Synonyms: None
Etiology: pTEN mutation
Associations: Multiple hamartomas, keratoacanthomas, neoplasms
Clinical: Hyperkeratotic folliculocentric papules
Histology: Proliferations of pale staining keratinocytes from epidermis
IHC repertoire: N/A
Staging: N/A
Prognosis: 100% survival
Adverse variables: Visceral neoplasms
Treatment: Careful screening
15
Cowden’s Syndrome
Trichilemmomas are benign epidermal neoplasms that may serve as an indicator of underlying malignancy.
Trichilemmomas appear, largely on the head and neck, as exophytic, small, hyperkeratotic papules (Figure 15.1).
There is no particular gender predilection and they usually arise during the second decade. When occurring as iso- lated lesions, these tumors are invariably benign and are of no clinical significance.
Multiple trichilemmomas may occur as part of the multiple hamartoma or Cowden syndrome (1). This syn- drome has an autosomal dominant inheritance pattern (2) and is associated with mutations in the pTEN gene located at 10q22–23 (3). Table 15.1 summarizes the sys- temic conditions associated with the syndrome (4–7).
These patients develop many hamartomatous lesions, fibrocystic changes in the breast, and breast and thyroid carcinomas. The neoplastic proliferations tend to be rela- tively indolent and confer a good prognosis for afflicted patients. The gastrointestinal polyps do not appear to harbor malignant potential. There are isolated reports of many other neoplasms occurring in patients with the syndrome (8).
Cowden syndrome displays other cutaneous manifesta- tions. These include cobblestone-like fibromas on the tongue and within the oral mucosa, sclerotic fibromas (9), lipomas, and hyperkeratotic plaques on the dorsa of the hands. While less common and less specific than trichil-
emmomas, these other processes can also be valuable clues in establishing the diagnosis.
Trichilemmomas have a characteristic histologic appearance. Keratinocytes proliferate down from the surface of the epidermis as an expansile plaque (Figure 15.2). There is frequently overlying parakeratosis, focal diminution of the granular layer, and clumped keratohyalin granules in other sections of the epidermis.
In some cases, a central hair follicle may be present.
The keratinocytes within the tumor have abundant, pale staining cytoplasm, resembling the appearance of the outer root sheath of follicular epithelium (Figure 15.3). The bottom of the lesion may have a lobulated configuration. Inward turning rete ridges may be seen at the periphery of the lesion. One characteristic fi nding is the presence of a thickened, PASD positive basement membrane immediately beneath the intraepi- dermal proliferation (Figure 15.4). This membrane is refractile. Squamous eddies are present. Some authors have contended that these lesions represent human papilloma virus infections involving hair follicles, but the scientific evidence for that position is lacking (10, 11).
Desmoplastic trichilemmoma is a histologic variant that may be confused with squamous cell carcinoma or basal cell carcinoma on microscopic examination. The overall architecture of the lesion is preserved; however, in 74
FIGURE 15.1. Multiple skin-toned papules distributed on the face of a patient with Cowden’s disease.
FIGURE 15.2. Low power photo- micrograph depicting plate-like growth of the epithelium observed in tricholemmoma.
Table 15.1. Cowden Syndrome
Incidence (Percentage) in Patients with
Abnormality Cowden Syndrome
Breast carcinoma 25–36 Fibrocystic changes of breast 53 Thyroid adenomas 68 Follicular carcinoma, thyroid 3 Gastrointestinal polyps and
fibromas 35–60
Lipoma 31
Neuroma 5
Angiod streaks, eyes 13 Acanthosis nigricans 11 Enlarged head circumference 70–80 Adenocarcinoma, uterus 6
Trichilemmomas >80
Bone cysts
Hepatic hamartomas Meningiomas Ovarian cysts Retinal gliomas
Sclerotic fibromas 76 Oral cobblestone fibromas >50 Palmoplantar hyperkatoses >50
Hemangioma 18
FIGURE 15.3. High power photo- micrograph depicting pale staining keratinocytes with basilar palisad- ing resembling the outer root sheath of the follicle.
FIGURE 15.4. High power photo- micrograph depicting the pro- minent eosinophilic basement membrane surrounding the tumor periphery.
the center of the growth, islands of proliferating keratino- cytes are separated by a desmoplastic stromal response, mimicking an invasive growth pattern. Mitoses may be present. Careful attention to the overall growth pattern should prevent misdiagnosis.
There is a very rare malignant variant known as trichilemmal carcinoma. This neoplasm invades the
dermis and is characterized by abundant mitoses, includ- ing atypical variants, zonal necrosis, and marked cyto- logic atypia.
Sclerotic fibroma, also known as storiform collagenoma and plywood fibroma, grows as nodular dermal prolifera- tions. The epidermis is often atrophic, with effacement of rete ridges (Figure 15.5). Within the dermis, there is a
FIGURE 15.5. Low power photo- micrograph depicting well- circumscribed laminated app- earance of sclerotic fibroma.
FIGURE15.6. High power detail of the sclerotic fibroma.
sparse proliferation of spindle-shaped cells that grow in a storiform pattern. Dense, keloidal collagen is present between these cells in a pattern that has been described as resembling plywood (Figure 15.6). The exact nature of this process and the dermal cells is not fully established.
Some investigators believe these lesions to represent end- stage lesions of dermatofibromas (12), while others main- tain that they represent de novo growths (13). Sclerotic fibromas may occur as sporadic lesions unassociated with Cowden syndrome (14).
References
1. Lloyd KM, Dennis M. Cowden’s disease: A possible new symptom complex with multiple system involvement. Ann Int Med 1963; 58: 136–142.
2. Barax CN, Lebwohl M, Phelps RG. Multiple hamartoma syndrome. J Am Acad Dermatol 1987; 17: 342–346.
3. Eng C. Genetics of Cowden syndrome: Through the looking glass of oncology. Int J Oncol 1998; 12: 701–701.
4. Starink TM, van derVeen JPW, Arwert F, de Waal LP, de Langer GG, Gille JJ, Eriksson AW. The Cowden syndrome:
A clinical and genetic study in 21 patients. Clin Genet 1986;
29: 222–233.
5. Elston DM, James WD, Rodman OG, Graham GF. Multiple hamartoma syndrome (Cowden’s disease) associated with non-Hodgkin’s lymphoma. Arch Dermatol 1986; 122:
572–575.
6. Starink TM. Cowden’s disease: An analysis of fourteen new cases. J Am Acad Dermatol 1984; 11: 1127–1141.
7. Salem OS, Steck WD. Cowden’s disease (multiple hamartoma syndrome). J Am Acad Dermatol 1983; 8: 686–695.
8. Mallory SB. Cowden syndrome (multiple hamartoma syndrome). Dermatologic Clinics 1995; 13: 27–31.
9. Weary PE, Gorlin RJ, Gentry WC, Comer JE, Greer KE.
Multiple hamartoma syndrome (Cowden’s disease). Arch Dermatol 1972; 106: 682–690.
10. Starink TM, Meijer CJLM, Brownstein MH. The cutaneous pathology of Cowden’s disease: New fi ndings. J Cutan Pathol 1985; 12: 83–93.
11. Johnson BL, Kramer EM, Lavker RM. The keratotic tumors of Cowden’s disease: An electron microscopic study. J Cutan Pathol 1987; 14: 291–298.
12. Pujol RM, de Castro F, Schroeter AL, Su WPD.
Solitary sclerotic fibroma of the skin: A sclerotic dermatofibroma? Am J Dermatopathol 1996; 18:
620–624.
13. McCalmont TH. Sclerotic fibroma: A fossil no longer.
J Cutan Pathol 1994; 21: 82–85.
14. Requena L, Gutierrez J, Sanchez Yus E. Multiple sclerotic fibromas of the skin: A cutaneous marker of Cowden’s disease. J Cutan Pathol 1991; 19:
346–351.
