Introduction
Neurofibroma may occur as
a solitary tumor or as multiple lesions which may assume a wide distribution or
segmental in pattern. All NFs types are histologically and clinically identical
in behavior whether they occur as a part of neurofibromatosis or as solitary
tumors distinct from neurofibromatosis. [1].
Cutaneous neurofibroma
presents itself as a mass that protrudes just above the surface of the skin or
lies under the skin with an overlying violaceous hue. They are softer than the
surrounding connective tissue, often creating a “buttonholing” sensation when a finger
is rubbed gently over the surface. Neurofibromas show no site of predilection,
although they rarely occur on the palms and soles. They can develop anywhere on
the skin, and there is a wide variation in their shape and size. They are
considered as one of the hallmarks of neurofibromatosis. [2, 3]
Microscopically, NFs
consists of spindle cells (Schwann cells, fibroblasts, and perineural cells)
with thin elongated wavy nuclei that regularly spaced between collagen bundles
in a loose matrix. The spacing between adnexal structures is usually preserved.
[4] Mast cells as a histopathologic clue are sparse between spindle cells.
Mitoses in classic examples of NFs are uncommon, but mitotic figures can be
frequent in atypical variants or those that develop in the context of
neurofibromatosis. [1] Several histopathological variants have been described
including extraneural, sporadic cutaneous NF (ENSCN), diffuse NF, intraneural
NF, and plexiform NF.[4] The histologic differential diagnoses for NF include a
number of neoplastic and non-neoplastic neuronal lesions such as schwannoma,
nerve sheath myxoma, ganglioneuroma, traumatic neuroma and non-neuronal
neoplasms such as dermatofibrosarcoma protuberance.
The term “sebaceous
induction”
should be precisely defined. Ackerman et al. described sebaceous induction as
“a single lobule, unaffiliated with a hair follicle or several lobules joined
in a normal fashion to a villous follicle by a sebaceous duct. [5] In another
study, sebaceous induction was defined as more than one rudimentary sebaceous
glands overlying the lesion at an abnormally superficial level of the dermis
without a normal hair follicle associated with them. [6].
Follicular induction is
defined as the formation of germ (nubbins of basaloid cells on the undersurface
of the epidermis) and associated papillae or formation of rudimentary villous
hair and associated sebaceous gland in a very superficial location.
Although the
histopathologic diagnosis of NFs in most cases is straightforward, sometimes is
challenging when other possible diagnoses such as dermatofibrosarcoma
protuberance (DFSP) or other spindle cell neoplasms come into the
consideration, specifically when the pathologist is dealing with superficial
biopsies. In this study, we assessed the frequency of sebaceous induction in NF
and whether or not it can be used as a histopathologic clue for diagnosis of
it.
Materials and methods
This is a retrospective study of 100 cases of
neurofibromas. All slides were pulled from the archive of the pathology
department at King Hussein Medical Center from 2012 until 2016 with use of the
key word 'neurofibromas'. A senior dermatologist and a dermatopathologist
reviewed all cases for followingy.
parameters: age, gender,
anatomical site, histopathologic variant, sebaceous induction, follicular
induction, epidermal change, and the presence of mitotic figures per 10
high-power fields (HPF).
In this study, we defined
sebaceous induction as an increase in number of sebaceous lobules (at least
more than two lobules) that they are not affiliated with a normal hair
follicle. A short, rather distended sebaceous lobule away from the site of
normal sebaceous gland is also considered as sebaceous induction. These changes
are easily appreciated when the biopsy was taken from anatomical sites other
than the face, it is difficult to interpret the enlarged or hyperplastic
sebaceous gland in the face, therefore it was excluded from the
study. Consulted cases in which the slides were no longer available were
also excluded.
Microsoft Excel 2020 was
used in our statistical analysis. The data (scores) had been entered into a
Microsoft Excel 2020 worksheet and configured properly. Mean (± standard
deviation) have been used to describe continuous variables (i.e. age). Count
(frequency) have been used to describe other nominal variables (i.e. gender).
Results
One hundred consecutive
NFs were evaluated from 100 patients, NFs were as common in females as males
(male to female ratio 1: 1), 49 patient were male ,while 51 were female .The
mean age was 64 ± 13.7 years (range, 14–91 years), with 47% diagnosed in between
60 and 80 years.(Table 1) The most common sites were the upper extremities
(20%) and the back (16%) followed by abdomen (13%), chest (11%) and neck (11%).
(Table 2) The detailed clinical history was not available for all cases.
The histopathological features
that were observed in our slides include delicate wavy spindle cells embedded
in a loose stroma composed of thin collagen bundles. The most common variant
was extraneural sporadic cutaneous NF (95%), with only 3 cases of plexiform NF
(3%) and 2 cases of diffuse NF (2%). No abnormal mitotic figures or necrosis
were identified in all cases studied (figure 1).
Sebaceous induction was
present in 22% of NFs with exclusion of NFs located on the face (forehead,
chin, cheek, and nose) which constitute about 10 % of cases. The sites of
distribution for NFs with sebaceous induction showed as follows: Upper
extremities (3%), lower extremities (1%), chest (4%), back (5%), abdomen (3%),
neck (4%), perianal (1%), ear lobe (1%), scalp (5%).
Table I: Age distribution of NF cases.
|
Age (years)
|
Number of cases
|
|
0-20
|
1
|
|
20-40
|
6
|
|
40-60
|
38
|
|
60-80
|
47
|
|
Above 80
|
8
|
Table II: anatomic location of NF cases.
|
Anatomic location
|
Number of cases
|
|
Face
|
21
|
|
Upper extremities
|
15
|
|
Back
|
13
|
|
Abdomen
|
12
|
|
Chest
|
11
|
|
Scalp
|
8
|
|
Lower extremities
|
6
|
|
Neck
|
5
|
|
Perianal
|
5
|
|
Earlobe
|
4
|
Figure legends
Figure 1: Neurofibroma with sebaceous induction. Biopsy was taken from midback (A, H&E: 100x), perianal area (B,H&E: 100x), mid trunk (C,H&E: 20x) and Knee (D,H&E: 20x).
Discussion
In this study, we report
sebaceous induction in a large series of NF that has not been studied before.
Follicular induction has been mentioned as a phenomenon associated with a
variety of lesions such as dermatofibromas, dermatofibrosarcoma protuberance, focal
mucinosis, wart, seborrheic keratosis, neurofibroma, scar, angioma, nevus
sebaceous, anetoderma, pilomatricoma and chronic lymphedema
[5-8].
Sebaceous induction has also been mentioned in neurofibroma in a study done by
Requena et.al.[9] However, they did
not obtain the frequency of this phenomenon and also there is no any
cross-sectional study in the literature after a thorough search. In our work,
sebaceous induction was identified in 22% of our retrospectively cases and all
reported cases fulfilled the criteria for sebaceous induction (more than two
lobes, very superficial in location or not affiliated with hair follicle). The
mean age in our study was 64 years somehow older for the development of NFs.
[10] No gender predilection was found in our study. In contrast, in none of our
cases studied, follicular induction was identified.
As a well-established phenomenon, epidermal,
sebaceous and follicular induction has been frequently described in dermatofibroma. [5, 10-16] One study showed sebaceous and follicular
induction is associated with dermatofibroma (especially the cellular variant)
in 16% of cases.[6] In another large study, Shuweiter and Boer have showed
sebaceous and follicular inductions are present in 31.6% of dermatofibromas.
[17] They included mantle differentiation as a part of sebaceous induction in
their assessment and this would be the reason why they reached to a higher
percentage of induction by dermatofibromas compared with previous works. [17]
Considering the above numbers in dermatofibromas, sebaceous induction in .
neurofibromas as 22% in
our study should be interpreted as a common finding. However in none of
our cases follicular induction was noticed.
In another study,
follicular induction has been reported overlying one case of DFSP. [18]
Following this finding, the authors reviewed all cases of DFSP for the previous
eight years. In a total of 28 cases of DFSP studied by the authors, neither
follicular nor sebaceous induction was identified. This is important, because
sebaceous induction could be used as a histopathologic clue for diagnosing of
neurofibroma in differential with DFSP. Moreover, Ackerman reviewed “induction
of follicles” in different lesions in the skin and illustrated another case of
DFSP that was associated with follicular induction. [19] In none of these two
cases of DFSP,sebaceous induction was identified.
The etiology of
underlying sebaceous induction in NF is unknown, but probably is similar to
sebaceous induction in dermatofibroma where epidermal-mesenchymal cellular
interactions, like induction, occur in response to injury with tissue repair.
Epidermal growth factor (EGF) is one of the important soluble mediators which
are known to stimulate the proliferation and differentiation of a variety of
transformed and benign tissues. Expression of epidermal growth factor receptor
(EGF-R) in dermal spindle cells and the epidermis has been suggested as a cause
of sebaceous induction. [20] Other authors have suggested a role for Hedgehog
pathway and beta-catenin in regulation of sebocyte development. Aberrant
Hedgehog signaling results in formation of sebaceous glands in the areas of the
skin that normally devoid of hair and associated structures, whereas low levels
of beta-catenin stimulate sebaceous differentiation. [21].
We think in a similar way, the balance of these two pathways may influence whether or
not sebaceous induction occurs in NFs, but the exact mechanism has not
completely been elucidated.
Although the frequency of
22% is significant in our work, it should be supported by other studies and
more samples to be fully considered as one histopathological clue for
diagnosing of NFs.
Limitations
The findings of this study
have to be seen in the light of some limitations. First, the detailed clinical history was not
available for all cases; as in most retrospective studies. Therefore, we could
not evaluate if there is any clinical implication or correlation for those
patients who have NFs with sebaceous induction. Second, there is no any
cross-sectional study in the literature after a thorough search. Therefore, we
did not have the opportunity to compare our results with other studies. Further
studies with larger sample size is needed to further elaborate the significance
of this finding.
Conclusion
Sebaceous
induction is an interesting and not uncommonly observed feature in NFs, not
previously studied in a series of cases. On the other hand, follicular induction was not shown
to be associated with neurofibromas.
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