comments. Am. J. Dermatopathol. 2009; 31;
9496.
26. Lazar AJ, Lyle S, Calonje E. Sebaceous neoplasia and Torre
Muir syndrome. Curr. Diagn. Pathol. 2007; 13; 301319.
27. Troy JL, Ackerman AB. Sebaceoma. A distinctive benign
neoplasm of adnexal epithelium differentiating toward sebaceous cells. Am. J. Dermatopathol. 1984; 6; 713.
28. Misago N, Mihara I, Ansai S, Narisawa Y. Sebaceoma and
related neoplasms with sebaceous differentiation: a clinicopathologic study of 30 cases. Am. J. Dermatopathol. 2002; 24;
294304.
29. Misago N, Suse T, Uemura T, Narisawa Y. Basal cell carcinoma
with sebaceous differentiation. Am. J. Dermatopathol. 2004; 26;
298303.
30. Kazakov DV, Kutzner H, Rutten A, Mukensnabl P, Michal M.
Carcinoid-like pattern in sebaceous neoplasms: another distinctive, previously unrecognized pattern in extraocular sebaceous carcinoma and sebaceoma. Am. J. Dermatopathol. 2005;
27; 195203.
31. Misago N, Narisawa Y. Rippled-pattern sebaceoma. Am. J.
Dermatopathol. 2001; 23; 437443.
32. Nielsen TA, Maia-Cohen S, Hessel AB, Xie DL, Pellegrini AE.
Sebaceous neoplasm with reticulated and cribriform features: a
rare variant of sebaceoma. J. Cutan. Pathol. 1998; 25; 233
235.
33. Dinneen AM, Mehregan DR. Sebaceous epithelioma: a review
of twenty-one cases. J. Am. Acad. Dermatol. 1996; 34; 4750.
34. Sachez Yus E, Requena L, Simon P, del Rio E. Sebomatricoma:
a unifying term that encompasses all benign neoplasms with
sebaceous differentiation. Am. J. Dermatopathol. 1995; 17;
213221.
35. Leboeuf NR, Mahalingam M. Acanthomatous superficial sebaceous hamartoma? A study of six cases with clarification of the
nomenclature. J. Cutan. Pathol. 2007; 34; 865870.
36. Friedman KJ, Boudreau S, Farmer ER. Superficial epithelioma
with sebaceous differentiation. J. Cutan. Pathol. 1987; 14; 193
197.
37. Lee MJ, Kim YC, Lew W. A case of superficial epithelioma
with sebaceous differentiation. Yonsei Med. J. 2003; 44; 347
350.
38. Steffen C. Mantleoma. A benign neoplasm with mantle
differentiation. Am. J. Dermatopathol. 1993; 15; 306310.
39. Collins GL, Somach S, Morgan MB. Histomorphologic and
immunophenotypic analysis of fibrofolliculomas and trichodiscomas in BirtHoggDube syndrome and sporadic disease.
J. Cutan. Pathol. 2002; 29; 529533.

145

40. Dores GM, Curtis RE, Toro JR, Devesa SS, Fraumeni JF Jr.
Incidence of cutaneous sebaceous carcinoma and risk of
associated neoplasms: insight into MuirTorre syndrome.
Cancer 2008; 113; 33723381.
41. Dowd MB, Kumar RJ, Sharma R, Murali R. Diagnosis and
management of sebaceous carcinoma: an Australian experience. ANZ J. Surg. 2008; 78; 158163.
42. Song A, Carter KD, Syed NA, Song J, Nerad JA. Sebaceous cell
carcinoma of the ocular adnexa: clinical presentations, histopathology, and outcomes. Ophthal. Plast. Reconstr. Surg. 2008;
24; 194200.
43. Dasgupta T, Wilson LD, Yu JB. A retrospective review of 1349
cases of sebaceous carcinoma. Cancer 2009; 115; 158165.
44. Xu XL, Li B, Sun XL et al. Eyelid neoplasms in the Beijing
Tongren Eye Centre between 1997 and 2006. Ophthalmic Surg.
Lasers Imaging 2008; 39; 367372.
45. Deprez M, Uffer S. Clinicopathological features of eyelid skin
tumors. A retrospective study of 5504 cases and review of
literature. Am. J. Dermatopathol. 2009; 31; 256262.
46. Gonzalez-Fernandez F, Kaltreider SA, Patnaik BD et al. Sebaceous carcinoma. Tumor progression through mutational
inactivation of p53. Ophthalmology 1998; 105; 497506.
47. Buitrago W, Joseph AK. Sebaceous carcinoma: the great
masquerader: emerging concepts in diagnosis and treatment.
Dermatol. Ther. 2008; 21; 459466.
48. Rao NA, Hidayat AA, McLean IW, Zimmerman LE. Sebaceous
carcinomas of the ocular adnexa: a clinicopathologic study of
104 cases, with five-year follow-up data. Hum. Pathol. 1982;
13; 113122.
49. Pereira PR, Odashiro AN, Rodrigues-Reyes AA, Correa ZM, de
Souza Filho JP, Burnier MN Jr. Histopathological review of
sebaceous carcinoma of the eyelid. J. Cutan. Pathol. 2005; 32;
496501.
50. Cibull TL, Thomas AB, Badve S, Billings SD. Sebaceous
carcinoma of the nipple. J. Cutan. Pathol. 2008; 35; 608610.
51. Omura NE, Collison DW, Perry AE, Myers LM. Sebaceous
carcinoma in children. J. Am. Acad. Dermatol. 2002; 47; 950
953.
52. Wick MR, Goellner JR, Wolfe JT 3rd, Su WP. Adnexal
carcinomas of the skin. II. Extraocular sebaceous carcinomas.
Cancer 1985; 56; 11631172.
53. Metze D, Soyer HP, Zelger B et al. Expression of a glycoprotein
of the carcinoembryonic antigen family in normal and
neoplastic sebaceous glands. Limited role of carcinoembryonic
antigen as a sweat gland marker. J. Am. Acad. Dermatol. 1996;
34; 735744.
54. Izumi M, Tang X, Chiu CS et al. Ten cases of sebaceous carcinoma
arising in nevus sebaceus. J. Dermatol. 2008; 35; 704711.
55. Izumi M, Mukai K, Nagai T et al. Sebaceous carcinoma of the
eyelids: thirty cases from Japan. Pathol. Int. 2008; 58; 483488.
56. Muthusamy K, Halbert G, Roberts F. Immunohistochemical
staining for adipophilin, perilipin and TIP47. J. Clin. Pathol.
2006; 59; 11661170.
57. Sramek B, Lisle A, Loy T. Immunohistochemistry in ocular
carcinomas. J. Cutan. Pathol. 2008; 35; 641646.
58. Fan YS, Carr RA, Sanders DS, Smith AP, Lazar AJ, Calonje E.
Characteristic Ber-EP4 and EMA expression in sebaceoma is
immunohistochemically distinct from basal cell carcinoma.
Histopathology 2007; 51; 8086.
59. Yang HM, Cabral E, Dadras SS, Cassarino DS. Immunohistochemical expression of D2-40 in benign and malignant
sebaceous tumors and comparison to basal and squamous cell
carcinomas. Am. J. Dermatopathol. 2008; 30; 549554.

 2010 The Authors. Journal compilation  2010 Blackwell Publishing Ltd, Histopathology, 56, 133147.

146

S C Shalin et al.

60. Heyl J, Mehregan D. Immunolabeling pattern of cytokeratin 19

expression may distinguish sebaceous tumors from basal cell
carcinomas. J. Cutan. Pathol. 2008; 35; 4045.
61. Cabral ES, Auerbach A, Killian JK, Barrett TL, Cassarino DS.
Distinction of benign sebaceous proliferations from sebaceous
carcinomas by immunohistochemistry. Am. J. Dermatopathol.
2006; 28; 465471.
62. Abdel-Rahman WM, Peltomaki P. Lynch syndrome and related
familial colorectal cancers. Crit. Rev. Oncog. 2008; 14; 122.
discussion 2331.
63. Lucci-Cordisco E, Zito I, Gensini F, Genuardi M. Hereditary
nonpolyposis colorectal cancer and related conditions. Am. J.
Med. Genet. A 2003; 122A; 325334.
64. Hsieh P, Yamane K. DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech. Ageing Dev. 2008; 129; 391
407.
65. Yuen ST, Chan TL, Ho JW et al. Germline, somatic and
epigenetic events underlying mismatch repair deficiency in
colorectal and HNPCC-related cancers. Oncogene 2002; 21;
75857592.
66. Kruse R, Rutten A, Hosseiny-Malayeri HR et al. Second hit in
sebaceous tumors from MuirTorre patients with germline
mutations in MSH2: allele loss is not the preferred mode of
inactivation. J. Invest. Dermatol. 2001; 116; 463465.
67. Schwartz RA, Torre DP. The MuirTorre syndrome: a 25-year
retrospect. J. Am. Acad. Dermatol. 1995; 33; 90104.
68. Cohen PR, Kohn SR, Davis DA, Kurzrock R. MuirTorre
syndrome. Dermatol. Clin. 1995; 13; 7989.
69. Jones B, Oh C, Mangold E, Egan CA. MuirTorre syndrome:
diagnostic and screening guidelines. Australas. J. Dermatol.
2006; 47; 266269.
70. Kruse R, Ruzicka T. DNA mismatch repair and the significance
of a sebaceous skin tumor for visceral cancer prevention. Trends
Mol. Med. 2004; 10; 136141.
71. Orta L, Klimstra DS, Qin J et al. Towards identification of
hereditary DNA mismatch repair deficiency: sebaceous neoplasm warrants routine immunohistochemical screening
regardless of patients age or other clinical characteristics.
Am. J. Surg. Pathol. 2009; 33; 934944.
72. Abbas O, Mahalingam M. Cutaneous sebaceous neoplasms
as markers of MuirTorre syndrome: a diagnostic algorithm.
J. Cutan. Pathol. 2009; 36; 613619.
73. Marcus VA, Madlensky L, Gryfe R et al. Immunohistochemistry
for hMLH1 and hMSH2: a practical test for DNA mismatch
repair-deficient tumors. Am. J. Surg. Pathol. 1999; 23; 1248
1255.
74. Lindor NM, Burgart LJ, Leontovich O et al. Immunohistochemistry versus microsatellite instability testing in phenotyping
colorectal tumors. J. Clin. Oncol. 2002; 20; 10431048.
75. Umar A, Boland CR, Terdiman JP et al. Revised Bethesda
Guidelines for hereditary nonpolyposis colorectal cancer
(Lynch syndrome) and microsatellite instability. J. Natl Cancer
Inst. 2004; 96; 261268.
76. Boland CR, Thibodeau SN, Hamilton SR et al. A National
Cancer Institute Workshop on Microsatellite Instability for
cancer detection and familial predisposition: development of
international criteria for the determination of microsatellite
instability in colorectal cancer. Cancer Res. 1998; 58; 5248
5257.
77. Nishizawa A, Nakanishi Y, Sasajima Y, Yamazaki N, Yamamoto A. MuirTorre syndrome with intriguing squamous lesions:
a case report and review of the literature. Am. J. Dermatopathol.
2006; 28; 5659.

78. Paraf F, Sasseville D, Watters AK et al. Clinicopathological

relevance of the association between gastrointestinal and
sebaceous neoplasms: the MuirTorre syndrome. Hum. Pathol.
1995; 26; 422427.
79. Rishi K, Font RL. Sebaceous gland tumors of the eyelids and
conjunctiva in the MuirTorre syndrome: a clinicopathologic
study of five cases and literature review. Ophthal. Plast.
Reconstr. Surg. 2004; 20; 3136.
80. Tsalis K, Blouhos K, Vasiliadis K, Tsachalis T, Angelopoulos S,
Betsis D. Sebaceous gland tumors and internal malignancy in
the context of MuirTorre syndrome. A case report and review
of the literature. World J. Surg. Oncol. 2006; 4; 8.
81. Mangold E, Pagenstecher C, Leister M et al. A genotype
phenotype correlation in HNPCC: strong predominance
of msh2 mutations in 41 patients with MuirTorre syndrome.
J. Med. Genet. 2004; 41; 567572.
82. Chhibber V, Dresser K, Mahalingam M. MSH-6: extending the
reliability of immunohistochemistry as a screening tool in
MuirTorre syndrome. Mod. Pathol. 2008; 21; 159164.
83. Rutten A, Burgdorf W, Hugel H et al. Cystic sebaceous tumors
as marker lesions for the MuirTorre syndrome: a histopathologic and molecular genetic study. Am. J. Dermatopathol.
1999; 21; 405413.
84. Abbott JJ, Hernandez-Rios P, Amirkhan RH, Hoang MP. Cystic
sebaceous neoplasms in MuirTorre syndrome. Arch. Pathol.
Lab. Med. 2003; 127; 614617.
85. Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR.
Histopathological identification of colon cancer with microsatellite instability. Am. J. Pathol. 2001; 158; 527535.
86. Ponti G, Venesio T, Losi L et al. BRAF mutations in multiple
sebaceous hyperplasias of patients belonging to MYH-associated polyposis pedigrees. J. Invest. Dermatol. 2007; 127; 1387
1391.
87. Barnetson RA, Devlin L, Miller J et al. Germline mutation
prevalence in the base excision repair gene, MYH, in patients
with endometrial cancer. Clin. Genet. 2007; 72; 551555.
88. Ajith Kumar VK, Gold JA, Mallon E, Thomas S, Hodgson SV.
Sebaceous adenomas in an MYH associated polyposis patient of
Indian (Gujarati) origin. Fam. Cancer 2008; 7; 187189.
89. Ponti G, Ponz de Leon M, Maffei S et al. Attenuated familial
adenomatous polyposis and MuirTorre syndrome linked to
compound biallelic constitutional MYH gene mutations. Clin.
Genet. 2005; 68; 442447.
90. Reitmair AH, Redston M, Cai JC et al. Spontaneous intestinal
carcinomas and skin neoplasms in Msh2-deficient mice. Cancer
Res. 1996; 56; 38423849.
91. Edelmann W, Yang K, Umar A et al. Mutation in the mismatch
repair gene Msh6 causes cancer susceptibility. Cell 1997; 91;
467477.
92. Watt FM, Collins CA. Role of beta-catenin in epidermal stem
cell expansion, lineage selection, and cancer. Cold Spring Harb.
Symp. Quant. Biol. 2008; 73; 503512.
93. Lazar AJ, Calonje E, Grayson W et al. Pilomatrix carcinomas
contain mutations in CTNNB1, the gene encoding betacatenin. J. Cutan. Pathol. 2005; 32; 148157.
94. Chan EF, Gat U, McNiff JM, Fuchs E. A common human skin
tumour is caused by activating mutations in beta-catenin. Nat.
Genet. 1999; 21; 410413.
95. Niemann C, Unden AB, Lyle S, Zouboulis Ch C, Toftgard R,
Watt FM. Indian hedgehog and beta-catenin signaling: role in
the sebaceous lineage of normal and neoplastic mammalian
epidermis. Proc. Natl Acad. Sci. USA 2003; 100 (Suppl. 1);
1187311880.

 2010 The Authors. Journal compilation  2010 Blackwell Publishing Ltd, Histopathology, 56, 133147.

Sebaceous neoplasms and MuirTorre syndrome

96. Niemann C, Owens DM, Hulsken J, Birchmeier W, Watt FM.

Expression of DeltaNLef1 in mouse epidermis results in differentiation of hair follicles into squamous epidermal cysts and
formation of skin tumours. Development 2002; 129; 95109.
97. Niemann C, Owens DM, Schettina P, Watt FM. Dual role of
inactivating Lef1 mutations in epidermis: tumor promotion and
specification of tumor type. Cancer Res. 2007; 67; 29162921.
98. Takeda H, Lyle S, Lazar AJ, Zouboulis CC, Smyth I, Watt FM.
Human sebaceous tumors harbor inactivating mutations in
LEF1. Nat. Med. 2006; 12; 395397.
99. Zanesi N, Croce CM. Fragile histidine triad gene and skin
cancer. Eur. J. Dermatol. 2001; 11; 401404.
100. Fong LY, Fidanza V, Zanesi N et al. MuirTorre-like syndrome
in Fhit-deficient mice. Proc. Natl Acad. Sci. USA 2000; 97;
47424747.
101. Huber O, Weiske J. Beta-catenin takes a HIT. Cell Cycle 2008;
7; 13261331.
102. Weiske J, Albring KF, Huber O. The tumor suppressor Fhit acts
as a repressor of beta-catenin transcriptional activity. Proc. Natl
Acad. Sci. USA 2007; 104; 2034420349.

147

103. Goldberg M, Rummelt C, Foja S, Holbach LM, Ballhausen WG.

Different genetic pathways in the development of periocular
sebaceous gland carcinomas in presumptive MuirTorre syndrome patients. Hum. Mutat. 2006; 27; 155162.
104. Holbach LM, von Moller A, Decker C, Junemann AG, RummeltHofmann C, Ballhausen WG. Loss of fragile histidine triad
(FHIT) expression and microsatellite instability in periocular
sebaceous gland carcinoma in patients with MuirTorre
syndrome. Am. J. Ophthalmol. 2002; 134; 147148.
105. Benjamin CL, Ananthaswamy HN. p53 and the pathogenesis
of skin cancer. Toxicol. Appl. Pharmacol. 2007; 224; 241
248.
106. Das P, Kotilingam D, Korchin B et al. High prevalence of p53
exon 4 mutations in soft tissue sarcoma. Cancer 2007; 109;
23232333.
107. Blanpain C, Fuchs E. Epidermal homeostasis: a balancing act of
stem cells in the skin. Nat. Rev. Mol. Cell Biol. 2009; 10; 207
217.
108. Watt FM, Lo Celso C, Silva-Vargas V. Epidermal stem cells: an
update. Curr. Opin. Genet. Dev. 2006; 16; 518524.

 2010 The Authors. Journal compilation  2010 Blackwell Publishing Ltd, Histopathology, 56, 133147.