Friday, 15 October 2010

Trichoepithelioma

The appendageal tumours either differentiate towards or arise from the pilosebaceous apparatus (including the apocrine gland) and eccrine sweat gland. Their clinical picture is commonly non-specific and the diagnosis in the great majority can be reached by histopathology. Studies on the role of the sonic hedgehog gene and related proteins (see below) in basal cell carcinomas (BCCs) have been extended to hair-follicle tumours. Basal cell carcinomas are now believed to arise from pluripotential cells that form continuously during life due to malfunctioning of the hedgehog patched pathway. The pilosebaceous apparatus is concentrated in the head and neck area, with the pilar element predominant on the scalp and the sebaceous element on the face, chest and upper back. Thus, tumours arising from these structures are found predominantly at these anatomical sites.

Trichoepithelioma is a hamartoma of the hair germ (follicular germinative cells) composed of immature islands of basaloid cells with focal, primitive follicular differentiation and induction of a fibrous cellular stroma. The “hair germ” is actually the germ for the entire folliculo-sebaceous-apocrine unit because germinative cells of an embryonic follicle are responsible for formation of the entire follicle and of sebaceous and apocrine units too.


Solitary trichoepitheliomas [are not inherited (sporadic) and sometimes associated with deletions at chromosome 9q22.3] are commoner than multiple trichoepitheliomas (autosomal dominant, chromosome 9p21).

Sporadic trichoepitheliomas have a different pathogenesis from hereditary counterparts. The site of the human homologue of the Drosophila patched gene is the human patched gene located on chromosome 9q22.3, and loss of heterozygosity (deletions at chromosome 9q22.3) has been identified in sporadic trichoepitheliomas. Some cases of sporadic basal cell carcinomas also show this deletion. The gene encodes a protein which is the receptor for sonic hedgehog also originally discovered in Drosophila (named after a video game character, Sonic the Hedgehog!). Rather than the normal pattern of denticles, hedgehog mutant larvae tend to have "solid lawns" of denticles. The appearance of the stubby and "hairy" larvae inspired the name 'hedgehog'.


The hedgehog signalling pathway is important during embryonic development and when it malfunctions it leads to developmental abnormalities. When it malfunctions in adults it leads to neoplasia. A region at 9p21 has been suspected to be involved in pathogenesis in hereditary trichoepitheliomas, and deletions within this area harbour known tumour suppressor genes. In other words, because several tumour suppressor genes are in this region, the gene for the development of hereditary trichoepitheliomas also encodes for a tumour suppressor. If altered, cellular proliferation may be up-regulated because of a poorly functioning or absent tumour suppressor.

Trichoepitheliomas whether solitary or multiple are most commonly seen on the face as expected (see above). Trichoepitheliomas [Brooke’s tumour] have been reported to coexist with other conditions such as: with alopecia/myasthenia gravis, in Rombo syndrome (named after the oldest family member in the pedigree, affected individuals of Rombo syndrome develop vermiculate atrophoderma, milia, hypotrichosis, trichoepitheliomas and peripheral vasodilatation in addition to BCCs), in Rasmussen syndrome (multiple trichoepitheliomas associated with cylindromas and milia) and in Brooke–Spiegler syndrome (multiple trichoepitheliomas [Brooke’s tumour] associated with cylindromas [Spiegler’s tumour] and occasionally spiradenomas). As stated before, tumours develop from undifferentiated germinative cells of the pilosebaceous–apocrine unit and this explains why in some cases the same tumours have features of cylindroma and/or spiradenoma, particularly in the Brooke–Spiegler syndrome; there may be an admixture with trichoepitheliomas, either in separate tumours or sometimes in the same tumour. There is an apocrine line of differentiation at least in a percentage of spiradenomas (generally considered to be of eccrine sweat gland origin but Ackermann regarded it as apocrine in type and it is one of the painful skin tumours). Mutations in CLYD (cylindromatosis) gene, encoding for a tumour suppressor gene mapped to chromosome 16q12–13, may result in one of 3 syndromes: Brooke-Spiegler syndrome (epithelioma adenoides cysticum), familial cylindromatosis, and familial trichoepitheliomas.

Trichoepithelioma is regarded as part of the spectrum of trichoblastoma (benign counterpart of basal cell carcinoma). The designation ‘trichoblastoma’ has evolved to be an overarching label for benign proliferations with follicular germinative differentiation. Trichoepithelioma and giant trichoepitheliomas (a very large, polypoid lesion presenting on the lower trunk, frequently in the perianal area), represent the more mature end of the spectrum of trichoblastoma.


Solitary desmoplastic [sclerosing] trichoepithelioma (much commoner than multiple desmoplastic trichoepitheliomas) can be easily misinterpreted as sclerosing (morphoeic) BCC. Small incomplete biopsies may cause uncertainty about excluding sclerosing BCC or microcystic adnexal carcinoma, and re-excision or resampling may be necessary for a definitive diagnosis or complete eradication in uncertain cases. Merkel cells are present in desmoplastic trichoepithelioma and absent in microcystic adnexal carcinoma and in most cases of morphoeic basal cell carcinoma. Immunostaining with cytokeratin 20, to identify Merkel cells, is therefore useful in the differential diagnosis of these neoplasms. Testing for the immunohistochemical expression of androgen receptor is useful (usually negative in trichoepithelioma and positive in basal cell carcinomas) and also testing the stromal cells surrounding the cellular islands in desmoplastic trichoepithelioma for CD34 is useful (focally positive in desmoplastic trichoepithelioma, whereas the stromal cells around basal cell carcinomas and microcystic adnexal carcinomas are usually negative). Malignant transformation of trichoepithelioma is extremely rare.

The presentation of a solitary lesion is that of a smooth, skin coloured, nodule, usually on the face, which clinically resembles a non-ulcerated basal cell carcinoma. At times differentiating between the trichoepitheliomas and basal cell carcinoma can be difficult. The separation (retraction) artefact, where dermal connective tissue (surrounding stroma) separates away from islands of basal cell carcinoma cells, helps in differentiating a basal cell carcinoma from a trichoepithelioma (retraction artefact between tumour cells and the surrounding stroma is absent).


Multiple trichoepitheliomas are seen as multiple, small, firm, pearly lesions, mainly on centrofacial skin. A few patients reveal plaques or nodules due to coalescing of several lesions. The condition usually presents in childhood or around puberty. They tend to be larger, more multi-lobulated than milia. By comparison, syringomas tend to be smaller, rather less superficial, more flat-topped and disposed more evenly over the cheeks and eyelids, rather than favouring the nasolabial creases and there is no family history. The firm, pearly skin-coloured papules of multiple trichoepitheliomas must be differentiated from the firm, red-brown, telangiectatic papules of angiofibromas seen in tuberous sclerosis complex.

The histopathology is identical for solitary or multiple lesions and consists of lobules of small, dark basaloid cells, often with a degree of peripheral palisading surrounding a central area of eosinophilic amorphous material. Occasionally, hair shaft-like structures can be seen in these central areas but with no formation of actual hair shafts as occurs in trichofolliculoma. The islands can have a “paisley tie” appearance. The aggregations of basaloid cells are arranged in different morphologic patterns e.g. cribriform (classic) and columnar (desmoplastic). In some lesions, there is more than one predominant morphologic pattern. Trichoepitheliomas are dermal tumours with focal continuity with the epidermis at times.

Solitary lesions can be treated by surgical excision. Multiple lesions can be smoothed down by resurfacing the skin with laser, dermabrasion, electrosurgery or cryotherapy. This procedure is repeated at regular intervals, as the lesions recur gradually. A Brazilian study*of several types of cutaneous tumours, in 2009, reported a partial response for trichoepithelioma to 5% imiquimod cream.


* Alessi SS, Sanches JA, de Oliveira WR, Messina MC, Pimentel ER, Festa Neto C. Treatment of cutaneous tumors with topical 5% imiquimod cream. Clinics (Sao Paulo). 2009; 64(10): 961-6. 

This page was last updated in January 2014.

2 comments:

  1. Note that:

    1) In trichoepithelioma there are:

    • Circumscribed basaloid tumour islands, often in a cribriform pattern (interconnecting cords), sometimes resembling poorly developed hair follicles.

    • Peripheral palisading of nuclei, but no artefactual retraction between tumour and stroma (the fibrocytic stroma typically maintains tightly adherent contact to the neoplastic follicular germinative cells).

    • Loose stroma with many fibroblasts surrounds basaloid islands

    2) In desmoplastic trichoepithelioma there are thinner strands and ribbons of basaloid cells, horn cysts usually present, with a dense fibrous stroma surrounding both, resembling a sclerosing basal cell carcinoma.


    3) In BCC there are clefts between basaloid cells and stromal elements [the separation (retraction) artefact].

    4) Cylindromas are sometimes associated with multiple trichoepitheliomas in the
    Brooke–Spiegler syndrome (with spiradenomas in addition) and in Rasmussen syndrome (with milia in addition). Cylindroma is a tumour of basaloid cells in the dermis arranged in islands that often fit together like a jigsaw puzzle (jigsaw-puzzle architecture) - apocrine/sweat duct lumina often present within tumour islands - cylindromas are more likely to be related to the apocrine gland than to the eccrine gland.

    ReplyDelete
  2. Cylindroma [Spiegler’s tumour]* is a tumour of basaloid cells in the dermis arranged in islands that often fit together like a jigsaw puzzle (jigsaw-puzzle architecture), the islands are surrounded by conspicuous eosinophilic band (hyaline) - apocrine/sweat duct lumina often present within tumour islands - cylindromas are more likely to be related to the apocrine gland than to the eccrine gland.

    Cylindromas are sometimes associated with multiple trichoepitheliomas [Brooke’s tumour] in the Brooke–Spiegler syndrome (with occasionally spiradenomas in addition) and also in Rasmussen syndrome (with milia in addition).

    Trichoepitheliomas develop from undifferentiated germinative cells of the pilosebaceous–apocrine unit and this explains why in some cases the same tumours have features of cylindroma and/or spiradenoma, particularly in the Brooke–Spiegler syndrome; there may be an admixture with trichoepitheliomas, either in separate tumours or sometimes in the same tumour. There is an apocrine line of differentiation at least in a percentage of spiradenomas (generally considered to be of eccrine sweat gland origin but Ackermann regarded it as apocrine in type and it is one of the painful skin tumours and it is not surprising to know that pain is an occasional symptom in cylindroma). Mutations in CLYD (cylindromatosis) gene, encoding for a tumour suppressor gene mapped to chromosome 16q12–13, may result in one of 3 syndromes: Brooke-Spiegler syndrome (epithelioma adenoides cysticum), familial cylindromatosis, and familial trichoepitheliomas.

    *Sometimes called turban (عمامة) tumour (multiple tumours on the scalp).

    ReplyDelete

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Main Works of Reference List (The first eight are my top favourites)

  • British National Formulary
  • British National Formulary for Children
  • Guidelines (BAD - BASHH - BHIVA - Uroweb)
  • Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health
  • Oxford Handbook of Medical Dermatology
  • Rook's Textbook of Dermatology
  • Simple Skin Surgery
  • Weedon's Skin Pathology
  • A Concise Atlas of Dermatopathology (P Mckee)
  • Ackerman's Resolving Quandaries in Dermatology, Pathology and Dermatopathology
  • Andrews' Diseases of the Skin
  • Andrology (Nieschlag E FRCP, Behre M and Nieschlag S)
  • Bailey and Love's Short Practice of Surgery
  • Davidson's Essentials of Medicine
  • Davidson's Principles and Practice of Medicine
  • Fitzpatrick's Colour Atlas and Synopsis of Clinical Dermatology (Klaus Wolff FRCP and Richard Allen Johnson)
  • Fitzpatrick’s Dermatology in General Medicine
  • Ganong's Review of Medical Physiology
  • Gray's Anatomy
  • Hamilton Bailey's Demonstrations of Physical Signs in Clinical Surgery
  • Hutchison's Clinical Methods
  • Lever's Histopathology of the Skin
  • Lever's Histopathology of the Skin (Atlas and Synopsis)
  • Macleod's Clinical Examination
  • Martindale: The Complete Drug Reference
  • Oxford Handbook of Clinical Examination and Practical Skills
  • Oxford Textbook of Medicine
  • Practical Dermatopathology (R Rapini)
  • Sexually Transmitted Diseases (Holmes K et al)
  • Statistics in Clinical Practice (D Coggon FRCP)
  • Stockley's Drug Interactions
  • Treatment of Skin Disease: Comprehensive Therapeutic Strategies
  • Yen & Jaffe's Reproductive Endocrinology