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Keratoacanthoma centrifugum marginatum accompanied by extensive granulomatous foreign body reaction

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Keratoacanthoma centrifugum marginatum accompanied by extensive granulomatous foreign body reaction.
P Kurschat1, S Hess2, N Hunzelmann1, K Scharffetter-Kochanek3
Dermatology Online Journal 11 (2): 16

1Department of Dermatology, University of Cologne, Germany, 2Department of Virology, University of Cologne, Germany, and 3Department of Dermatology, University of Ulm, Germany.


We describe a 58-year-old woman with a 4-year history of papular lesions with a partly verruciform appearance on the eyelids and the adjacent areas of the nose. The lesions progressed slowly but constantly into the surrounding areas with central scaring. Histopathology showed epidermal endophytic proliferations under a pronounced hyperparakeratosis. In the adjacent dermis a lymphohistiocytic infiltrate with giant cells of the foreign-body-reaction type was seen in close contact to extracellular keratin deposits. Although some cytopathological signs typical for viropathic effects were observed, no human papilloma virus-DNA was detected within the lesions by polymerase chain reaction. According to the histological picture and the clinical course we diagnosed a keratoacanthoma centrifugum marginatum. We present this case because of the strong granulomatous foreign body reaction which might complicate the diagnosis and has not been described for this keratoacanthoma variant so far.


Keratoacanthomas are common benign epidermal tumors characterized by the rapid development of a firm, symmetrical dome-shaped nodule with a horn-filled crater in its center and a tendency for spontaneous regression. Approximately 98 percent of keratoacanthomas fall into the classic, solitary type that mainly occurs in elderly persons on exposed areas. Usually, this tumor is diagnosed clinically and confirmed by histopathological examination. Typical cases reach their full size of 1.0-2.5 cm within 6-8 weeks, followed by spontaneous involution within less than 6 months [1].

Occasionally, multiple keratoacanthomas develop sporadically, such as the eruptive keratoacanthomas of the Grzybowski type or in the context of familial syndromes like the Ferguson-Smith syndrome or the Muir-Torre syndrome. The genetic defects of these cases are still unknown, but mutations in the DNA mismatch repair gene hMSH2 have been observed [2]. Mutations of the tumor suppressor gene p53, which normally regulates cell proliferation by inhibiting cells from entering the S-phase, have been suggested in classic cases of keratoakanthoma, especially in immunosuppressed patients following organ transplantation [3, 4]. Activation of the oncogene H-ras has been reported as well, and this occurs even more frequently than in squamous cell carcinoma [5].

In addition to the main type, several variants of keratoacanthoma exist and are characterized by lack of spontaneous regression and progressive destructive growth. In contrast to squamous cell carcinomas there is no tendency to develop distant organ metastasis even in advanced cases, but differential diagnosis may be difficult. Clinically, three types of the persisting, destructive variant of keratoacanthoma can be distinguished: mutilating keratoacanthoma, aggregated keratoacanthoma, the keratoacanthoma centrifugum marginatum (KCM). We present a case of a KCM with a typical clinical picture but unusual histopathological features, including an extensive granulomatous reaction resembling a foreign body reaction, a feature that has not been described in combination with keratoacanthomas before.

Clinical synopsis

Figure 1 Figure 2
Figure 1. Aggregated small papules with a slightly verruciform surface initially appeared on the left upper and lower medial eyelid.
Figure 2 During the following months a continuous slow spreading could be observed, involving the left cheek and nose.

A 58-year-old woman presented with a 4-year history of small papules with a slightly verruciform surface that initially appeared on the left upper and lower medial eyelid (Fig. 1). Except for occasional pruritus, no symptoms were recognized. During the following months a continuous slow spreading was observed, leading to an involvement of the left cheek and nose (Fig. 2). After several unsuccessful attempts the tumor was completely excised by extensive surgery and the defect was closed in five consecutive plastic operations, leading to a good cosmetic result. There were no signs of recurrent disease during the following 2 years.

Figure 3 Figure 4
Figure 3. Histopathological examination. H&E staining shows an irregularly shaped crater filled with parakeratotic keratin. At the base and at the margins irregular epidermal proliferations with a partly solid and a partly netlike appearance can be seen (original magnification x 40).
Figure 4: In the dermis adjacent to the tumor a pronounced lymphohistiocytotic infiltrate is seen with giant cells of the foreign body type (H&E, original magnification x 200).

Histopathological examination of lesional skin taken from areas that were not pretreated by prior surgery showed an irregularly shaped crater filled with parakeratotic keratin (Fig. 3). At the base and at the margins irregular epidermal proliferations with a partly solid and a partly netlike appearance can be seen. In some areas the borderline to the surrounding stroma is only poorly demarcated. The periphery of the tumor cell nests is lined by basophilic non-keratinizing keratinocytes, whereas the center is characterized by rather large keratinocytes with homogenous, eosinophilic cytoplasm attributed to extensive, advanced keratinization. Cellular atypia was not detected. In the adjacent dermis a pronounced lymphohistiocytotic infiltrate is seen with giant cells of the foreign body type (Fig. 4).

Figure 5
Figure 5: By pankeratin staining it can be demonstrated that histiocytic cells and the giant cells are located in close contact to extracellular keratin deposits (APAAP-method, red neofuchsin signal with hemalaun counterstaining, original magnification x 200).

By pankeratin staining it can be demonstrated that histiocytic cells and the giant cells mentioned above are in close contact to extracellular keratin deposits, suggesting phagocytosis of the keratin as a phenomenon of regression and involution of the tumor (Fig. 5).

In some areas at the tumor surface a widening of the stratum granulosum with coarse keratohyalin granules and a perinuclear halo can be seen, resembling cytopathic effects often associated with human papilloma virus (HPV) infections. However, by polymerase chain reaction no HPV or epidermodysplasia verruciformis


virus DNA could be detected in 8 different tissue specimens.

Unlike squamous cell carcinomas (SCC), which develop from normal epidermal keratinocytes, keratoacanthomas (KA) are derived from the supraseboglandular parts of hair follicles and comprise their own entity with distinct clinical and histological features. The tendency for spontaneous regression and the extensive degree of keratinization are the most striking features, despite the typical symmetric architecture of the tumor.

Usually keratoacanthomas develop in three stages. The early phase of proliferation is often difficult to distinguish histologically from SCC since a high mitotic activity is observed, the degree of keratinization is still low and nuclear atypia is common, often to a higher degree than in SCC [6]. The fully developed lesion is normally diagnosed more easily and is followed by the phase of involution with frequent detection of apoptotic cells. Since suspicious lesions are often excised early this typical course is rarely observed and the differential diagnostic decision has to be made mainly by the dermatopathologist.

Kern and McGray reported that SCC could be fully excluded in only 81 percent of all KAs, whereas in only 86 percent of SCCs a KA could be ruled out with certainty [7]. A recent evaluation showed that a clear-cut distinction between SCC and KA is not possible in atypical and difficult cases and that these tumors should be treated like squamous cell carcinomas [8].

These diagnostic difficulties are especially true for the destructive, persisting variants of KA, such as giant KA, mutilating KA or KCM.

The keratoacanthoma centrifugum marginatum was first described in 1965 by Belisario as a separate entity [9]. Histologically these tumors often comprise infiltrative behavior, and atypical mitoses may be seen occasionally [10, 11]. Even perineural invasion has been described in the early proliferative stage [12].

In our case the diagnosis of a KCM could be made because of the clinical course with centrifugal expansion in association with central restitution or scaring and because of the typical histology. Nevertheless, two special histological features of this tumor need further attention.

First, in some areas of the epidermis cytopathic effects like those often associated with human papilloma virus (HPV) infection can be seen. The role of HPV infection for the development of different kinds of epithelial neoplasia is well established [13]. For KAs, the possible involvement of HPV is controversial. In 1997 Hsi and coworkers detected HPV types 11, 13, 24, 33 and 57 with a statistical significantly higher prevalence in KA compared to non-lesional skin [14]. On the other hand, Lu et al. found no association of HPV DNA with KA [15]. A recent study concluded that HPV is probably not generally associated with KA but may be relevant in individual cases especially as a cofactor for malignant transformation into SCC [16]. For the KCM variant of KA, only one investigation is published with the detection of HPV type 6 and 11 within the lesion [17]. In our case no HPV or epidermodysplasia verruciformis virus DNA could be detected using PCR technique.

Second, one of the histologically striking features of our case is a pronounced foreign body reaction with frequent giant cells in association with extracellular keratin deposits. Other diseases with similar granulomatous reactions, such as sarcoidosis, atypical mycobacteriosis, or regressive xanthogranuloma were excluded. We consider this foreign body reaction to be a secondary response following the unsuccessful attempt of histiocytotic cells to remove the extracellular keratin deposits. The persistent inflammatory process leads to the formation of giant cells that try to phagocytose the keratin, as demonstrated by pankeratin staining. To our knowledge this is the first report showing this type of chronic inflammatory response in association with a destructive, persistent keratoacanthoma.

The treatment of choice for all types of keratoacanthomas is still the surgical excision with histopathological verification of the diagnosis. If surgery is not possible a radiation therapy with tumor doses can be considered. Several other therapeutic options such as intralesional injections of interferon alpha, methotrexate, or bleomycin, and systemically administered retinoids have been reported to be effective in individual cases, but there are no controlled clinical studies demonstrating the efficiency of these treatments so far. Therefore these options can not be recommended generally and should be considered only in selected cases when contraindications for the more established therapies are present.


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