Skip to main content
Open Access Publications from the University of California

Dermatology Online Journal

Dermatology Online Journal bannerUC Davis

Basal cell carcinoma with neuroendocrine differentiation arising in a scar: A case report

Main Content

Basal cell carcinoma with neuroendocrine differentiation arising in a scar: A case report
Manuela Krokowski MD1, Josef Hoch MD2, Alfred C Feller MD1, Heinz-Wolfram Bernd MD1, Christoph Thorns MD1, Stefan Krueger MD3
Dermatology Online Journal 15 (10): 4

1. Department of Pathology, University Hospital of Schleswig-Holstein, Campus Luebeck, Germany.
2. Klinik für Hand-, Brust- und Plastische Chirurgie, Klinikum Neustadt, Neustadt i.H., Schön Kliniken, Germany
3. Institute for Pathology, Winsen/Luhe, Germany


Basal cell carcinoma (BCC), the most common cutaneous malignant tumor, may display neuroendocrine differentiation in very rare instances. We here describe a case of a BCC with neuroendocrine differentiation that arose in a scar resulting from a trauma 75 years earlier. Neuroendocrine differentiation was proven by immunohistochemistry and electron microscopy. The simultaneous occurrence of BCC development in a scar and neuroendocrine differentiation is quite rare.


Basal cell carcinoma (BCC) is the most common cutaneous malignancy, directly related to the exposure of ultraviolet radiation in sunlight. Occasionally, BCC may develop in scars resulting from previous injuries or burns [1, 2]. A number of histopathological subtypes of BCC have been defined. Among these, the solid (nodular) type is the most common variant, accounting for approximately 70 percent of all cases. In very rare instances neuroendocrine differentiation has been described in BCC [3-11]. We here describe another case, which arose in a scar resulting from an old trauma.


A 79-year-old woman presented with a 3 x 1.5 cm ulceration over the anterior tibia. The ulceration was located in the centre of an 8 x 5 cm scar that resulted from a 75-year-old trauma. The patient did not remember the exact circumstances of the trauma. She had been aware of the ulceration for about six months and reported that it was slowly increasing in size and displayed no tendency of healing under conservative treatment ordered by her family doctor. The patient was otherwise healthy and had no history of previous skin tumors.

Figure 1Figure 2
Figure 1. Macroscopic appearance of the lesion showing a large scar with central ulceration over the anterior tibia

Figure 2. Ulcerated tumor with solid and trabecular pattern (H&E, x40)

On macroscopic examination an ulceration surrounded by a scar was seen (Fig. 1). Despite the clinical lack of evidence for a neoplasm, a biopsy was performed, which surprisingly revealed an ulcerated BCC. Consequently, the whole tumor was completely excised. Histology confirmed the initial diagnosis of ulcerated BCC with epidermal connection, typical peripheral palisading, and a mucinous stroma (Fig. 2). Because the tumor showed focally a morphological neuroendocrine aspect with a trabecular pattern and nuclei with fine granulated chromatin (Fig. 3), additional immunohistochemical stainings were performed, which revealed significant positivity of the tumor cells for chromogranin-A (Fig. 4); to a weaker extent, synaptophysin and neurone specific enolase (NSE) were revealed. Immunostains for serotonin, somatostatin, calcitonin and ACTH were negative. Tumor cells further showed positivity for CK14, CK5/6, and BerEp4 and were negative for CK7, CK20, and TdT.

Figure 3Figure 4
Figure 3. Area at tumor margins with trabecular pattern and typical palisading of tumor cells. Nuclei with fine granulated chromatin (H&E, x200)

Figure 4. Chromogranin-A positivity of tumor cells (Chromogranin-A, x400)

Figure 5
Figure 5. Ultrastructural detection of dense-core secretory granules (insert with higher magnification)

The tumor's neuroendocrine differentiation was additionally confirmed ultrastructurally by the demonstration of dense-core secretory granules (Fig. 5). Following a delayed, but successful, primary wound healing the patient was discharged from the hospital in a healthy state. Examination at 12 months and at 5 years showed no evidence of tumor recurrence.


Basal cell carcinomas can exhibit both a variety of growth patterns (superficial, nodular, micronodular or infiltrating), and a variety of types of differentiation, such as basosquamous/metatypical, keratotic, sebaceous, pilar, apocrine, eccrine, or fibroepithelial. Other very rare morphological variants, such as cystic, adenoid, sklerosing/morphoeiform, infundibulocystic, pigmented, and miscellaneous (clear-cell, signet-ring-cell, granular, giant/monster-cell, adamantanoid, schwannoid), account for less than 10 percent of all basal cell carcinomas [12].

Neuroendocrine differentiation in BCC has been described in only a few studies or case reports since the late 1970s by demonstrating dense-core secretory granules upon ultrastructural analysis, argyrophilia, and immunhistochemical detection of neuropeptides, such as ACTH, calcitonin or somatostatin, and other neuroendocrine markers (chromogranin-A, synaptophysin or neuron-specific enolase) [3-11]. Macadam and Eusebi et al. were the first to describe BCCs that showed electron-dense cytoplasmic granules in 1 of 32, respectively 4 cases [3, 4].

The first immunohistochemical study by Dardi et al. showed positivity for one or more neuropeptides (calcitonin, somatostatin, ACTH) in 1-5 percent of cells in 7 out of 10 BCCs [5]. In a larger study by Visser and Bosman neuroendocrine differentiation could be demonstrated in 5 out of 50 BCCs by using histochemical (Grimelius technique, Fontana Masson), immunhistochemical (serotonin, ACTH, somatostatin, gastrin, pancreatic polypeptide, calcitonin, insulin, glucagon) or ultrastructural analysis [6]. Likewise in another larger study by George et al. only 2 out of 53 BCCs showed neuroendocrine differentiation applying the Churukian-Schenk method and immunohistochemistry (chromogranin-A, synaptophysin, neurofilament protein, Leu-7) [8].

Visser and Bosman stated that argyrophilia is no final proof for neuroendocrine differentiation because it also stains macrophages, lipid droplets in epithelial cells, or melanin granules. Additionally, the detection of peptide hormones was not definitive evidence for neuroendocrine differentiation because tumor cells could have absorbed rather than produced them [6].

Concerning the concept of neuroendocrine differentiation variable interpretations coexist. True neuroendocrine differentiation of BCC is possible as well as the concept of a common precursor cell with neuroendocrine carcinoma, which have been viewed as stem-cell-like tumors because of their ability to show mixed patterns of differentiation [8]. Others however, dispute the possibility of neuroendocrine differentiation in BCCs and question the results of the above-mentioned studies in terms of the interpretation of stains, in particular because of false positive cases generated by the low specifity and sensitivity of argyrophilia. Schulz and Hartschuh therefore analyzed 205 cases of BCC and 36 cases of trichoblastoma using low molecular weight cytokeratin-stains (CK8, CK18, CK20) and chromogranin-A for detection of Merkel cells. They found no multifocal positive cells, but only a few mainly superficially located primarily-entrapped Merkel cells. For this reason, they refuse to consider the possibility of neuroendocrine differentiation in BCC and therefore the hypothesis of a common stem cell of keratinocytes and Merkel cells. Because they could detect an increased number of Merkel cells in 4 out of 36 trichoblastomas they postulated that cases with scattered neuroendocrine cells are actually trichoblastomas, which were mistaken for BCCs [13].

Other authors have discussed whether BCCs are too primitive to exhibit demonstrable hair follicle or Merkel cell differentiation [14]; in one study 11 of 20 cases showed a focal positivity for chromogranin-A and affirmed the neuroendocrine differentiation in 3 analyzed cases by detection of mRNA of chromogranin-A in the RT-PCR [10].

In our case tumor cells exhibited positivity for CK5/6, CK14, and BerEp4, without evidence for CK20- or TdT-positive cells, arguing for a clear-cut BCC. Because of the typical multifocal pattern of growth with an epidermal connection, the predominant peripheral palisading of tumor cells, the mucinous stroma, and the immunohistochemical profile, a merkel cell carcinoma could be excluded. The diagnosis is supported by the indolent clinical course without evidence of tumor recurrence or metastases after 5 years of follow up. The positivity for chromogranin-A predominantly in the deeper marginal parts of the tumor and the verification of dense-core secretory granules in the ultrastructural analysis in our opinion support the neuroendocrine differentiation in the presented case.

Association between BCC and scar tissue from previous trauma, surgical incisions, burns, or dog bites is well known and frequently reported [1, 2, 15, 16, 17]. There are also reports describing BCC that developed after radiation therapy within an area of chronic radiation dermatitis [18] and in vaccination scars [19]. The pathogenesis is not yet fully elucidated; chronic irritation and lack of immunologic response in scar tissue might be possible explanations [17].

In summary, reports regarding neuroendocrine differentiation in BCC are controversial and its relevance in terms of prognosis and therapy is unclear because of the limited number of published cases. To the best of our knowledge, a case of BCC with neuroendocrine differentiation arising in a scar has not yet been reported in the literature.


1. Ozyazgan I, Kontas O. Previous injuries or scars as risk factors for the development of basal cell carcinoma. Scand. J Plast Reconstr Hand Surg. 2004; 38 (1): 11-15. [PubMed]

2. Kowal-Vern A, Criswell BK. Burn scar neoplasms: A literature review and statistical analysis. Burns 2005; 31 (4): 403-413. [PubMed]

3. Macadam RF. An electron microscopic study of basal cell carcinoma. J Pathol 1978; 126: 149-156. [PubMed]

4. Eusebi V, Mambelli V, Tison V, et al. Endocrine differentiation in basal cell carcinoma. Tumori 1979; 65: 191-199. [PubMed]

5. Dardi LE, Memoli VA, Gould VE. Neuroendocrine differentiation in basal cell carcinoma. J Cutan Pathol 1981; 8: 335-341. [PubMed]

6. Visser R, Bosman FT. Neuroendocrine differentiation in basal cell carcinomas: a retrospective immunohistochmical and ultrastructural study. J Cutan Pathol 1985; 12: 117-124. [PubMed]

7. Aneiros-Cachaza J, Caracuel MD, Cámara M, et al. Neuroendocrine changes in basal cell carcinoma. Acta Cytol 1988; 32 (3): 431. [PubMed]

8. George E, Swanson PE, Wick MR. Neuroendocrine differentiation in basal cell carcinoma. An immunohistochemical study. Am J Dermatopathol 1989; 11 (2): 131-135. [PubMed]

9. Tawfik O, Casparian JM, Garrigues N, et al. Neuroendocrine differentiation of a metastatic basal cell carcinoma in a patient with basal cell nevus syndrome. [PubMed]

10. Collina G, Macrì L, Eusebi V. Endocrine differentiation in basal cell carcinoma. Pathologica 2001; 93: 208-212. [PubMed]

11. Foschini MP, Eusebi V. Divergent differentiation in endocrine and nonendocrine tumors of the skin. Semin Diagn Pathol 2000; 17 (2): 162-168. [PubMed]

12. Kossard S, Epstein EM, Cerio R, et al. In: WHO Classification of tumors, Pathology and Genetics of Skin tumors (LeBoit PE, Burg G, Weedon D, Sarasin A, eds), 1st edn. IARC-Press: Lyon 2006; 13-19.

13. Schulz T, Hartschuh W. Merkel cells are absent in basal cell carcinomas but frequently found in trichoblastomas. An immunhistochmical study. J Cutan Pathol 1997; 24: 14-24. [PubMed]

14. Collina G, Eusebi V, Capella C, et al. Merkel cell differentiation in trichoblastoma. Virchows Arch 1998; 433: 291-296. [PubMed]

15. Robins DN, Shvatzman LA. Basal cell carcinoma occurring in scar tissue following excision of a parotid gland pleomorphic adenoma. Dermatol Surg 2004: 30(11): 1412-1414. [PubMed]

16. Oezyazgan I, Kontas O. Basal cell carcinoma arising from surgical scars: a case report and review of the literature. Dermatol Surg 1999; 25 (12): 965-968. [PubMed]

17. Misago N, Ogusu Y, Narisawa Y. Keloidal basal cell carcinoma after radiation therapy. Eur J Dermatol 2004; 14: 182-185 [PubMed]

18. Curry JL, Goulder SJ, Nickoloff BJ. Occurrence of a basal cell carcinoma and dermatofibroma in a smallpox vaccination scar. Dermatol Surg 2008; 34: 132-134. [PubMed]

19. Smith VH, Soon C, Dharma B, et al. Basal cell carcinoma arising in travel vaccination scars. Clinical and Experimental Dermatology 2008; 33: 500-522. [PubMed]

© 2009 Dermatology Online Journal