Role of immunohistochemistry in diagnosing tumors of cutaneous appendages.

In recent years, there has been significant progress in immunohistochemistry as an ancillary tool in diagnostic dermatopathology. In most instances, the histologic diagnosis can be rendered with the routine histologic sections; however, immunohistochemistry can help to narrow the differential in diagnosing neoplasms of cutaneous appendages in some settings including adnexal versus epidermal origin, benign versus malignant adnexal neoplasms, and primary adnexal carcinoma versus cutaneous metastases as outlined in this review.

p63 Immunohistochemistry is a useful adjunct in distinguishing sclerosing cutaneous tumors.

Cutaneous sclerosing epithelial neoplasms are often difficult to diagnose. Though various immunohistochemical markers have proved useful, some cases remain a diagnostic challenge. We aimed to assess the utility of p63 immunohistochemical staining in distinguishing microcystic adnexal carcinoma (MAC) from sclerosing basal cell carcinoma (SBCC) and desmoplastic trichoepithelioma (DTE). Biopsy samples from 20 SBCC, 10 DTE, and 5 MAC were examined after immunohistochemical staining with p63. Although all adnexal tumors examined demonstrated p63 expression, the pattern of staining was strikingly different in MAC when compared with other tumor types. MAC exhibited a scattered pattern with p63-positive cells around the periphery of tumor nests and minimal staining within the center of the tumor islands. This pattern was more pronounced at increased depth of infiltration into the dermis. A robust and consistent diffuse pattern of staining with p63 was observed in all SBCCs and DTEs. We believe this pattern reflects the multi-differentiation pathway of MAC, with eccrine/sebaceous differentiation occurring at deeper levels of the dermis. The different staining patterns of MACs compared with DTEs and SBCCs can thus serve asa useful diagnostic adjunct in difficult lesions.

[Immunohistochemical study of calretinin in normal hair follicles and tumors with follicular differentiation]. / Estudio inmunohistoquímico de la calretinina en el folículo piloso normal y neoplasias con diferenciación folicular.

BACKGROUND: Selective immunostaining for calretinin labels the innermost layer of the outer root sheath of normal hair follicles, which is difficult to distinguish with hematoxylin-eosin staining. OBJECTIVE: The aim of this study was to determine whether immunohistochemistry for calretinin allows identification of cutaneous adnexal tumors with follicular differentiation towards cells of the outer root sheath. MATERIAL AND METHODS: We analyzed the staining pattern for calretinin by immunohistochemistry in 49 biopsies of cutaneous adnexal tumors with follicular differentiation. RESULTS: Fifteen biopsies corresponded to trichilemmomas/inverted follicular keratosis and had staining for calretinin in the epithelium of the most superficial areas of the lesions and in squamous eddies. Ten were trichilemmal cysts, which displayed staining of the cyst wall. Three were basal cell carcinomas with variable staining according to the type of follicular differentiation in each variant. One was a panfolliculoma that had focal staining. Two were folliculosebaceous cystic hamartomas with staining of the excretory duct of the sebaceous glands. Two pilomatricomas and 3 proliferative trichilemmal tumors had positive staining in the cellular layers close to the lumen of the cystic structures. Nine trichoblastomas/trichoepitheliomas, 2 infundibular cysts, 1 dilated pore of Winer, and 2 acanthomas of the follicular sheath were negative for calretinin. CONCLUSION: Immunohistochemistry for calretinin allows identification of cutaneous adnexal tumors of the hair follicle or a component of the follicle with differentiation towards cells of the outer root sheath.

Trichilemmal carcinoma with neuroendocrine differentiation.

We report a 12-mm nodular, cream-coloured skin lesion that appeared on the left nasal ala in an 81-year-old man. This trabecular infiltrative tumour showed keratin microcysts, stromal hyalization, cytoarchitectural malignancy features, colonizing melanocytes, and immunoexpression of epithelial membrane antigen, cytokeratin 15/20, chromogranin, synaptophysin and CD56. To our knowledge, this is the first documented case of a trichilemmal carcinoma with neuroendocrine differentiation and melanocyte colonization, which is suggested by the trabecular growth pattern and requires immunohistochemical confirmation. The colonization of the epithelial nests by nonatypical dendritic or spindle melanocytes is a clue to morphological recognition of pilar neoplasms, along with the presence of stromal induction (CD34-positive peritumoral spindle cells), catagen-like apoptotic bodies, calcifications, keratin microcysts and cell balls.

Microcystic adnexal carcinoma: an immunohistochemical reappraisal.

Even though immunohistochemical comparisons of microcystic adnexal carcinoma vs infiltrative basal cell carcinoma and desmoplastic trichoepithelioma exist, they are mostly restricted to the use of a single stain. In addition, a comparison with squamous cell carcinoma has not been reported previously. In this study, we compare the expression of cytokeratin (CK) 15, CK7, CK20, CK903, carcinoembryonic antigen (CEA), CD10, CD15 and BerEP4 in 13 microcystic adnexal carcinoma, eight desmoplastic trichoepithelioma, 10 infiltrative basal cell carcinoma, and eight squamous cell carcinoma of which five exhibited ductal differentiation. We found that the majority of microcystic adnexal carcinoma (92%) and desmoplastic trichoepithelioma (100%) cases expressed CK15 while the infiltrative basal cell carcinoma and squamous cell carcinoma cases were all negative. Forty percent of infiltrative basal cell carcinoma expressed CK7; while only two microcystic adnexal carcinoma cases (15%) and one squamous cell carcinoma with ductal differentiation (12%) expressed CK7 in the remaining three tumor categories. None of the desmoplastic trichoepithelioma expressed CK7. All tumors were strongly positive for CK903. While the neoplastic cells were negative, luminal staining of ductal structures was noted for CK7, CD15 and CEA in some of the microcystic adnexal carcinoma, desmoplastic trichoepithelioma and squamous cell carcinoma with ductal differentiation cases. Sixty percent of infiltrative basal cell carcinoma, 31% of microcystic adnexal carcinoma, and 25% of squamous cell carcinoma express CD10. BerEP4 expression was noted in 38% of microcystic adnexal carcinoma, 57% of desmoplastic trichoepithelioma, 100% of infiltrative basal cell carcinoma, and 38% of squamous cell carcinoma. In conclusion, we found CK15 to be a useful marker in distinguishing microcystic adnexal carcinoma from infiltrative basal cell carcinoma and squamous cell carcinoma with ductal differentiation. Our experience indicates that microcystic adnexal carcinoma and desmoplastic trichoepithelioma have a similar immunohistochemical profile that is, CK15+ and BerEP4+/-; thus, additional studies are needed to separate these two entities.

Microcystic adnexal carcinoma with mandibular bone marrow involvement: a case report with immunohistochemistry.

Microcystic adnexal carcinoma is a rare, locally aggressive cutaneous neoplasm with a high probability of persistence locally but a low probability of metastasis. We report a case of a 69-year-old female patient with an indurated plaque at the mental region. Histologically, the tumor cells invaded the subcutaneous tissue and mandibular bone. The tumor consisted mainly of squamous and basaloid epithelial nests and cords embedded in a desmoplastic stroma. A few keratin-filled microcysts and ductal structures were also observed. Perineural encroachment was also noted but there was no mitosis, cytologic features of malignancy, or metastasis. The epithelial nests were positive to various cytokeratins except for CK20 and the lumina of the ductal structures were positive to carcinoembryonic antigen. Our results indicate that microcystic adnexal carcinoma consists of tumor cells capable of both follicular and eccrine differentiation. It is locally aggressive, extends far beyond its clinical presentation and may involve the bone. It may persist and remain asymptomatic for so many years without metastasis. A lifetime postsurgery monitoring is mandatory to ensure early and proper management.

Trichoepithelioma with giant and multinucleated neoplastic epithelial cells.

We report an unusual example of trichoepithelioma containing giant and multinucleated cells in the epithelial compartment. The patient was a 52-year-old woman who presented with a solitary nodule on the scalp measuring 2 cm of apparently long duration. The biopsy revealed a typical trichoepithelioma. The unusual feature was the presence in some epithelial nodules of large epithelial cells with hyperchromatic nuclei and no visible nucleoli that exceed 3 to 5 times the adjacent follicular germinative cells. Often, multinucleated cells were seen. Rare nodules were almost entirely composed of giant/multinucleated cells. The majority of the nodules containing giant cells were situated in the deeper portion of the neoplasm. No mitoses were seen in these giant cells. No enlarged or multinucleated cells were seen in the stroma. The neoplastic epithelial cells were diffusely reactive for bcl-2, including the giant and multinucleated cells. The proliferating rate was low; Ki-67 stained some giant cells. CD34 stained the stroma. We believe that the focal presence of pleomorphic giant cells in trichoepithelioma has no clinical or prognostic implications and does not denote its "malignant transformation".

Carcinosarcoma arising in a patient with multiple cylindromas.

Familial cylindromatosis (Brooke-Spiegler syndrome) is a rare autosomal dominant inherited disease characterized by the development of adnexal tumors, mostly cylindromas, but also trichoepitheliomas and spiradenomas. Malignant tumors may occur, usually with the features of a cylindrocarcinoma. The authors describe the case of a 75-year-old woman with the Brooke-Spiegler syndrome who presented with multiple nodules of the scalp, face, and trunk. In 1997 she underwent surgical excision of the entire forehead and scalp with skin grafting. Histologic examination revealed multiple cylindromas, some with areas of spiradenoma and one with an extensive adenomatous component; some trichoepitheliomas were also evident. In 2002, a nodule of the trunk suddenly increased in size and became painful. The lesion was excised and histologic and immunohistochemical evaluation revealed a malignant cutaneous biphasic tumor extending into the subcutis, consisting of a major portion with the features of an adnexal carcinoma and of a minor one of atypical spindle cells. Biphasic malignant skin tumors are rare and only a limited number have been described, none in association with the Brooke-Spiegler syndrome. The authors discuss the morphogenesis of the folliculosebaceous-apocrine unit from which the tumors in this syndrome derive, and the pivotal role of mesenchymal cells in determining the process. Since the Brooke-Spiegler syndrome is characterized by a germline mutation in the CYLD oncosuppressor gene, a biphasic tumor in this setting may represent a true carcinosarcoma.

Sebaceous carcinoma, trichoblastoma, and sebaceoma with features of trichoblastoma in nevus sebaceus.

A 73-year-old woman had a linear yellowish plaque on the upper part of her right ear since birth. She presented because of the sudden growth of a nodule within the plaque. The plaque was waxy and yellowish, arching around the upper part of the ear. A reddish to yellowish large nodule was seen within the central part of the arc-shaped plaque; in addition, a small pigmented nodule, a small skin-colored nodule, and a few pigmented papules were observed in the anterior half of the arched plaque. Histopathologic examination revealed the large nodule to be sebaceous carcinoma, the small pigmented nodule to be trichoblastoma, the small skin-colored nodule to be sebaceoma with the features of trichoblastoma, a few pigmented papules to be superficial trichoblastomas due to primitive follicular induction, and the linear yellowish plaque to be nevus sebaceus. Although our literature search revealed scanty reports of definite cases of sebaceous carcinoma in nevus sebaceus, the presented case demonstrated the occurrence of sebaceous carcinoma in nevus sebaceus. Malignant neoplasms occurring in nevus sebaceous seem to be extremely rare, but care should be taken when a large nodule suddenly grows in a lesion of nevus sebaceus, especially in older adults. The presented case also suggested a close relation between trichoblastoma and sebaceoma. The cytokeratin staining pattern could not distinguish between sebaceous and follicular neoplasms in our case.

Merkel cells and sclerosing epithelial neoplasms.

Merkel cells are normal constituents of the basal layer of the epidermis and the follicular epithelium. They have been identified in benign neoplasms with follicular germinative differentiation but seem to be absent in basal cell carcinomas (BCCs). Because sclerosing epithelial neoplasms are often sampled by small biopsies, any method that enables distinction among them would be welcome. We used immunohistochemical staining for cytokeratin 20 to assess the presence of Merkel cells in 14 cases of desmoplastic trichoepithelioma (DTE), 12 specimens of syringoma, 11 samples of morpheiform BCC, and 8 specimens of microcystic adnexal carcinoma (MAC). Merkel cells were found in association with all 14 specimens of DTE and in 1 of 11 cases of morpheiform BCC (p < 0.005) but in none of the specimens of syringoma or MAC. Our study supports previous findings that Merkel cells are seen in association with cutaneous neoplasms that are benign and of a follicular germinative origin. Although MAC may differentiate along follicular-sebaceous-apocrine lines, the absence of Merkel cells within it is consistent with its malignancy. The identification of Merkel cells in a sclerosing epithelial neoplasm of the skin points to DTE as the most likely diagnosis.

Microcystic adnexal carcinoma associated with primary immunodeficiency, recurrent diffuse herpes simplex virus infection, and cutaneous T-cell lymphoma.

Cutaneous microcystic adnexal carcinoma (MAC) is a rare and poorly understood tumor that predominantly occurs in the head and neck. MAC usually affects people in their fourth and fifth decades. Some patients have had a history of radiation. We present a case of MAC occurring in the left antecubital fossa of an 18-year-old white woman with an unusual immunodeficiency syndrome. The patient also developed a squamous cell carcinoma, a cutaneous T-cell malignancy, and a perigastric leiomyoma. A congenital infection of herpes simplex virus (HSV) persisted throughout her life. The association of HSV infection with MAC and squamous cell carcinoma and that of peripheral T-cell lymphoma with Epstein-Barr virus is discussed in relation to her immunodeficiency.

A tumour derived from Ebner's glands: microcystic adnexal carcinoma of the tongue.

Microcystic adnexal carcinoma (MAC) is known as an infiltrating but non-metastasizing tumour of the skin, that derives from sweat glands or follicular epithelium. We report on a rare case of MAC of the tongue. The patient had noticed the tumour for two years with slowly increasing dysphagia but no other symptoms of an oropharynx carcinoma. Histological and immunohistochemical analyses showed a similarity between the tumour derived from Ebner's glands of the tongue and MAC of the sweat glands.

Use of CD34 in assessing the relationship between stroma and tumor in desmoplastic keratinocytic neoplasms.

It has been hypothesized that the ability for neoplastic growth of epithelial-derived neoplasms depends upon the stroma. There are currently some studies which show that the stroma surrounding basal cell carcinomas (BCC) is derived from the tumor. In contrast, other studies provide evidence that the stroma is a host-derived response to the tumor. In order to further examine the nature of stroma enveloping cutaneous epithelial neoplasms, we examined a series of tumors which contain abundant stroma, including morpheic type BCC (MBCC), desmoplastic trichoepitheliomas (DTE), and microcystic adnexal carcinomas (MAC). The spindle-shaped cells surrounding the epithelial islands of the two malignant tumors, MBCCs and MACs, were negative in 70% and 100% of cases, respectively, for CD34. In contrast, the spindle-shaped cells surrounding the islands of the benign DTEs were positive for CD34 in 80% of cases. The results suggest that whereas stromal cells surrounding DTEs resemble the CD34-positive perifollicular cells, the spindle-shaped stromal cells surrounding MBCC and MAC are CD34 negative, and may be derived from sources other than the normal mesenchymal tissue surrounding cutaneous appendages.