ARTICLE
Chronic repeated exposure to ultraviolet radiation (UV) results in skin
photoaging and skin cancer, inducing the development of cutaneous lesions
such as solar keratosis (SK), basal cell carcinoma (BCC) and squamous
cell carcinoma (SCC) [1-5].
The most common epithelial precancerous lesions found in photo-damaged
skin is SK. Lever [6] defined SK as squamous cell carcinoma in situ
due to the presence of anaplastic cells in the lesion. Other dermatologists
classified SK as squamous cell carcinoma grade 1/2 [7].
Transition of SK to SCC is well-documented in the literature [8]. Reported
rates of malignant transformation range from 12 to 25% [8]. The transition
from SK to SCC, where the same type of cells are involved, can be easily
understood. However, the transition between SK and BCC is more difficult
to explain. Cells of SK and BCC, products of two different pathways of
differentiation, have different morphology, antigenic characteristics
and biological behavior [6, 9, 10].
In the dermatopathological literature, the relation between SK and BCC
is rarely mentioned. Marks et al. conducted a clinical study on
2,643 patients with SK and concluded that BCC almost certainly does not
arise from SK [11].
Conversely, Eller & Eller noted in 1951 that BCC may uncommonly
appear from SK [12]. In 1981, Lambert and Schwartz also raised the possibility
that BCC originates from SK. They examined a series of 52 biopsy specimens
which contained SK and BCC and found that in 48 specimens the two processes
were contiguous [13].
Nogita et al. [14] suggested that pre-existent cutaneous changes
might play an important role in the etiology of BCC on the lower extremities.
They reported ten cases of BCC occurring in several pre-existing cutaneous
lesions, one of which was SK. Recently, Goldberg et al. [15] reported
three patients who developed BCC within areas encompassed by proliferative
SK. They stated that the proliferative form of SK has an increased tendency
to develop into skin cancer, either BCC or SCC.
During routine examination of histological slides we noticed a gradual
and continuous transition between SK and BCC. In this study, we attempted
to evaluate the prevalence of this phenomenon and to identify its histological
characteristics.
Methods
Forty slides, each containing SK and BCC, dating from 1984 to 1994,
were retrieved from a collection in the Institute of Pathology of Beilinson
Medical Center. These slides were prepared from biopsy specimens, excised
from the head and neck regions chronically exposed to the sun, from 40
patients. All slides had previously been stained with hematoxylin and
eosin. Each slide was examined by two of the authors.
Parameters examined
1. Type of SK, according to Lever's classification [6].
2. Type of BCC, according to Lever's classification [9].
3. BCC-tumor depth:
The maximal depth of each tumor was measured vertically from the granular
layer of the epidermis to the deepest point of penetration, analogous
to the measurements of melanoma microstaging [16].
4. The relation between SK and BCC was recorded for each slide. Statistical
analysis was done using the chi square test for the following parameters:
a. Type of SK versus type of BCC.
b. Type of SK versus tumor's depth of BCC.
Consequently, in order to estimate the prevalence of this phenomenon,
73 additional slides which had been diagnosed initially as BCC were re-examined.
All these slides were prepared from specimens excised during January and
February, 1991 in the Beilinson Medical Center. All specimens had been
excised from the head and neck regions of 73 patients. In addition to
the BCC which had previously been diagnosed, we recorded the presence
of spinous layer atypia in each slide, as an initial marker for the development
of SK. The spinous atypia is manifested by variation in size and shape
of the disorderly arranged keratinocytes, with paler cytoplasm.
Results
In the 40 slides examined, in which both SK and BCC were histologically
identified, the following results were obtained:
1. Type of SK: examination of 40 slides revealed 24 atrophic, three
hypertrophic, two acantholytic and two bowenoid SK lesions. Nine slides
which did not conform to any of the above, were labeled unclassifiable.
2. Type of BCC: examination of 40 slides revealed 23 solid circumscribed,
seven invasive, four superficial, three solid circumscribed with adenoid
features, one fibrosing, one fibrosing with adenoid features and one clear-cell
BCC lesion. A slight pigmentation (which was not consistent with the definition
of pigmented BCC) was found in five lesions.
3. The mean depth of invasion of BCC lesions was 2.33 mm (range 0.8-4.8
mm).
4. Three levels of relation between SK and BCC were recorded:
a) A gradual and continuous transition between SK and BCC was found
in 15 (37.5%) slides. In the epidermis, the keratinocytes showed loss
of polarity, pleomorphism and atypia of their nuclei. These findings are
consistent with SK. From this area there is an extension where the cells
become gradually and continuously more basophilic, until they appear as
typical cells of BCC in a characteristic arrangement of peripheral palisading.
b) SK and BCC adjoining each other (without gradual transition) was
found in 3 (7.5%) slides.
c) In the remaining slides, SK and BCC were found to have neither a
common border, nor a transition zone.
The results are summarized in Table
I. No statistically significant difference was found between the
type of SK and type of BCC or between the type of SK and BCC tumor depth.
Revision of 73 additional slides, diagnosed previously only as BCC revealed
the presence of spinous layer atypia in 26 (35.6%). In seven (9.6%) of
these 73 slides a gradual and continuous transition between atypical spinous
cells and BCC was found.
A gradual and continuous transition between atypical cells of the spinous
layer and BCC is shown in Figures
1.
Discussion
Forty slides containing both SK and BCC were examined. We found a gradual
and continuous transition between these two processes in 15 (37.5%) of
them. Examination of 73 additional slides, previously diagnosed as BCC,
revealed adjacent atypia of the spinous layer in 26 (35.5%). In seven
(9.6%), the transition between atypical spinous cells and BCC was gradual
and continuous.
Both SK and BCC are very common cutaneous lesions. Reported SK prevalence
rates range from 11 to 25% in various northern hemisphere populations
[17]. BCC accounts for more than 75% of the non-melanoma skin cancers
diagnosed in the USA each year [10]. Yet, the high occurrence of adjacent
lesions of SK and BCC found in our study, demands further clarification.
Possible explanations for these findings are:
1) UV radiation as a common factor which induces development of both
SK and BCC.
2) Local effects of one pathological process on the other.
3) Malignant transformation of a stem cell common to both SK and BCC.
1. UV radiation. Following chronic exposure
to the mutagenic effect of UV light, there is a high probability that
several cells of different types and locations will simultaneously undergo
neoplastic transformation. Therefore, the simultaneous appearance of both
SK and BCC in a patient is, in any case, not incidental.
2. Local effects. Extracts of BCC inhibited T cell response to phytohemagglutinin
to a greater extent than extracts of normal epidermis [18]. Sherertz et
al. [19] demonstrated that the inhibition of lymphocyte response correlated
with the level of aggressiveness of BCC lesions. They suggested that BCC
might cause inhibition of local lymphocyte response.
Decreased immune function is known to result in malignant transformation
[18, 20]. Therefore, we suggest that a cutaneous lesion (either SK or
BCC) might release local factors which induce the development of the other,
possibly by inhibiting the local immune response.
3. Malignant transformation of a common stem cell. A pluripotent stem
cell may undergo malignant transformation followed by differentiation
into two or more different pathways. Diversity within a population of
malignant cells and the clinical implications of the phenomenon, termed
"tumor-cell heterogeneity" were described by Schnipper in 1986 [21]. Analogous
processes occur, for example, in myeloproliferative diseases where all
the cell lines which originate from a common stem cell may be involved
in the neoplastic changes [22, 23]. In testicular germ cell tumors there
is also a high occurrence (62%) of mixed tumors which contain at least
two types of neoplastic cell lines; a finding which is attributed to malignant
transformation of a pluripotent germ cell [24]. One may assume, therefore,
that the end result of a transformed epidermal stem cell could be the
development of both SK and BCC. Moreover, the gradual transition demonstrated
between SK and BCC, as well as the the presence of intermediate cells
might be an expression of cellular heterogeneity derived from the existence
of a common stem cell.
The form of intermediary type of basosquamous carcinoma described previously
by Darier and Ferrand [25] and later by Faria in 1985 [26] contains definite
areas of BCC and SCC, as well as areas where tumor cells appear in intermediate
stages of differentiation between BCC and SCC. The presence of different
cell types in the tumor might also represent cellular heterogeneity derived
from a common stem cell. This type of carcinoma can be regarded as an
advanced form of a lesion which contains gradual and continuous transition
between SK and BCC (as demonstrated in our study), with a later transformation
of SK to SCC.
Further investigations should be focused upon these intermediate cells
found in the gradual and continuous form between SK and BCC. Comparison
of genetic and antigenic characteristics of the intermediate cells, SK
and BCC cells might go some way to explaining the observations presented
herein.
CONCLUSION
Acknowledgement
The authors wish to thank Mrs. Bilha Savell for preparing this manuscript
for publication.
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