ACCME/Disclosure USCAP Head & Neck Companion Society Meeting

4/8/2016

Brooke-Spiegler syndrome and phenotypic variants Dr. Kazakov has nothing to disclose

Dmitry V. Kazakov, MD

Department of Pathology, Charles University Medical Faculty Hospital & Bioptical Laboratory Pilsen, Czech Republic

1892 Brooke HG: Epithelioma adenoides cysticum

1892 Fordyce JA: Multiple benign cystic epithelioma

1899 E. Spiegler: Endothelioma capitis „Brooke-Fordyce trichoepitheliomas“

„Ancell-Spiegler Cylindromas“ Ancell H, 1842 Fordyce JA, 1892

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Variation in severity

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Spiradenocylindroma

Spiradenoma and cylindroma

Spiradenocylindroma Spiradenocylindroma and trichoblastoma Cylindroma

„Hybrid“ histopatologic features

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CYLD gene

•20 exons (3 first are untranslated) •Codes 956 amino acid protein •Tumor supressor gene •Second hit: LOH and somatic mutations

CYLD gene

NO HOTSPOT

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CYLD germline mutation rate (PCR based approach: exons & exon- intron junctions)

Classical Brooke-Spiegler syndrome 80-85%

Why?

CYLD germline mutation rate CYLD germline mutation rate

• Classical Brooke-Spiegler syndrome 80-85% • Classical Brooke-Spiegler syndrome 80-85%

Why? Why? • Large deletions • Large deletions • Mutations in introns

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CYLD germline mutation rate CYLD germline mutation rate

• Classical Brooke-Spiegler syndrome 80-85% • Classical Brooke-Spiegler syndrome 80-85%

Why? Why? • Large deletions • Large deletions • Mutations in introns • Mutations in introns • Another gene • Another gene • Epigenetic mechanisms

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Malignant transformation : 5‐10%

Courtesy of Bernhard Zelger, MD, Austria

Malignant transformation: sudden rapid growth, ulceration and bleeding

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Inclusion criteria

1) a residuum of an unequivocally benign neoplasm regardless of size

2) a malignant neoplasm regardless of its histological type.

Malignant tumors from preexisting benign spiradenomas and cylindromas 1. Salivary gland type basal cell adenocarcinoma‐like pattern, low‐grade 2. Salivary gland type basal cell adenocarcinoma‐like pattern, high‐grade 3. Invasive adenocarcinoma, not otherwise specified 4. Sarcomatoid (metaplastic) carcinoma

1&2: most common in Brooke‐Spiegler syndrome

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Salivary gland type basal cell adenocarcinoma-like pattern, low-grade (n=11) P53

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Salivary gland type basal cell adenocarcinoma- Invasive adenocarcinoma, not otherwise like pattern, high-grade (n=14) specified (n=3)

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Adenocarcinoma in situ (1 case) Metaplastic (sarcomatoid carcinoma)

Metaplastic (sarcomatoid) carcinoma Metaplastic (sarcomatoid) carcinoma

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Other malignant neoplasms are rare in classic Brooke‐Spiegler syndrome How many syndromes are there?

Basal cell carcinoma

Multiple familial trichoepithelioma: papules in naslolabial folds

Multiple familial trichoepitheliomas

and Brooke-Spiegler syndrome

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Confluence in nasolabial folds and inner aspects of eyebrows Confluence in nasolabial folds and inner aspects of eyebrows

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Multiple familial trichoepithelioma: mild phenotype Multiple familial trichoepithelioma: severe phenotype

Courtesy of J. Andrew Carlson, USA

Multiple familial trichoepithelioma: severe phenotype Multiple familial trichoepitehlioma, disease progression

1987 (3 yo) 1991 (7 yo) 2008 (24 yo)

Courtesy of J. Andrew Carlson, USA Courtesy of Jorg Schaller, Germany

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Twins: 11 yo

12 yo Courtesy of Martin Sangueza, MD, Bolivia

Multiple familial trichoepithelioma Trichoepithelioma/ cribriform trichoblastoma (WHO 2006)

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“Hybrid” morphology occasionally (spiradenoma‐like area) CYLD or PTCH?

• 1996, Harada et al, linked a gene for MFT to chromosome 9p2l.

• 1996, Johnson et al, identified the PTCH gene (Drosophila patched gene) located at 9q22.3.

• 1996-1999 mutations in PTCH in sporadic BCC and in nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome).

CYLD or PTCH?

• 1999, Aszterbaum et al, studied a Ptch+/- mice who develop primordial follicular neoplasms resembling human trichoblastomas, which after exposure to ultraviolet radiation or ionizing radiation manifested an increase in the number and size of these tumors and resembled human BCC

• 2000, Matt et al identified LOH at 9q22.3 in 14 (48%) of 29 cases of sporadic trichoepitheliomas, whereas LOH at 9p21 could not be demonstrated.

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Multiple familial trichoepithelioma: malignant transformation

6 pacients – mutations in CYLD 9 pacients – no mutations in PTCH

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Multiple familial trichoepithelioma: malignant transformation

Rare aggressive basaloid neoplasms can occur

c) a) b)

Courtesy of Vera Baur, MD, Nurnberg, Germany Courtesy of Vera Baur, MD, Nurnberg, Germany

Influence of CYLD on Hedgehog signalling, ( from Masoumi et al., 2011) a: CYLD tumour suppressor gene is active and leads to deubiquination and thus stabilisation of SUFU. Consequently Hedgehog signalling is absent.

a) Before treatment with Vismodegib. b) After two months of treatment with Vismodegib 150 mg/d partial regression of b: In the case of a CYLD mutation, SUFU is ubiquinated which leads to its trichoepitheliomas in the face is evident. proteasomal degradation. Thus, Gli is translocated to the nucleus, where it promotes the transcription of target genes leading to tumour progression. Courtesy of Vera Baur, MD, Nurnberg, Germany

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Extracutaneous lesions in Salivary gland involvement Brooke-Spiegler syndrome •Rare (1%) •Usually parotis • Salivary glands •After age of 40 yrs

• Breast •Subcutaneous mass •Maybe bilateral

• Lung (single case of cylindroma reported •Rarely multicentric in the literature) •Basal cell adenoma, membranous type

Salivary gland involvement Salivary gland involvement

•Rare (1%) •Rare (1%)

•Usually parotis •Usually parotis

•After age of 40 yrs •After age of 40 yrs

•Subcutaneous mass •Subcutaneous mass

•Maybe bilateral •Maybe bilateral

•Rarely multicentric •Rarely multicentric

•Basal cell adenoma, •Basal cell adenoma, membranous type membranous type

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Salivary gland involvement Salivary gland involvement

•Rare (1%) •Rare (1%)

•Usually parotis •Usually parotis

•After age of 40 yrs •After age of 40 yrs

•Subcutaneous mass •Subcutaneous mass

•Maybe bilateral •Maybe bilateral

•Rarely multicentric •Rarely multicentric

•Basal cell adenoma, •Basal cell adenoma, membranous type membranous type

Salivary gland involvement Salivary gland involvement

•Rare (1%) •Rare (1%)

•Usually parotis •Usually parotis

•After age of 40 yrs •After age of 40 yrs

•Subcutaneous mass •Subcutaneous mass

•Maybe bilateral •Maybe bilateral

•Rarely multicentric •Rarely multicentric

•Basal cell adenoma, •Basal cell adenoma, membranous type membranous type mostly

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Dr. Agnes Witkiewicz, Philadelphia, USA

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Cylindroma of the breast So far no reports of salivary gland tumors in multiple familial trichoepithelioma

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Thank you!