Adnexal Tumors

Clinical Findings

Trichoblastoma typically presents as sporadic, solitary, flesh-colored, small (2- to 8-mm) papules on the face. Rarely, it may form a larger nodule (reported in the literature as giant solitary TE). Uncommonly, multiple TBLs ( Fig. 11-5 ) can occur in families as an autosomal dominant condition or as part of Brooke-Spiegler or Rombo syndrome, with mutations of the CYLD or PATCH genes. TBL is a common secondary neoplasm in nevus sebaceus.

Histologic Features

Trichoblastomas are fibroepithelial tumors composed of basaloid epithelial cells with a cellular fibrous stroma distinctly different from the surrounding normal reticular dermis ( Fig. 11-6, A ). A characteristic finding is the presence of papillary-mesenchymal bodies ( Fig. 11-6, B ), which are cuplike proliferations of basaloid cells engulfing fibroblasts, thereby recapitulating the follicular papilla of the hair follicle. Mitotic figures or apoptotic bodies can also be present, but they are not as frequently seen as in BCCs. Stromal calcifications are commonly associated with TBLs.

Superficial lesions of TBL (TEs) typically contain small keratocysts with infundibular keratinization and may form connections to the epidermis. More deeply located tumors usually lack epidermal connections and infundibular cysts.

Trichoblastoma may be inflamed. What has been described in the literature as cutaneous lymphadenoma represents inflamed TBL.

Ancillary Studies

The peritumoral stromal cells are immunopositive for CD34. Bcl-2 is expressed in the basaloid keratinocytes located at the periphery of the cords. Because TBLs are follicular-derived lesions, they usually contain Merkel cells, which can be detected with anti-CK20. A recent marker, CD10, is expressed by the peritumoral spindle cells in TBL and by some of the epithelial tumor cells in BCC. PHLDA1 is primarily expressed in TBL and not in BCC ( Fig. 11-6, C and D ).

Differential Diagnosis

The main diagnostic distinction is from BCC. In contrast with BCC, the stroma of TBL shows a tight association with the basaloid epithelial cells. No clefts or retractions are seen between epithelium and stroma, as is characteristic of BCC. Instead, TBL shows a distinct demarcation between its periepithelial stroma and the surrounding dermal collagen. TBL typically contains papillary mesenchymal bodies, which are usually absent in BCC. Mitoses and apoptotic bodies can occur in TBL but are not as common as in BCC. Certain stromal alterations, such as mucin or amyloid deposits, which are typical of BCC, would be unusual for TBL.

Trichoblastic proliferations simulating superficial BCC may occur as an inductive phenomenon along the dermal-epidermal junction overlying a dermatofibroma ( Fig. 11-7 ) or along the follicular epithelial interface in association with a blue nevus.

Clinical Findings

This tumor typically presents as a small (2- to 9-mm), asymptomatic, slowly growing, indurated area, which may have an atrophic, depressed center ( Fig. 11-8 ).

Histologic Features

Desmoplastic or sclerosing TE is quite different in appearance from conventional TE or TBL. Although TBL usually forms a spherical nodule, the silhouette of desmoplastic TE is usually that of a superficial dermal plaque. The tumor is characterized by a triad of thin strands of basaloid epithelial cells, keratinous cysts, and a dense fibrous stroma ( Fig. 11-9 ). Additional features may include foreign body giant cell reactions to keratin and calcifications. Focal papillary mesenchymal bodies may be seen.

Ancillary Studies

Immunohistochemistry may help because intracytoplasmic lumina may be easier to identify using antibodies for carcinoembryonic antigen (CEA) or BR2 (positive staining argues against desmoplastic TE). CK20-positive Merkel cells are commonly associated with the tumor ( Fig. 11-9, C ). PHLDA1 has recently been reported to be primarily expressed in all types of TBL and TE but not in most BCC.

Differential Diagnosis

Desmoplastic TE needs to be distinguished from morpheaform BCC and MAC. Morpheaform BCC tends to show greater asymmetry in its growth and infiltrates more deeply. Furthermore, the degree of nuclear atypia, number of mitoses, or apoptotic bodies is higher in BCC. After foci of more typical features of BCC, such as sheets or small nodules of basaloid cells with peripheral palisading and retraction artifact, are identified, the diagnosis is straightforward. Another helpful feature is the presence of cytologically bland keratocysts. They are commonly seen in desmoplastic TE. Keratocysts may be seen in infiltrative BCCs but rarely in morpheaform variants. If they are present, the tumor cells surrounding the cystic structures are atypical. A possible pitfall is the observation of perineural involvement in desmoplastic TE. Its presence per se does not necessarily imply a diagnosis of carcinoma.

Microcystic adnexal carcinoma or syringoma may also be confused with desmoplastic TE, especially in a small superficial shave biopsy. The presence of papillary mesenchymal bodies excludes syringoma and MAC. On the other hand, if ductal differentiation is identified, desmoplastic TE can be excluded. The identification of CK20- or chromogranin-positive Merkel cells in the tumor is also helpful to support follicular differentiation and to distinguish desmoplastic TE from syringoma or MAC ( Fig. 11-9, C ).

Clinical Findings

Tricholemmomas are solitary lesions typically present on the face of young individuals ( Fig. 11-11 ). Most of them are sporadic solitary lesions. Multiple lesions are a marker for Cowden syndrome (CS; see the following).

Histologic Features

Tricholemmomas are usually small, circumscribed tumors composed of one or more lobules of cuboidal cells with central, round nuclei and lightly pink or clear cytoplasm ( Fig. 11-12 ). There is typically a small popular exophytic component as well as an endophytic part extending into the upper reticular dermis. The lobules tend to connect to the epidermis or follicular infundibulum at several points. At the periphery of the lobules is a layer of columnar basaloid cells with nuclear palisading resembling the outer root sheath. They are usually surrounded by a hyaline pink band reflecting thickened basement membrane material. Clear cell changes are common and reflect abundant cytoplasmic glycogen. Keratinization and squamous eddies may be present.

A variant of tricholemmoma shows a hyalinized or desmoplastic stroma ( Fig. 11-13 ), in which the tumor cells often display an irregular and seemingly infiltrative growth pattern (desmoplastic tricholemmoma).

Ancillary Studies

Tricholemmoma typically strongly label for CD34 by immunohistochemistry. A periodic acid-Schiff (PAS) and PAS-diastase (PAS-D) stain can help highlight the presence of glycogen (positivity with PAS is removed after treatment with diastase).

Differential Diagnosis

Tricholemmomas share many features with inverted follicular keratosis. However, the latter lacks hyaline membranes, and clear cell or basaloid features are less common. Tricholemmomas show overlap with warts affecting hair follicles, thereby inducing a trichilemmal hyperplasia (so-called trichilemmal warts). Such warts typically have a papillomatous exophytic component ( Fig. 11-14 ). On a partial superficial biopsy, tricholemmoma, especially when irritated and inflamed, may be confused with basal cell or even squamous cell carcinoma (SCC). Attention to the bland cytology of the tumor cells should avoid this pitfall. In problematic cases, immunohistochemistry for CD34 can help because strong labeling is only seen in tricholemmomas but not basal or SCC. Tricholemmoma differs from a trichilemmal carcinoma by the lack of atypia and a benign, that is, noninfiltrative, silhouette.

Clinical Findings

Pilomatricomas manifest usually as solitary, small (but rarely up to 5 cm in size), tan, firm nodules on the face and upper extremities, although they may occur in almost any hair-bearing area ( Fig. 11-15 ). The majority of lesions arise during the first two decades of life, but they can also develop in elderly individuals. Familial occurrence is rarely reported, particularly in association with myasthenia gravis or Gardner's syndrome.

Histologic Features

Pilomatricomas tend to present as well-circumscribed nodules in the dermis or superficial subcutis (or both) ( Fig. 11-16 ). A typical pilomatricoma is composed of basaloid (matrical) cells with mitotic figures and “ghost” cells (polygonal, deeply eosinophilic cell remnants, with a centrally located clear area corresponding to the absent nucleus). There is often an associated foreign body–type giant cell reaction. Calcifications are commonly found. Some pilomatricomas contain melanophages in the stroma and dendritic melanocytes within the clusters of basaloid cells (pigmented pilomatricoma or melanocytic matricoma). The early (proliferative) stage of pilomatricomas has a higher proportion of basaloid cells (often with numerous mitoses). In a later stage, the basaloid component may be minimal or absent. Tumors in the proliferative stage have also been termed proliferating tricholemmomas .

Ancillary Studies

Pilomatricomas show nuclear and cytoplasmic labeling for β-catenin.

Differential Diagnosis

Pilomatricoma needs to be distinguished from pilomatrix carcinoma. The main feature that helps in differentiating between them is the silhouette of the tumor. Whereas nodular circumscribed lesions should be considered as benign, infiltrative lesions may recur or, rarely, metastasize. Pilomatrix carcinomas typically show a high proportion of basaloid cells or features indistinguishable from SCC. Cytologic atypia and necrosis are often present in larger tumors.

On occasion, pilomatricoma also needs to be distinguished from BCC, which may show focal matrical differentiation with ghost cells. Identification of classic features of BCC in parts of the tumor is helpful in this regard. Hybrid cysts of patients with Gardner's syndrome may show mixed features of pilomatricoma and other follicular cysts.

Clinical Findings

Both fibrofolliculomas and trichodiscomas may be single or multiple, a few millimeters in diameter, yellow-white, on the head and neck. Multiple lesions are associated with Birt-Hogg-Dubé syndrome (see the following).

Histologic Features

Fibrofolliculomas have elongated, interlacing trabeculae of basaloid cells surrounded by fibromyxoid stroma. A dilated hair follicle may be seen in the center of the lesion. Trichodiscomas typically appear as perifollicular or parafollicular elliptical nonencapsulated angiofibromatous stromal proliferation ( Fig. 11-17 ).

Clinical Findings

The most common appearance is that of a papule or nodule, which may be eroded or ulcerated (ulcus rodens). Papules of BCC may clinically be confused with a nevus, fibroma, or folliculitis. BCC may also manifest as an erythematous patch ( Fig. 11-18 ), papule, nodule, or plaque ( Fig. 11-19 ), which is often eroded, ulcerated ( Fig. 11-20 ), or indurated ( Fig. 11-21 ). It may be difficult or impossible to distinguish BCC clinically from Bowen's disease or irritated or lichenoid keratoses. At times pigmentation may be present ( Fig. 11-22 ), and BCC may simulate a nevus or melanoma.

Histologic Features

Basal cell carcinoma is histologically characterized by the presence of basaloid cells, peripheral palisading, mitotic figures, apoptotic bodies, myxoid stroma, and peritumoral clefting ( Fig. 11-23 ). Among these features, the presence of myxoid stroma and peripheral clefting has been suggested to be the most helpful ones to distinguish BCC from other basaloid tumors, such as TBL. A number of secondary features may occur in BCCs, such as dystrophic calcifications, amyloid deposition, or inflammatory reactions with or without features of partial regression.

Several patterns of BCC have been described. One pattern may predominate or be present in pure form. Many times, however, a combination of patterns is seen. Furthermore, within these patterns, many additional variations may be noted (e.g., presence of melanin pigment, squamous metaplasia, stromal fibrosis). The main patterns include the following.

Superficial Pattern

The superficial pattern is characterized by the presence of aggregates of basaloid tumor cells, which are still attached to the epidermis or adnexal structures ( Fig. 11-24 ). Such basaloid nests are typically multifocal and separated from each other by intervening areas of normal epidermis (also known as skip areas). We have recently shown that measurement of the depth of invasion (similar to Breslow thickness) helps predict response to topical therapy (i.e., imiquimod). In that large series, lesions thinner than 0.4 mm did not recur.

Nodular Pattern

The nodular pattern is characterized by nodular aggregates of tumor cells in the dermis, at least focally detached from the epidermis and involving the reticular dermis ( Figs. 11-23 and 11-25 ). The nodules vary in size and shape. Some writers have proposed to distinguish BCC with large dermal nodules from those with multiple small nodules, which have been referred to as the micronodular pattern ( Fig. 11-26 ). The actual size of these nests required to distinguish micronodular from nodular BCC is subjective. Some authors recommend considering micronodular lesions as those that have nests smaller than 0.5 mm in diameter; such a definition would include a majority of BCCs. We render a diagnosis of micronodular BCCs when there are numerous similarly sized nests (occupying at least 25% of the base of the lesion) and these nests are smaller than a medium vessel (≈0.2 mm).

Morpheaform and Infiltrative Pattern

Although nodular BCCs are invasive carcinomas, the term infiltrative is generally applied to describe a tumor with less of a solid nodular growth pattern (or none of it) and a predominance of small often irregularly shaped cell aggregates, narrow strands of cells, multiple micronodules, or even single cells in the stroma. The haphazard distribution of such small tumor cell aggregates together with ill-defined interfaces with the surrounding stroma gives the tumor its infiltrative silhouette ( Fig. 11-27 ). Not all infiltrative BCCs are morpheaform, that is, sclerosing in a strict sense. We reserve the terms morpheaform, sclerodermoid, and sclerosing for BCCs that are associated with prominent stromal fibrosis ( Fig. 11-28 ). In this variant of BCC, the tumor cell aggregates are typically compressed into very narrow cords. Large solid nodules are usually absent or rare.

Fibroepitheliomatous Pattern

The fibroepitheliomatous pattern (fibroepithelioma of Pinkus) is characterized by cords and columns of basaloid cells with a fenestrated growth pattern associated with prominent fibroplasia ( Fig. 11-29 ).

Infundibulocystic Basal Cell Carcinoma

Infundibulocystic (aka hamartomatoid ) BCC is usually a small indolent lesion characterized by the presence of small keratocysts and bland basaloid cells, often arranged in small cords or a racemiform growth pattern ( Fig. 11-30 ). This lesion has features intermediate between BCC and TBL, including immunohistochemical findings such as CD34 expression by the peritumoral stromal cells. It may be associated with conventional BCC ( Fig. 11-30, B ). Multiple lesions of infundibulocystic BCC are often seen in patients with basal cell nevus syndrome.

Miscellaneous additional phenotypic variations of BCC exist, such as the following.

Adenoidal Basal Cell Carcinoma

Basal cell carcinomas may show a cribriform or pseudoglandular architecture (usually with an overall nodular growth pattern) associated with mucinous stroma simulating at first glance an adenoid cystic carcinoma ( Fig. 11-31 ).

Pigmented Basal Cell Carcinoma

Any pattern of BCC can be pigmented (most often superficial BCCs and nodular BCCs). The histologic correlate of a clinically dark brown nodule is usually the presence of melanophages in the stroma ( Fig. 11-32 ). However, melanin pigment may also be present in the carcinoma cells. On occasion, one also finds dendritic melanocytes within the tumor compartment (melanocytes and Langerhans cells). Collisions of BCC and melanocytic proliferations (most often nevi, at times melanoma—usually lentigo maligna melanoma in situ) may also give rise to the clinical impression of pigmented BCC.

Basal Cell Carcinoma with Squamous Differentiation

At times, a BCC may show squamous differentiation, especially superficially underneath an ulcer. Squamous differentiation may also occur in deeper infiltrative parts of the tumor, especially in recurrent tumors. BCCs with squamous differentiation have also been referred to as metatypical BCCs ( Fig. 11-33 ). In a partial tissue sample, a squamatized BCC may be indistinguishable from SCC.

Clear Cell Basal Cell Carcinoma

This BCC is characterized by the presence of tumor cells with glycogen-rich clear cytoplasm ( Fig. 11-34, A ).

Basal Cell Carcinoma with Eccrine Differentiation

These are tumors with focal duct formation in the context of a classic BCC. Eccrine differentiation is a rare phenomenon. More often, one can observe preexisting sweat ducts, which may be ectatic, engulfed by BCC ( Fig. 11-35 ). These lesions may have an aggressive behavior with distant metastases.

Basal Cell Carcinoma with Matrical Differentiation

Occasionally, a tumor with features otherwise typical of BCC shows focal shadow cells similar to what is seen in bona fide pilomatrix tumors ( Fig. 11-36 ).

Basal Cell Carcinoma with Nuclear Pleomorphism

Occasionally, a BCC shows marked nuclear pleomorphism ( Fig. 11-37 ). To date, there is no evidence that this is a clinically significant finding.

Collision Scenarios

Basal cell carcinomas may collide with a number of epithelial and nonepithelial tumors. Common associations include BCC and SK ( Fig. 11-38 ) or BCC and melanocytic nevus ( Fig. 11-39 ).

Ancillary Studies

Immunohistochemistry may on occasion be helpful for the distinction of BCC from histologic mimics thereof. BCCs are typically immunoreactive for the following epithelial markers: 34BE12, MNF116, and Ber-EP4. They are usually negative with Cam5.2, AE1:AE3, epithelial membrane antigen (EMA), and CK7. Focal labeling with AE1:AE3 may be seen in the squamatized portion of a BCC. CD10 is expressed by some of the epithelial tumor cells. Immunoreactivity with Cam5.2 or anti-CK7 may be found when eccrine ducts are entrapped by BCC or in BCCs with focal eccrine differentiation. BCCs are negative for CK20, but a subset of BCCs is (usually only weakly) positive for chromogranin or synaptophysin.

Differential Diagnosis

The histologic diagnosis of BCC is usually straightforward. However, problems can arise from histologic overlap with other basaloid epithelial neoplasms and from insufficient histologic sampling.

Prognosis and Treatment

Basal cell carcinoma is usually a slow-growing tumor. Some variants of BCC, such as infundibulocystic BCC, tend to be indolent, with limited potential for tissue destruction over many years. Other so-called aggressive variants, which include infiltrating, morpheaform, and micronodular BCCs, may cause severe tissue destruction.

Based on a number of clinical and pathologic features, patients with BCCs are often classified into low- and high-risk categories.

The vast majority of superficial and nodular BCCs are cured by excision. Narrow excisions suffice. There is no need for wide margins. For early superficial lesions, local destructive modalities, such as cryotherapy, may be adequate. For facial lesions, surgery with frozen section examination is the treatment of choice. Postoperative or intraoperative complete circumferential peripheral and deep margin assessment with frozen or permanent sections is critical for large and infiltrative lesions. Radiation therapy is also an option for patients who are reluctant or unable to undergo surgery or in the case of positive margins or extensive perineural invasion.

In very rare cases, usually after repeated local recurrences, large and deeply infiltrative BCCs may metastasize to lymph nodes or distant sites, such as the lung, and become lethal.

Clinical Findings

Pilomatrix carcinoma is a rare tumor of middle-aged and elderly individuals. The head and neck area or extremities are most often affected. The tumors may present as papules or nodules. They may be large (larger than 5 cm) and are commonly ulcerated.

Histologic Features

The silhouette of the tumors is asymmetric and infiltrative with an overall lobular growth pattern. The tumors are composed of two major cell types: (1) basaloid cells with matrical features are arranged in lobules and sheets or cords and bands and (2) “ghost” or “shadow” cells as seen in pilomatricoma. Foci of necrosis are usually present ( Fig. 11-41 ). Mitotic figures among basaloid cells are easily identified and may be numerous (areas with up to 10 mitoses per high power field are not uncommon). The degree of nuclear atypia is variable. Some pilomatrix carcinomas show areas histologically indistinguishable from SCC.

Ancillary Studies

Pilomatrix tumors contain β-catenin mutations and show a distinct cytoplasmic and nuclear labeling of tumor cells ( Fig. 11-42 ) in contrast to the membranous labeling of normal epidermis or SCCs.

Differential Diagnosis

Pilomatrix carcinoma needs to be distinguished from pilomatricoma, BCC, and SCC. Pilomatrix carcinoma differs from pilomatricoma primarily by its infiltrative growth pattern and the presence of cytologic atypia. Furthermore, carcinomas tend to be larger and are more likely to have necrosis and features of squamous metaplasia simulating the appearance of SCC.

Basal cell carcinoma, which may show focal matrical differentiation, differs from pilomatrix carcinoma (and pilomatricoma) by the presence of typical features of BCC, such as palisading nuclear arrangement, stromal mucin, clefts, or connections to the epidermis or non-neoplastic follicular structures.

Squamous cell carcinomas are best distinguished from pilomatrix carcinomas by the presence of a precursor lesion (SCC in situ), connection of invasive keratinizing tumor to the skin surface, and lack of ghost cells.

Prognosis and Treatment

Pilomatrix carcinomas are slowly growing, locally aggressive tumors. They are usually cured by excision, but rare tumors metastasize to lymph nodes and visceral sites. Too few cases have been studied to establish prognostic parameters.

Clinical Findings

These are clinically indistinct tumors, typically presenting as flesh-colored papules or nodules. Some may arise in association with nevus sebaceus.

Histologic Features

These are benign tumors with glandular differentiation (presence of ducts, lumina) ( Figs. 11-43 to 11-45 ). They tend to be centered in the dermis and are well circumscribed. They may show tubular, cribriform, papillary, micropapillary, or mixed growth patterns. The ductal lining is bilayered, with luminal cuboidal secretory cells and peripheral cuboidal or flat myoepithelial cells. The epithelial cells may be small or large cuboidal or flat. The cytoplasm may range from dense pink to a clear cell appearance. Focal squamous or mucinous metaplasia may occur. The stroma of adenomas has various degrees of fibrosis and may be hyalinized.

Adenomas can be classified further based on the predominant growth pattern (e.g., tubular, cribriform, or papillary adenomas, the latter being identical to hidradenoma papilliferum). At the current time, we see little value in detailed subclassification of benign sweat gland adenomas. The important issue is simply to recognize them as being benign. On the other hand, some subtypes of sweat gland adenomas have become such established and familiar entities (e.g., hidradenoma papilliferum, nodulocystic hidradenoma) that they are discussed separately here.

Differential Diagnosis

The important issue is to distinguish adenomas (circumscribed lesions) from well-differentiated adenocarcinomas. In the majority of cases, this distinction is straightforward because many carcinomas are large and infiltrative and show significant cytologic atypia. However, in some instances, such as digital lesions, ductal adenocarcinomas may be deceptively “bland” with regard to their cytologic appearance (see aggressive papillary digital adenoma—adenocarcinoma).

Clinical Findings

This lesion is typically found in the vulva and perianal region as a solitary papule or small nodule but may occur anywhere, especially along the “milk line.”

Histologic Features

Hidradenoma papilliferum is a well-circumscribed dermal nodule composed of both solid and cystic regions. The hallmark of this lesion is the papillary architecture, with a layer of luminal secretory cells surrounded by myoepithelial cells ( Fig. 11-45 ). Occasionally, there are large cuboidal cells identical to those seen in apocrine metaplasia of mammary glands. Because identical lesions can be seen in other anatomic locations, an alternative name for all of these lesions may be papillary apocrine adenoma.

Differential Diagnosis

In contrast with syringocystadenoma papilliferum, hidradenoma papilliferum does not show prominent plasma cell infiltrates.

Clinical Findings

Hidradenomas are solitary skin-colored or reddish papules or nodules ( Fig. 11-46 ). They may be large, measuring up to 2 cm or more in diameter. They can occur at any anatomic location and any age.