Brooke‐Spiegler syndrome with parotid gland involvement

ARTICLE

Auteur(s) : Despoina KAKAGIA^a, George ALEXIADIS^b, Anastasia KIZIRIDOU^c, Maria LAMBROPOULOU^c

^a Department of Surgery, Thraki Medical Center, 1 Komninon Str, 68100 Alex/polis, Greece 
^b Alex/polis Radiodiagnostic Center, 59 Venizelou Str, 68100 Alex/polis, Greece 
^c Department of Pathology, Theagenio Anticancer Hospital, 2 Simeonidi Str, Thessalonica, Greece

Article accepted on 25/02/2004

Brooke-Spiegler syndrome (BSS), also known as familial cylindromatosis, is an autosomal dominant hereditary disease with female preponderance, presenting as coexistent multiple skin lesions, usually cylindromas, trichoepitheliomas or spiradenomas [1]. The association of BSS with salivary gland tumours is known though not common. Major salivary glands are involved and the lesions may be benign or malignant, solitary or multifocal [2, 3]. It is known that the syndrome is caused by mutations in a tumour suppressor gene localized to chromosome 16q12-q13 [4], and this fact enables genetic counseling of patients. A case of a 67-year-old woman with facial trichoepitheliomas, scalp cylindromas and parotid gland adenoma is presented. Due to the potential malignancy, screening for salivary gland tumours is suggested for all patients with familial cylindromatosis skin lesions.

Case report

A 67-year-old lady presented with a long- standing history of multiple non-tender scalp nodules from 0.8 to 5.2 cm in diameter, with progressive growth over the past 35 years. The skin over some of the lesions was telangiectasic or ulcerated (Fig. 1). Small papular non-tender lesions coalesced along the nasolabial folds and the forehead. The clinical examination revealed a palpable solid, painless lump of 1.5 cm in diameter at the left preauricular area. The patient had not been aware of this lesion and there was no clinical evidence of facial nerve or cervical lymph node involvement. Routine blood investigations and CT scans of the head, neck, chest and abdomen were requested. Fungal and quantitative swab cultures were obtained from the ulcerated scalp lesions. Multiple incisional biopsies and two shave biopsies were taken from the scalp lesions and the nasolabial folds respectively, and a fine needle aspiration was obtained from the preauricular lump.
The patient’s 43-year-old daughter was noticed to have papular lesions over her face similar to her mother’s but no obvious lesions on the scalp.

Microscopic, laboratory and imaging findings

Histological examination of the scalp lesions revealed irregularly sized and shaped nests of cells that fit together tightly (jigsaw puzzle pattern). Each nest was surrounded by eosinophilic basement membrane material. The findings are consistent with dermal cylindromas. The nasolabial papules consisted of nests of basaloid cells with peripheral palisading arrangement in fibromucinous stroma without atypia, findings suggestive of trichoepitheliomas (Fig. 2). The preauricular lesion was characterized by peripheral cell palisading and excessive hyaline basement membrane without cytonuclear atypia, mitosis and focal necrosis (Fig. 3). Due to the patient’s age and in order to differentiate the parotid tumour from basal cell adenocarcinoma, further immunohistochemical studies were performed [5]. The lesion showed a Ki-67 labeling index (Ki-67 LI) < 1%, was strongly positive for bcl-2 and negative for p53 and epidermal growth factor receptors (EGFR). The ultrastructural and immunohistochemical profile of the lesion was consistent with parotid gland adenoma.
Fungal and quantitative swab cultures from the ulcerated lesions were negative.
Apart from confirmation of the preauricular lesion by CT, all routine blood investigations as well as head, neck, chest and abdominal CT scans were normal. Following the patient’s wish, no further genetic studies were performed.

Clinical course

The patient underwent wide en bloc resection of the scalp cylindromas extending to the level of the galea and left total parotidectomy. The scalp skin deficit was covered by split thickness skin grafts harvested from the anteromedial thigh surface. The trichoepitheliomas of the face were not treated.

Histological examination of the operative specimens confirmed the preoperative diagnosis as well as the absence of malignancy. The patient has been on three-month follow up program for 4 years and there has not been any evidence of recurrence. The trichoepitheliomas on her face remain stable in size and number.

Discussion

Brooke-Spiegler syndrome (BSS) is an autosomal dominantly inherited disease, characterized by concomitant presence of different tumors such as trichoepitheliomas, cylindromas, milia, spiradenomas or basal cell carcinomas [1]. Salivary gland involvement is rare, occurring almost exclusively in the parotid or the submandibular gland [2, 3].
The syndrome is caused by mutations in a tumor suppressor gene that encodes CYLD protein and has been localized to chromosome 16q12-q13 [4]. CYLD has been found to inhibit transcription factor NF-kB, which is essential for appropriate cellular homeostasis of skin appendages. Loss of CYLD activity causes increased activation of NF-kB and subsequent inhibition of apoptosis, a mechanism that explains the generation and growth of cylindromas [6].
Cylindromas may be solitary or multiple. Multiple coalescent scalp cylindromas appear like a turban. Dermal cylindromas may occasionally become malignant and metastasize to liver, lymph nodes, lungs and spinal cord [7, 8].
The spectrum of parotid tumors associated with BSS includes basal cell adenomas [9, 10], basal cell adenocarcinomas [3], malignant lymphoepithelial lesions [11] and adenoid cystic carcinomas [3, 5].
Basal cell adenomas of the parotid occur most commonly after the sixth decade of life and there is female preponderance. They must be diagnostically differentiated from other basal cell tumors, adenoid cystic carcinomas and metastatic basal cell carcinomas. Facial nerve invasion suggests malignant transformation. Basal cell adenomas may be multifocal and tend to recur in 30% of the cases. Malignant transformation with cervical lymph node metastasis has been reported [3, 5].
Although salivary gland involvement is rare, patients with BSS should be investigated for salivary gland tumors [2]. Screening for skin lesions in all patients with basal cell tumors of the salivary glands is also suggested [3].
Treatment modalities for cylindromas include dermabrasion and CO₂ laser ablation, but the recurrence rate is high. Wide excision is the treatment of choice for multiple cylindromas. Pharmacological inhibitors of the NF-kB factor, like steroid and non-steroid anti-inflammatory agents are currently being tested for the treatment of cylindromas [6].
Total rather than superficial parotidectomy is suggested for basal cell adenomas of the parotid due to possible multifocal origin and the menacing risk of recurrence and malignant transformation [5, 8, 10]. Thorough and regular postoperative follow-up is necessary for early detection of recurrence or malignancy.
As the genetic background of BSS is now well understood, families with BSS patients can be offered genetic counseling [4, 6]. n

References

1. Welch JP, Wells RS, Kerr CB. Ancell-Spiegler cylindromas (turban tumours) and Brooke- Fordyce trichoepitheliomas: evidence for a single genetic entity. J Med Genet 1968; 5: 29-35.

2. Baican A, Has C, Crisan C. Multiple cutaneous cylindromas associated with parotid and submandibular gland cylindromas. Ann Dermatol Venereol 1998; 125: 909-10.

3. Yu GY, Ubmuller J, Donath K. Membranous basal cell adenoma of the salivary gland: a clinicopathologic study of 12 cases. Acta Otolaryngol 1998; 118: 588-93.

4. Biggs PJ, Wooster R, Ford D, et al. Familial cylindromatosis (turban tumour syndrome) gene localized to chromosome 16q12-q13: evidence for its role as a tumour suppressor gene. Nature Genet 1995; 11: 441-3.

5. Chhieng DC, Paulino AF. Basaloid tumors of the salivary glands. Ann Diagn Pathol 2002; 6: 364-72.

6. Trompouki E, Hatzivassiliou E, Tsichritzis T, et al.: CYLD is a deubiquitinating enzyme that negatively regulates NF-kB activation by TNFR family members. Nature 2003; 424: 793-6.

7. Lin PY, Fatteh SM, Lloyd KM. Malignant transformation in a solitary dermal cylindroma. Arch Pathol Lab Med 1987; 111: 765-7.

8. Lotem M, Trattner A, Kahanovich S. Multiple dermal cylindroma undergoing a malignant transformation. Int J Dermatol 1992; 31: 642-4.

9. Issing PR. Bilateral basal cell adenoma of the parotid gland and multiple cylindromas of the skin – is there a syndromal coincidence ? Laryngorhinootologie 1999; 78: 155-9.

10. Jungehulsing M, Wagner M, Damm M. Turban tumour with involvement of the parotid gland. J Laryngol Otol 1999; 113: 779-83.

11. Harmainen H, Paakko P, Alavaikko M, et al. Familial occurrence of malignant lymphoepithelial lesion of the parotid gland in a Finnish family with dominantly inherited trichoepitheliomas. Cancer 1988; 61: 161-6.