Diagnostic and Therapeutic Standards in Dermatological Oncology:

Basal Cell Carcinoma (Basalioma, Basal Cell Epithelioma)

Helmut Breuninger and Claus Garbe

1. General Information
1.1 Definition and Epidemiology
1.2 Clinical Manifestations and Histology
1.3 Prognosis and Staging
2. Diagnosis
3. Therapy
3.1 Micrographic Surgery
3.2 Conventional Surgery
3.3 Cryotherapy
4. Radiotherapy
5. Chemotherapy/Immunotherapy
5.1 Local Chemotherapy/Immunotherapy
5.2 Systemic Chemotherapy for metastasizing basal cell carcinoma
6. Other Forms of Therapy
7. Follow Up Evaluation
8. References
Basal Cell Carcinoma -2-

1. General Information

1.1 Definition and Clinical Epidemiology

Basal cell carcinoma is a locally destructive tumor, that usually does not metastasize. In the
literature only isolated cases of metastases formation are described. The basal cell carcinoma
is one of the most common malignant tumors in Central Europe. In Germany there are about
100 new cases per 100.000 residents a year. The average age is around 60 years. There is a
tendency though towards a younger age of manifestation. Men and women are affected
equally. In about 80% of the cases It appears in the head-and-neck area. In rare cases basal
cell carcinoma can lead to death through a destructive growth per continuitatem in vital
structures of the head-and-neck area, but generally there is no formation of metastases [Lo et
al. 1991]. Aetiological factors are in particular a genetic disposition with little skin
pigmentation as well as overexposure of the skin to UV radiation. Generally the growth of the
tumor begins without a pre-cancerous stage. Basal cell carcinomas on scars and on nevi
sebacei have been observed occasionally. Arsenic has been recognized as a cause of basiloma.
Long-term drug induced immune suppression increases the risk of basal cell carcinomas. It
can also develop within associated syndromes such as xeroderma pigmentosum, basal cell
nevus syndrome [Woolgar et al. 1987; Gorlin, 1987] and albinism.
1.2 Clinical Manifestations and Histology

A typical basal cell carcinoma is a slightly raised, defined, yellow-reddish lesion with a
translucent pearly border. Other variations exist, such as the superficial erythomatous basal
cell epithelioma which tends to occur on covered portions of the trunk or the so called
sclerosing type which resembles a scar. More advanced basal cell carcinomas progress into
erosions and ulcerations, and can destroy underlying tissue (muscle, cartilage, bone).
Histogenetically, basal cell carcinomas arise from basal cells of the epidermis and/or from the
external rootsheet of hair follicles. Partially they show a differentiation that resembles
appendages (follicles, sebaceous glands, eccrine or apocrine sweat glands). The histological
subtyping of basal cell carcinoma is based on different patterns of differentiation, which are
expressed in the current histological classifications of the WHO [Lever, Schaumburg-Lever,
1990; Heenan et al. 1996]. This classifications proved to be effective:
• Multifocal superficial basal cell carcinoma (superficial multi-centric)
• Solid nodular basal cell carcinoma
Basal Cell Carcinoma -3-

• Adenoid nodular basal cell carcinoma

• Cystic nodular basal cell carcinoma
• Infiltrative basal cell carcinoma, non-sclerotic, sclerotic (desmoplastic, morphea like)
• Fibroepithelial basal cell carcinoma
• Basal cell carcinoma with an adnexoid differentiation, follicular, eccrine
• Basosquamous carcinoma
• Keratotic basal cell carcinoma
• Pigmented basal cell carcinoma
• Basal cell carcinoma associated with basal cell nevus syndrome
• Micronodular basal cell carcinoma
(Please note: the three subtypes of the nodular basal cell carcinoma, the solid, the adenoid and
the cystic nodular basal cell carcinoma are categorized in the WHO classification under one
number. The clinical infiltrative behavior, however, is different according to clinical
experience: the adenoid nodular basal cell carcinoma demonstrates a significantly wider
subclinical infiltration than the cystic one, the solid nodular basal cell carcinoma occupies the
middleground between the two. Therefore a separate listing of these types seems necessary).
More and more we find mixed forms of these types. Collision tumors with squamous-cell
carcinoma are possible. Alongside these forms there are a number of rare varieties, such as the
adamantoid basal cell carcinoma, and the clear cell basal cell carcinoma among others. The
infiltrative type of basal cell carcinoma demonstrates the highest malignancy, with a high risk
of local recurrence. The so called meta-typical basal cell carcinoma demonstrates focal
structures of a squamous-cell carcinoma. Consequently it is a "real" malignant tumor with the
possibility of metastases formation. Here the desmoplastic squamous-cell carcinoma, which
resembles the fibrosing basal cell carcinoma, must be differentiated and excluded.

1.3 Prognosis and Staging

The basal cell carcinoma of the skin develops over months or years and progresses into
ulcerous lesions(ulcus rodens) that can also destroy deeper tissue structures (ulcus terebrans).
There is a danger of a lethal ending, if this destruction includes vital structures. The incidence
of metastases has been estimated to be less than 1:1000. For basal cell carcinomas as for
squamous-cell carcinomas and other carcinomas of the skin the staging according to the
UICC classification is still valid. However, it is clinically useless, because the T-classification
Basal Cell Carcinoma -4-

is too rough and the categories N and M practically don't exist. To ensure the quality of the
therapy the following information is important:
• Tumor size (horizontal tumor diameter)
• Localisation
• Type of basalioma
• Histological spreading into deeper tissue (vertical tumor diameter)
• Therapeutical safety margin (in case of an excision, radiotherapy, or cryotherapy)
• Margins of surgical resection microscopically in healthy tissue or not in healthy tissue.
For this reason the histopathological preparation of the tumor material is important (see
section 3.).

2. Diagnosis

The diagnosis is made clinically [Presser, Taylor, 1987]. The histological confirmation
through an incisional biopsy, an excisional biopsy, or therapeutic excision depending on the
size of the tumor and the therapeutical approach is necessary. The pre-operative imaging by
means of an ultrasonic diagnostics is not necessary, but useful under certain circumstances
[Hoffmann et al. 1990]. Clear definition of tumor boundaries can not be realized reliably
[Anargyrou, Breuninger, 1993; Gassenmaier et al. 1990]. When dealing with pigmented
basalioma reflective light microscopy is useful for differentiated diagnosis. With destructively
growing basal cell carcinomas further classification of the depth of the infiltration by means
of CT or MRI is necessary.
In case of clinical suspicion of metastases formation in the lymph nodes or internal organs,
the usual examinations, such as lymph node sonography, chest x-ray, computer tomography
of the abdomen etc. are carried out for continuing diagnosis.

3. Therapy

Operative therapy in combination w with histological confirmation is the standard procedure

for the treatment of basal cell carcinomas. In case of incomplete removal spontaneous
regression of remaining tumor parts is possible. However, depending on the type of tumor the
extent of the regression varies accordingly. It is more likely to happen with the solid type than
with the infiltrative type. Since the spontaneous regression is not predictable, a follow up
operation has to be carried out, if the tumor is located on the face or especially if it is the
Basal Cell Carcinoma -5-

infiltrative type. This needs to be done until the margins of surgical resection have been
proven to be tumor free [Richmond, Davie, 1987; Breuninger et al. 1992; De Silva, Dellon,
1985]. The spectrum of further therapy modalities is wide[Fleming et al. 1995]. Because of
the locally destructive character of the basal cell carcinoma and the fact that partially its
subclinical growth can not be recognized pre-therapeutically [Breuninger, Dietz, 1991;
Breuninger, 1993], the results of the different treatment procedures vary.

Diagram displaying the stages for the therapy of the basal cell carcinoma
Least danger of recurrence: micrographic surgery
Necessary: a) Infiltrative type of basal cell carcinoma of the head and of the distal
extremities.
b) Larger basal cell carcinomas (over 5 mm in diameter) situated in
problematic locations: Noses, orbital and auricular areas and large
tumors (over 20 mm diameter) in the other areas of the face.
c) Recurring tumors.
Recommended: For other types of basal cell carcinoma then the infiltrative type under
20 mm in unproblematic regions of the face, since it offers of the
possibility of minimally invasive surgery.
Otherwise: Conventional surgery with safety margins from 3-10 mm.
Radiotherapy as an alternative to conventional surgery or in cases of
Alternatives primary inoperability as well as after incomplete surgical removal
(R1, R2).
Cryotherapy: Smaller superficial tumors with patients of advanced
age, when surgery would be to difficult.
Further alternatives: Shave-excision, CO2 laser removal, photodynamic therapy, local
chemotherapy (5-FU) in case of superficial basal cell carcinomas.

3.1 Micrographic Surgery (Complete Border Cut Histology)

The local infiltrative growth of all types of basal cell carcinomas is characterized by
asymmetric, mostly very thin-lined subclinical fringes, partially far reaching (up to several
cm) in horizontal direction [Breuninger et al. 1989c; Breuninger et al. 1989a]. The probability
of permanent healing through micrographic surgery is high (95-99,5%) [Kopke, Konz, 1995;
Hruza, 1994; Breuninger et al 1989b; Rowe et al. 1989b; Riefkohl et al. 1985]. The
Basal Cell Carcinoma -6-

recurrence rate can go up 15% in case of recurring tumors [Rigel et al. 1981; Weissmann et al.
1981].
Micrographic surgery implies the careful surgical excision of the tumor (2-4 mm safety
margin) with topographical marking and a subsequent complete histological examination of
the whole outside surface of the excised material (see picture) [Breuninger, Schaumburg-
Lever, 1988; Breuninger, 1984; Holzschuh, Breuninger, 1996]. Herewith a topographical
categorization of the subclinical fringes is possible, if necessary followed up by excisions,
until the outside of the excised material is tumor free.

Picture

Micrographic surgery is especially recommended with recurrent basal cell carcinoma and with
large tumors in problematic locations or with invasive growing types of basiloma due to their
large subclinical infiltration potential and the high risk of recurrence [Sahl, 1995; Breuninger,
1987; Randle, 1996; Richmond, Davie, 1987]. Different methods for frozen sections (for
example, the Mohs' technique common in America) and also for paraffin sections (for
example, the border cut technique according to Breuninger) have been developed. These
methods allow the complete verification of the margins of surgical resection and help to
reduce the safety margin. Therefore, this procedure can also be useful with small
unproblematic tumors. Because of the high diagnostic accuracy, healthy skin can be saved
and is only excised in accordance with histologically confirmed tumor infiltration. This
procedure is safe and offers good cosmetic results.
This examination can be carried out using either the frozen sections or the paraffin sections
procedure. In case of spread out tumors, tumors in difficult locations or with diffuse borders,
the defect should be left open until the complete removal of all tumor parts has been proven.

3.2 Conventional Surgery

Conventional surgery with random histological sampling [Breuninger et al. 1988] involves a
higher risk of recurrence, amounting to about 5-10%, because of the specific local infiltration
of the basal cell carcinoma [Silverman et al. 1991a; Steinkogler, Scholda, 1993; Rowe et al.
1989c; Robinson et al. 1989; Rowe et al. 1989b; Dubin, Kopf, 1983; Silverman et al. 1992a].
Some authors even state 50% recurrence, especially if collectives with recurrent tumors are
considered [Casson, 1980; Conley, 1974; Koplin, Zarem, 1980; Lang, Maize, 1986; Levin,
Basal Cell Carcinoma -7-

1983; Marchac et al.1982; Nevrkla, Newton, 1974; Payne, 1966; Reyman, 1980; Rowe et al.
1989a; Schid-Ganz, Eichmann, 1989; Schubert et al. 1979; Taylor, Baarisoni, 1973;
Waldmann, Wätzig, 1979]. Analyzing this data, the composition of the collectives according
to tumor size, type of tumor, and location as well as treatment of the primary tumor or the
recurrent tumor play an important role. This data is sufficiently documented only in a few
publications, so that a comparison of the different treatments is only possible within certain
limits. In order to ensure a minimal risk of relapse of the tumor using conventional surgery
large safety margins (0,3-1 cm) must be used at the expense of the patient even in case of
small tumors without ever accomplishing the high safety of micrographic surgery. A solitary
cross section examination with narrow levels of section also delivers good results (recurrence
rate 1-2%) for small solid tumors (< 5 mm). Even completely excised lesions that are
clinically suspicious of being basiloma should be worked over in a special manner, for
example by means of a serial layer technique, in order to make an evaluation of the margins
of surgical resection possible. Simple representative cuts are not sufficient.

3.3 Cryotherapy

Cryotherapy with liquid nitrogen using either the contact or the spray technique at -196° is a
procedure that can produce results comparable to conventional therapy, if it is applied
appropriately and if similar safety margins are used [Hall et al. 1986; Tuppurainen, 1995;
Rowe et al. 1989c; Rowe et al. 1989b]. In case of clearly defined not too large superficial
tumors cryotherapy can serve as an alternative especially for patients of advanced age.

4. Radiotherapy

Radiotherapy has comparable healing prospects to conventional surgery [Silverman et al.

1991a; Rowe et al. 1989c; Rowe et al. 1989b; Dubin, Kopf, 1983; Silverman et al. 1992b;
Smith, Grande, 1991; Lovett et al. 1990; Grieb et al. 1995]. However because micrographic
surgery produces better results than either it is the preferred treatment for tumors of the face
neck and hand areas. Radiotherapy is necessary in case of primary inoperability, or of
postoperative micro- or macroscopic (R1-resection or R2-resection) rest tumors. Moreover it
becomes necessary if recurrence occurs postoperatively, and a insano-resection is improbable.
Radiation Technique: The standard treatment consists of soft x-ray therapy. The radiation area
covers the visible tumor and a safety margin ranging from about 0,5 to 1,5 cm depending on
Basal Cell Carcinoma -8-

the size of the tumor. The surrounding tissue as well as high risk organs like the eyes
including the lids, the lashes and the lacrimal glands or the ear cartilage must be protected by
lead masks. The dosage is determined according to size, localization and the surrounding
structures and radio sensitivity. Single dosages lie between 1,8 Gy and 5 Gy. Lower single
dosages should be given preference to protect normal tissue. The total applied dosages should
lie between 50 Gy (adjuvant situation) and 70 to 74 Gy [Griep et al. 1995].

5. Chemotherapy/Immunotherapy

5.1 Local Chemotherapy/Immunotherapy

Local Chemo- or Immunotherapy can become necessary as an alternative to other procedures

in case of multiple basal cell carcinomas ( of the torso). The cytostatic agent 5-fluorouracil is
applied topically daily for 4-6 weeks (1-5% in cream or ointment). For the most part 5-
fluorouracil works selectively on the hyper-proliferative parts of the epidermal tumor.
However irritations also appear on healthy skin. After 1-2 weeks the treated areas begin to
develop inflammations and erosive changes. The main problem of this treatment is to ensure
the compliance of the patients [Tsuji et al. 1993].
Basal cell carcinomas respond to intralesional treatment with type I interferons (a, b) at a rate
of 50-90% with clinical regression. The interferon is given over three weeks, 1-3 million IE
3x a week. This treatment is still in its experimental phase, studies over a long period of time
with rates of recurrence have not been published yet. The question whether there is an
advantage in case of spread out basal cell carcinomas remains to be examined [Stenquist et al.
1992; Reymann, 1979]. An analysis of the gains and costs has not yet been made.

5.2. Systemic Chemotherapy for Metastasized Basal Cell Carcinoma

The prognosis for metastasizing basal cell carcinomas is unfavorable and the average survival
rate is reported to be 10-20 months. Successful treatments with cisplatin (100 mg/m2 every 3
weeks) and with 5-fluorouracil combined with cisplatin (100 mg/m2 cisplatin d1 and 1000
mg/m2 5-fluorouracil as a continuous infusion d1-d5 every 3 weeks) were reported [Lo et al.
1991; Khandekar 1990]. The rates of remission with this chemotherapy are apparently higher
than 50%, but the periods of remission normally only last for a few months.
Basal Cell Carcinoma -9-

6. Further Methods of Therapy

Curettage, tangential removal (shave excision), and electrodessication are applicable

specifically in treatment of superficial types of basal cell carcinoma in the areas of the torso
and the limbs, in some cases photodynamic therapy and laser therapy are also useful
[Gregory, Goldman, 1986; Szeimies, Landthaler, 1995; Adams, Price, 1979; Rowe et al.
1989c; Spiller, Spiller, 1984; Dubin, Kopf, 1983; Silverman et al. 1991b]. With all other types
these modes of therapy lead to increased recurrence rates.

7. Follow Up Evaluation

Despite the small recurrence rate after micrographic surgery, follow up treatment is necessary
nonetheless necessary, because of the possibility of new tumors appearing (approximately in
30% of the cases). With other therapeutic procedures the recurrence rates after an
unrecognized subtotal excision are clinically recordable within a period of three years.
However, they can also appear after more than 10 years. Therefore the education of the
patient combined with exact instruction for self-examination are of greatest importance. A
yearly clinical follow up examination for at least three years is recommended. Patients with
local recurrences, or with tumors that were not excised in toto, or patients with a higher risk
of further developing new tumors (immunosuppression [Leigh, Glover, 1995], genetic
disposition) need to be checked more thoroughly in accordance with the individual case
[Marghoob et al. 1993].

8. References

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dioxide laser. J Dermatol Surg Oncol 5:803-806
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3. Breuninger H (1984) Histologic control of excised tissue edges in the operative
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62:269-279
Basal Cell Carcinoma - 10 -

5. Breuninger H (1993) Mikrographische Chirurgie. Die Therapie, die dem lokalen

Infiltrationsverhalten des Basalioms gerecht wird. In: Petres J, Lorisch P (eds) Das
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6. Breuninger H, Dietz K (1991) Prediction of subclinical tumor infiltration in basal cell
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