Case 1 History
The patient is a 34-year-old female with a skin-colored 5-mm papule on her cheek near the nasolabial fold.
Microscopic Findings
Sections show a circumscribed dermal proliferation of follicular germinative cells arranged in variably sized nests and collections ( Fig. 13.1 ). There is encompassing eosinophilic fiborous stroma without significant retraction artifact (between tumor and stroma). Microcystic areas of infundibular differentiation and mature areas of follicular germinative differentiation (papillary mesenchymal bodies) can also be found.
Diagnosis
Trichoepithelioma
Clinical Presentation
Trichoepitheliomas are benign tumors that emulate follicular germinative portions of the hair follicle with accompanying fibrous stroma. The head and neck are favored sites of occurrence. Trichoepitheliomas can present in multiplicity in the context of Brooke disease or Brooke-Spiegler syndrome, which is an autosomal dominant tumor predisposition syndrome caused by inherited mutations in the CYLD gene in which patients develop spiradenomas, cylindromas, and trichoepitheliomas. Patients with Brooke disease or Brooke-Spiegler syndrome typically notice the onset of tumors during childhood or adolescence.
Histopathology
Trichoepitheliomas are circumscribed dermal tumors that recapitulate components of the hair follicle and its associated follicular mesenchymal elements. Germinative cells are arranged in variably sized nests. Sometimes there is a racemose or retiform arrangement. The mitotic index is commonly low. There is an associated investing eosinophilic fibrocollagenous stroma intimately associated with tumor islands. Retraction artifact between tumor islands and stroma, which is common in conjunction with basal cell carcinoma (BCC), is uncommon in a trichoepithelioma. In most cases, papillary mesenchymal bodies can be found. These neoplastic structures recapitulate the follicular papillae. Desmoplastic trichoepithelioma (DTE) represents a subtype of trichoepithelioma with a cordlike distribution of follicular germinative cells in desmoplastic stroma ( Fig. 13.2 ). Associated microcysts, tiny granulomas, and microcalcification are common in conjunction with DTE. Ber-EP4 labels trichoepitheliomas, and CK20 highlights colonizing Merkel cells in most cases. PHLDA1 is typically positive in trichoepitheliomas, but androgen receptor is negative. Activating mutations affecting HRAS have been identified in a small subset of trichoepitheliomas.
Differential Diagnosis
The main differential diagnostic consideration is BCC ( Table 13.1 ).
| Trichoepithelioma | Desmoplastic Trichoepithelioma | Basal Cell Carcinoma | |
|---|---|---|---|
| Composition | Follicular germinative cells, fibrous stroma, papillary mesenchymal bodies | Cords of follicular germinative cells, sclerotic stroma, microcysts, calcification | Atypical basaloid cells with associated fibromucinous stroma |
| Retraction artifact | Uncommon | Uncommon | Common |
| Dermal configuration | Generally circumscribed | Interstitial in the reticular dermis | Poorly circumscribed |
| Immunophenotype | PHLDA1+; CK20+ colonizing cells present | PHLDA1+; CK20+ colonizing cells present | Ber-EP4+ with limited or absent CK20+ colonizing cells |
Basal Cell Carcinoma
Clinical Presentation
BCC presents as umbilicated or ulcerated papules or nodules on sun-exposed skin of older adults, but tumors may develop sporadically in younger patients. BCC can occasionally present at sun-protected sites, such as genital skin, as well. Patients with nevoid BCC syndrome (Gorlin syndrome) may develop multiple BCCs (in addition to odontogenic keratocysts, palmar and plantar cysts, and other abnormalities) secondary to inherited mutations in PTCH1 .
Histopathology
BCC shows a broad spectrum of microscopic morphology ( Figs. 11.12 to 11.15 ). The two key elements are atypical basaloid cells and accompanying fibromyxoid stroma. In superficial BCC , tumor collections attach to the undersurface of the epidermis. The tumor appearance is multifocal in two-dimensional sections, which is attributable to the spiderlike configuration of the tumor. Nodular BCC consists of rounded aggregates of basaloid cells that infiltrate the dermis with a pushing border. Micronodular BCC consists of small, rounded nests of basaloid cells that may be deeply infiltrative into the dermis. Infiltrative BCC invades the dermis as jagged, irregular islands of basaloid cells with an irregular silhouette. Infiltrative BCC may have associated keloidal stroma. Infundibulocystic BCC represents an indolent subtype with arborizing arrangement of follicular germinative cells, integrated infundibular microcysts, scant stroma, and infrequent retraction artifact. Conventional forms of BCC express Ber-EP4 and typically lack colonizing CD20+ cells because mature follicular germinative differentiation is absent. Infundibulocystic BCC is the exception because it exhibits limited mature follicular differentiation and is often rich in CK20+ cells.
Case 2 History
The patient is an 18-year-old female with a hard nodule on the top of the scalp.
Microscopic Findings
Sections show a proliferation of basaloid keratinocytes forming an expansile multilobulated cystic nodule in the dermis ( Fig. 13.3 ). Peripherally, there are compact matrical cells with round nuclei and minimal cytoplasm; centrally, there is keratinization characterized by an intervening layer of cells with pale eosinophilic cytoplasm and a central pyknotic nucleus. These blend with sheets of matrical corneocytes containing abundant pale eosinophilic cytoplasm and pale eosinophilic nuclear remnants (so-called ghost cells).
Diagnosis
Pilomatricoma
Clinical Presentation
Pilomatricomas can develop in patients of any age but commonly arise in children and adolescents. Pilomatricomas present as firm, slow-growing tumors or nodules on the head and neck and extremities. Multiple pilomatricomas and cystic pilomatricomas may be associated with Gardner syndrome, although other syndromic associations have been described.
Histopathology
Pilomatricomas consist of a variable admixture of matrical cells that blend together with ghost cells , which represent anucleate matrical corneocytes. The tumor typically presents as an expansile multilobulated nodule in the dermis, although some examples may extend to the subcutis. The peripheral portion of lobules usually contains a variable amount of matrical cells with round nuclei, minimal cytoplasm, and an elevated mitotic index. Matrical cells transition to partially cornified cells containing increased pale eosinophilic cytoplasm and pyknotic nuclei. Also present are stereotypical pilomatrical ghost or shadow cells, which represent pale cornified cells with abundant eosinophilic cytoplasm and pale eosinophilic nuclear remnants. The ratio of basaloid matrical cells to ghost cells in a pilomatricoma varies greatly, depending on their duration (older tumors contain more ghost cells), and some involutional tumors may contain only ghost cells. In the majority of cases, there is an associated mixed foreign body giant cell reaction with fibrosis. Most tumors of pilomatrical lineage harbor activating mutations in the β-catenin gene (CTNNB1) and therefore show nuclear positivity for β-catenin.
Differential Diagnosis
The differential diagnosis includes pilomatrical carcinoma ( Table 13.2 ).
| Pilomatricoma | Pilomatrical Carcinoma | |
|---|---|---|
| Age | Broad age range; most common in younger patients | More common in older patients |
| Location | Head and neck; extremities | Head and neck |
| Silhouette | Largely circumscribed | Infiltrative and poorly circumscribed |
| Cellular composition | Mix of basaloid matrical cells and ghost cells | Atypical basaloid matrical cells; ghost cells may be inconspicuous |
| Molecular alteration | Activating mutations in the β-catenin gene (CTNNB1) | Activating mutations in the β-catenin gene (CTNNB1) |
Pilomatrical Carcinoma
Clinical Presentation
Pilomatrical carcinoma most often develops in the head and neck region of older patients.
Histopathology
In contrast to pilomatricomas, pilomatrical carcinoma may show poor circumscription and an infiltrative silhouette ( Fig. 13.4 ). Pilomatrical carcinomas consist of aggregates of malignant matrical cells with enlarged irregular nuclei and an elevated mitotic index. Ghost cells may be minimally present or nonexistent. Areas of necrosis may be encountered. As for pilomatricoma, pilomatrical carcinoma harbors activating mutations in the β-catenin gene (CTNNB1) and thus shows nuclear positivity for β-catenin. There may also be nuclear expression of LEF-1 and CDX-2 as reflection of WNT-signaling pathway activation.
Case 3 History
A 32-year-old female presents with a skin-colored papule on the nasal ala.
Microscopic Findings
Sections show an exoendophytic tumor ( Fig. 13.5 ). The overlying epidermis exhibits verrucous hyperplasia with a bulbous or lobular profile below this. Central cytoplasmic pallor is flanked by peripheral palisading, which is flanked in turn by a thickened eosinophilic basement membrane.
Diagnosis
Trichilemmoma
Clinical Presentation
Trichilemmomas develop across a broad age range but typically present in adulthood. Most trichilemmomas are facial, but presentation at genital and truncal sites can occur. There is an association between multiple trichilemmomas and Cowden syndrome.
Histopathology
Trichilemmomas characteristically exhibit exoendophytic architecture. There may be associated surface verrucous acanthosis, which has triggered longstanding debate regarding the possibility of human papillomavirus (HPV) as a potential trigger. The tumor cells of trichilemmoma have abundant clear or pale cytoplasm. Peripheral palisading and an associated thickened basement membrane are common findings and represent neoplastic emulation of the follicular outer sheath. Desmoplastic trichilemmoma shows central areas with prominent desmoplastic stroma encompassing pale or pink tumor cells with a pseudoinfiltrative arrangement ( Fig. 13.6 ). Typically, desmoplastic trichilemmomas are accompanied by peripheral foci of conventional trichilemmoma.
The epithelial cells of trichilemmomas show variable but strong membranous labeling with CD34 but lack Ber-EP4 expression.
Differential Diagnosis
The differential diagnosis includes tumor of follicular infundibulum (TFI) and BCC ( Table 13.3 ).
| Trichilemmoma | Tumor of the Follicular Infundibulum | Superficial Basal Cell Carcinoma | |
|---|---|---|---|
| Age | Broad age range | Broad age range | Broad age range but common among older adults |
| Location | Face, commonly | Face or neck, commonly | Sun distribution |
| Histopathology | Verrucous exoendophytic silhouette | Plate like, perijunctional fenestrated distribution | Basaloid tumor collections with associated stroma |
| Immunohistochemical studies | CD34+ | Not used | Ber-EP4+ |
| Associations | Cowden syndrome | None | Nevoid basal cell carcinoma syndrome |
Tumor of Follicular Infundibulum
Clinical Presentation
TFI often presents as a thin facial tumor. Truncal or neck involvement can also occur. A deceptive clinical presentation consists of multiple areas of macular hypopigmentation.
Histopathology
TFI consists of a platelike array of pale adnexal keratinocytes integrated with the native epidermis and arranged in vaguely fenestrated fashion with multiple points of attachment to the epidermis and follicular infundibula ( Fig. 13.7 ). The keratinocytes composing TFI exhibit a distinctive pale pink cytoplasm that appears different from the keratinocytes of the overlying epidermis. TFI typically lacks prominent cytoplasmic clearing, by contrast to trichilemmoma, and lacks retraction artifact or peripheral palisading, by contrast to superficial BCC. It is not uncommon to see TFI coexistent with trichilemmoma.
Case 4 History
The patient is a 54-year-old male with a papule on the upper lip.
Microscopic Findings
Sections show a circumscribed cystic or patulous endophytic proliferation of pale keratinocytes arranged as peripheral lobules ( Fig. 13.8 ). A central comedonal space contains orthokeratin.
