Matrical differentiation in a cutaneous epithelial neoplasm represents a variant of follicular differentiation which shows basophilic cells resembling those in a mature follicular bulb in anagen as well as a final maturation to keratin designated as “shadow cells.” This keratinization is characterized by the appearance of ghost-like empty spaces in the shape of nuclei within the fully cornified cells.  Although pilomatricoma, matricoma, matrical carcinoma, and panfolliculoma are the prototypes of neoplasms with matrical differentiation, this pattern may also be observed rarely in other follicular neoplasms such as trichoblastoma and, occasionally, basal cell carcinoma (BCC). We report an unusual histopathological presentation of a BCC with matrical differentiation (BCCMD) in which focal islands of shadow cells were surrounded by granulomatous and lymphoplasmocytic infiltrates similar to a burned-out pattern of pilomatricoma.
An 80-year-old Caucasian male presented with a nodular lesion located on the right temple. Histopathological examination of the excisional specimen revealed a nodular basaloid neoplastic proliferation in the dermis with occasional connection to epidermis (Fig. 1). On higher power examination, the tumor islands were composed of basophilic cells with oval to elongated nuclei and scant cytoplasm resembling trichoblasts. The nuclei of the neoplastic cells were relatively monomorphous and prominent nuclear polymorphism or a high mitotic index were not observed. A peripheral palisading pattern of the tumor islands, retraction artifact separating the tumor lobules from the surrounding stroma, and individual cell necrosis were also identified (Fig. 2).
A striking feature of the neoplastic proliferation was the focal presence of islands of shadow cells indicating matrical differentiation (Fig. 3). Only in a focus, basophilic polygonal cells with large heterochromatic nuclei resembling cells of a mature follicular bulb in anagen were identified. There was no direct connection or remnants of the trichoblastic cell proliferation around these islands, whereas a perilesional histiocytic cell proliferation with occasional multinucleated giant cells and a dense lymphoplasmacytic infiltrate were detected. A CD68 stain confirmed the histiocytic cell proliferation (Fig. 4). Focal areas of metatypical BCC with full keratinization of some tumor nodules were also identified (Fig. 5). Staining with pancytokeratin was strongly positive in metatypical areas, whereas a more faint staining pattern was observed in the shadow cells.
Bcl-2, Ki-67, CD34, and androgen receptor staining of the excisional specimen together with a control specimen of a pilomatricoma were performed for a more accurate assessment of the matrical differentiation. Bcl-2 and Ki-67 stains of the excisional specimen revealed a diffuse staining throughout the basaloid neoplasm, whereas these stains were restricted to the matrical rather than supramatrical epithelium in the pilomatricoma specimen serving as control. CD34 stain showed focal staining of peritumoral stroma in pilomatricoma and was non-contributory in the excisional specimen of the BCC. Staining for androgen receptors was positive in the BCC but negative in the pilomatricoma. A final diagnosis of BCCMD was established based on the histopathological and immunohistochemical features.
Photomicrograph of an excisional specimen from the temple area showing basaloid neoplastic infiltration of the dermis; hematoxylin and eosin, X20.
Higher magnification highlights a peripheral palisading pattern, and clefts between aggregations of neoplastic cells and adjacent stroma; hematoxylin and eosin, X100.
Matrical differentiation with focal islands of shadow cells, surrounded by a granulomatous and lymphoplasmacytic reaction was also detected; hematoxylin and eosin, X40.
A CD68 stain highlights the histiocytic origin of the granulomatous immune response; CD68 stain, X40.
The neoplastic proliferation also revealed metatypical features with full keratinization of the basal cell neoplasm; hematoxylin and eosin, X100.
The main histopathological subtypes of BCC include superficial, nodular, morpheiform, metatypical, and fibroepithelial forms. Sometimes, unusual BCC variants such as granular, clear cell, adamantinoid, and BCC with matrical differentiation may pose a difficulty in diagnosis. BCCMD seems to be exceedingly rare with just 15 cases reported in the literature. BCCMD presents clinically as a nodule or plaque mainly localized on the face of elderly patients, as in our case. Extrafacial localizations such as lumbar region, back, forearm, and dorsal hand have also been described. [2-5]
Shadow cells are a pattern of keratinization with prominent cell outlines, eosinophilic fully keratinized cytoplasm, and loss of nuclei leaving behind a central pale area. They represent a flawed attempt to formation of a hair shaft. Apart from their presence in pilomatricoma, matricoma, panfolliculoma, matrical carcinoma, and BCCMD, shadow cells have been documented incidentally in various other skin conditions such as trichilemmal cyst, infundibular cysts of Gardner’s syndrome, apocrine mixed tumor of the skin, keratoacanthoma, and condyloma accuminatum. [2,6,7]
In the neoplasm presented here, the histopathological features of a basaloid neoplasm showing peripheral palisading, artificial clefting, and individidual cell necrosis in association with the areas of shadow cells are consistent with a diagnosis of BCCMD. The histopathological differential diagnoses include panfolliculoma, matrical carcinoma, and melanocytic matricoma. Although shadow cell changes in combination with a malignant basophilic neoplasm may also be observed matrical carcinoma, lack of a striking polymorphism of nucleoli, the presence of a low mitotic index, and the prominent population of trichoblasts helps to exclude this diagnosis.  Haskell et al. reported that immunohistochemical study with ß-catenin, a 92-kDA protein which has been shown to play a critical role in the hair cycle and development of tumors with matrical differentiation, showed a membranous staining pattern in BCCMD, in comparison with a nuclear membranous staining pattern in matrical carcinoma.  Melanocytic matricoma shows a dual cell population including admixed matrical cells with shadow cell formation and pigmented dendritic melanocytes but no trichoblasts.  Pigmented dendritic melanocytes were not detected in the lesion of our patient, but trichoblasts were the predominant cell population. Although panfolliculoma is a neoplasm which consists of trichoblasts and matrical cells, the nodules are arranged in a regular pattern and show a cell rich stroma with formation of germs and papilla. Artificial clefts are present between stroma and surrounding dermis but not between tumor lobules and stroma as it is the case in BCC.
In most reported cases of BCCMD, the matrical differentiation with shadow cell changes takes place centrally within BCC tumor lobules and shows a more widespread distribution. [2-5] The histopathological features of this case are unique in terms of focal arrangement of shadow cell islands surrounded by a histiocytic and lymphoplasmacytic infiltrate without any direct connection to surrounding BCC lobules. Only one report of a BCCMD can be found in the literature in which separate shadow cell islands were surrounded by a histiocytic infiltrate, as in our case.  The granulomatous reaction surrounding the shadow cells was highlighted with CD68 stain and appeared similar to a burned-out pattern observed in old pilomatricomas. It is possible that in the lesion presented here this phenomenon represents a burned-out area of BCC with focal matrical differentiation, in which the surrounding neoplastic basal cell proliferation was destroyed by an immune response similar to that seen in an old pilomatricomas. Alternatively, the histiocytic infiltration may represent merely a “foreign body” reaction to the masses of keratin.
Another possibility of interpretation of the neoplasm shown here is that of a collision tumor of BCC and pilomatricoma. However, this seems to be unlikely because of the clinical course of development of one new lesion without any history of a preexisting nodule at the same site. Recent studies indicate that CD34 staining of the peritumoral stroma of benign adnexal and hamartomatous lesions such as trichoblastoma, basaloid follicular hamartoma, and vellus hair hamartoma is an helpful feature for differentiation with BCC, which shows a negative peritumoral staining pattern. [11,12] The CD34 stain of a control pilomatricoma specimen yielded a focal peritumoral pattern, this pattern was not detected in the BCCMD specimen, a finding that also militates against the possibility of a collisional tumor. The presence of androgen receptors, which has recently been shown as a useful tool to differentiate BCC from desmoplastic trichoepithelioma,  as well as the diffuse staining pattern of bcl-2 and Ki-67, also helped to confirm the diagnosis of BCC as complementary findings in addition to histopathological features.
Last, the histopathological picture of the neoplasm shown here could be explained by a faulty keratinization of a preexisting terminal hair follicle, which was impaired in its development by the growing BCC. Some follicles in catagen may form masses of shadow cell keratin upon involution.  The feature of shadow cells in the BCC would then be a kind of an induction phenomenon at a preexisting follicle somewhat similar to proliferation of eccrine ductal epithelium seen sometimes in the vicinity o BCCs.
In summary, we present an example of BCCMD and offer various interpretations about the development of this lesion. Whether or not matrical differentiation in BCCMD is a characteristic feature of a distinctive variant of BCC, a collision, or an induction phenomenon, lesions like the one presented here need to be differentiated with surety from other adnexal neoplasms with matrical differentiation such as panfolliculoma, pilomatricoma, matricoma, and matrical carcinoma based on the criteria summarized above.
Basal cell carcinoma with matrical differentiation (BCCMD) is a rare histopathological variant of basal cell carcinoma (BCC), characterized by the presence of matrical cells and/or keratin with shadow cell appearance within the basal cell neoplasm. We report on an unusual histopathological presentation of a BCCMD, in which focal islands of shadow cells were surrounded by granulomatous and lymphoplasmocytic infiltrates reminiscent of a burned-out pattern of pilomatricoma. Additional immunohistochemical studies with CD34, CD68, bcl-2, Ki-67, and androgen receptors were performed to identify the ethiopathogenesis of this neoplasm. It is discussed whether BCCMD is a distinctive entity or a collision phenomenon.
Engin Sezer, M.D., is Associate Professor at Gaziosmanpasa University Faculty of Medicine, Department of Dermatology, Turkey. Almut Böer-Auer, M.D., is a dermatopathologist at the Dermatologikum Hamburg, Germany. This article was reviewed by Rohini Matthias, M.D., and Mihaela Costache, M.D. Contact author via email: firstname.lastname@example.org .
1. Jacobson M, Ackerman AB. “Shadow” cells as clues to follicular differentiation. Am J Dermatopathol. 1987;9:51-57.
2. Del Sordo R, Cavaliere A, Sidoni A. Basal cell carcinoma with matrical differentiation: expression of beta-catenin [corrected] and osteopontin. Am J Dermatopathol. 2007;29:470-474.
3. Ali F, Brown A, Gottwald L, et al. Basal cell carcinoma with metrical differentiation in a transplant patient: a case report and review of the literature. J Cutan Pathol. 2005;32:445-448.
4. Kim SH, Lee MG, Lee KG. Basal cell carcinoma with metrical differentiation. Yonsei Med J. 2003;44:523-525.
5. Aloi FG, Molinero A, Pippione M. Basal cell carcinoma with matrical differentation. Am J Dermatopathol. 1988;10:509-513.
6. LeBoit PE, Parslow TG, Choy SH. Hair matrix differentiation:occurrence in lesions other than pilomatricoma. Am J Dermatopathol. 1987;9:399-405.
7. Cooper PH, Fechner RE. Pilomatricoma-like changes in the epidermal cysts of Gardner’s syndrome. J Am Acad Dermatol. 1983;8:639-644.
8. Ackerman AB, Reddy VB, H. Soyer P. Neoplasms with Follicular Differentiation. New York: Ardor Scribendi, 2001
9. Haskell HD, Haynes HA, McKee PH, et al. Basal cell carcinoma with matrical differentiation: a case study with analysis of beta-catenin. J Cutan Pathol. 2005;32:245-250.
10. Williams CM, Bozner P, Oliveri CV, et al. Melanocytic matricoma: case confirmation of a recently described entity. J Cutan Pathol. 2003;30:275-278.
11. Poniecka AW, Alexis JB. An immunohistochemical study of basal cell carcinoma and trichoepithelioma. Am J Dermatopathol. 1999;21:332-336.
12. Ramos-Ceballos FI, Pashaei S, et al. Bcl-2, CD34 and CD10 expression in basaloid follicular hamartoma, vellus hair hamartoma and neurofollicular hamartoma demonstrate full follicular differentiation. J Cutan Pathol. 2008;35:477-483.
13. Costache M, Bresch M, Böer A. Desmoplastic trichoepithelioma versus morphoeic basal cell carcinoma: a critical reappraisal of histomorphological and immunohistochemical criteria for differentiation. Histopathology. 2008;52:865-876.
14. Ackerman AB, Böer A. Histopathologic Diagnosis of Adnexal Epithelial Neoplasms. New York City: Ardor Scribendi, Ltd. 2008