10/2/17. A 45-year-old female presents with a lesion on the cheek, rule out basal cell carcinoma. Overview

Transcription

1 10/2/17 Overview Desmoplastic trichoepithelioma vs. morpheaform BCC vs. microcystic adnexal carcinoma Trichilemmomas & Cowden s syndrome Cutaneous Adnexal Tumours with Clinical Impact Rajiv M. Patel, M.D. RCPA NZ ASM 2017 (9:00-9:45am, Saturday, ) Multiple trichoepitheliomas, cylindromas, spiradenomas & Brooke-Spiegler Digital papillary adenocarcinoma Sebaceous tumors & Muir-Torre syndrome Trichodiscoma fibrofolliculomas/acrochordons & Birt-Hogg-Dube syndrome Proliferating pilar tumor vs. SCC 2 A 45-year-old female presents with a lesion on the cheek, rule out basal cell carcinoma 1

2 BerEP4 CK20 Diagnosis? Morpheaform Basal Cell Carcinoma (MBCC) 2

3 MBCC: Clinical 5% of all BCCs Head and neck Ill-defined, tethered, pale and shiny plaque that resembles morphea Lacks translucent appearance MBCC: Histology Ill-defined borders Infiltrative narrow strands of basaloid cells +/- Epidermal connection Blue, densely fibrotic /desmoplastic stroma Patchy lymphoid aggregates Inconspicuous myxoid change and clefting between tumor strands and stroma Perineural invasion present in 3% of morpheaform and infiltrative BCCs MBCC MBCC Deep infiltrative growth MBCC MBCC Cellular desmoplastic stroma Mild pleomorphism Frequent apoptoses 3

4 MBCC MBCC: BerEP4 Coarse chromatin Mitoses MBCC: CK20 CK20 stain highlighting retained Merkel cells in DTE Absence of intratumoral Merkel cells Differential Diagnosis Sclerosing basaloid neoplasms: Morpheaform BCC (MBCC) Desmoplastic trichoepithelioma (DTE) Microcystic adnexal carcinoma (MAC) H&E histopathology is the key IHC helpful in superficial biopsies Desmoplastic trichoepithelioma: Flesh colored annular plaque with central dell 4

5 10/2/17 DTE DTE Sclerosing variant of trichoepithelioma Usually presents on central face of adults often with central umbilication Cords of basaloid tumor cells in desmoplastic stroma Keratocysts and calcification (key distinguishing features) Intrastromal clefts Papillary mesenchymal bodies usually not present Well circumscribed DTE DTE Intrastromal clefts Intrastromal clefts DTE: CK20 DTE: CK20 Intratumoral Merkel cells Intratumoral Merkel cells 5

6 MBCC DTE Circumscription Poor Good Epid. connection +/- +/- Keratinous cysts +/- + Stroma Desmoplastic, cellular (blue) Sclerotic (pink) Lymph. aggregates + +/- Clefting Between tumor and stroma Intrastromal Nuclear atypia + - Mitosis/Apoptosis + -/Rare Perineural invasion +/- -/+ MBCC DTE CK20 (Merkel cells) -/Rare + Androgen Receptor + - CD34 (stromal cells) - + BerEP4 Diffuse + Focal + Bcl-2 Diffuse + Peripheral + Microcystic adnexal carcinoma (MAC) MAC Clinical Features Adult patients (rare cases in children) Presents as firm plaque with central depression on upper lip, around mouth or eyelids Microscopic features Infiltrative growth pattern Basaloid strands of tumor cells Superficially keratocysts Duct lumen formation often seen in deeper aspects of tumor Perineural invasion Dense sclerotic pink stroma Diffuse dermal involvement MAC MAC Syringomatous keratinous cysts Infiltration of deep tissue 6

7 MAC MAC Sclerotic (pink) stroma Subtle infiltration by small nests MAC MAC: CEA Eccrine ductular differentiation Highlights ductal lumina MAC MAC: CK20 Perineural invasion Absence of intratumoral Merkel cells 7

8 MAC: BerEP4 MAC Behavior Locally destructive Recurrence rate 30-40%; lower with Mohs surgery Rarely metastasizes Practical tip Up to 85% of MACs misdiagnosed as DTE or syringoma on small biopsies If you are uncertain of diagnosis on shave biopsy, ask for a repeat punch biopsy to assess for infiltrative growth and perineural invasion MBCC MAC Circumscription Poor Poor Epidermal connection +/- +/- Keratinous cysts +/- + Ductules - + Stroma Desmoplastic (blue) Sclerotic (pink) Lymph. aggregates + Usually - Clefting + - Nuclear atypia + Minimal Mitosis/Apoptosis + Infrequent Perineural invasion +/- Frequently + MBCC MAC EMA - Ductules + CEA - Ductules + BerEP4 + - Bcl-2 Diffuse + Focal + Androgen Receptor + - CK20 (Merkel cells) - - CD34 (stromal cells) - - MBCC: Prognosis & Treatment Infiltrative, difficult to obtain clear margins More aggressive and higher recurrence rate compared to other BCC subtypes Nodal metastases extremely rare Mohs surgery for facial lesions +/- Radiation for perineural invasion MBCC: Key Points Look for the desmoplastic and inflamed stroma, nuclear atypia, mitoses and apoptoses Use a panel of immunostains in superficial biopsies or difficult cases If a definitive diagnosis cannot be established on a partial biopsy, recommend excision 8

9 A 33-year-old male with multiple, flesh colored papules around the nose Diagnosis? Multiple trichilemmomas Trichilemmoma Clinical features Usually presents on nose or lip of adults Multiple lesions major criterion of Cowden syndrome Part of the phosphatase & tensin homolog deleted on chromosome 10 (PTEN) hamartoma tumor syndrome (PHTS) Differential diagnosis Basal cell carcinoma with trichilemmal differentiation Mucinous change, clefting, apoptoses Inverted follicular keratosis Squamous eddies Verruca vulgaris No hair follicle involvement 9

10 Trichilemmoma Clear to pale cells Microscopic features Connects to epidermis Superficially coarse keratohyaline granules resembling koilocytes Endophytic growth Lobular architecture Clear to pale cells Peripheral palisading Eosinophilic basement membrane Peripheral palisading Cuticle Cowden s syndrome: Multiple trichilemmomas, acral keratoses, and oral mucosal cobblestoning. Increased risk of breast, thyroid, endometrial carcinomas Cowden (PTEN hamartoma) syndrome Sclerotic fibromas Major Criteria: Breast cancer Endometrial cancer Follicular thyroid cancer Lhermitte Duclos disease (LDD) (Gangliocytoma) Meningioma GI hamartomas or ganglioneuromas Macrocephaly ( 97 percentile: 58 cm for females, 60 cm for males) Macular pigmentation of the glans penis Multiple mucocutaneous lesions: Trichilemmomas ( 3, at least one biopsy proven) Acral keratoses Mucocutaneous neuromas ( 3) Oral papillomas Minor Criteria: Autism spectrum disorder Colon cancer Esophageal glycogenic acanthosis ( 3) Lipomas ( 3) Intellectual disability (i.e., IQ 75) Renal cell carcinoma Testicular lipomatosis Papillary thyroid cancer (papillary or follicular variant) Thyroid structural lesions (e.g., adenoma, nodule(s), goiter) Vascular anomalies (including multiple intracranial developmental venous anomalies) Operational diagnosis in an individual (either of the following): 1. Three or more major criteria, but one must include macrocephaly, LDD, or GI hamartomas; or 2. Two major and three minor criteria. Operational diagnosis in a family where one individual is diagnostic for Cowden syndrome: 1. Any two major criteria with or without minor criteria; or 2. One major and two minor criteria; or 3. Three minor criteria Multiple lesions associated with Cowden syndrome 10

11 Sclerotic fibroma: CD 34 Desmoplastic trichilemmoma Similar to conventional TL except areas with infiltrative appearance and desmoplastic stroma Key to diagnosis: areas resembling TL, bland cytologic features & peritumoral BM (PAS, laminin, COL IV+) Multiple lesions associated with Cowden syndrome Trichilemmoma: Key Points Desmoplastic stroma (peritumoral BM) Have a high index of suspicion for this lesion on the lips & nose Multiple lesions are associated with Cowden syndrome BCC & SCC (DTL) most important DDx More atypical, look for other histologic features of these tumors Recognition of peritumoral basement membrane is the key to recognizing desmoplastic TL (PAS, laminin, ColIV+) A 38-year-old female presents with multiple, non-descript flesh colored papules on the central forehead 11

12 Diagnosis? Multiple Trichoepitheliomas Trichoepithelioma AKA cribiform trichoblastoma Clinical features Presents as skin colored papule Usually central face but location variable Solitary or multiple Multiple lesions associated with Brooke-Spiegler syndrome Trichoepithelioma Microscopic features Centered in mid dermis Sometimes has attachment to overlying epidermis Basaloid tumor cells arranged in nodules, nests or cords Tumor nodules often have branching pattern Keratocyst formation Papillary mesenchymal bodies Fibroblastic stroma Papillary mesenchymal body 12

13 Ruptured keratocyst Keratocyst Thrichoepithelioma vs. Basal cell carcinoma Dermal mucin in stroma Trichoepithelioma Younger adults Fibroblastic stroma No atypia, low mitotic rate No tumor retraction present Retained Merkel cells on CK20 stain Basal cell carcinoma Older adults Mucinous stroma May have atypia, more mitotic figures Tumor retraction often present No retained Merkel cells on CK20 stain Trichoepithelioma: Key points Head & neck esp. the face Multiple TE associated with multiple cylindromas, spiradenomas, salivary gland tumors, trichilemmomas, or BCC (Brook-Spiegler) Multiple & ruptured keratocysts a clue to Dx Generally lacks apoptotic bodies seen in BCC Demonstrates retained CK20 + Merkel cells, unlike BCC Tumor-stroma retraction space 13

14 22-year-old female with multiple smooth red papules & nodules on the scalp Diagnosis? Tumor with features of spiradenoma (right) and cylindroma (left) Spiradenocylindroma 14

15 Cylindroma Clinical features Adult F:M ratio 9:1 Smooth red papules, nodules (turban tumors) 90% head and neck, especially scalp Associated with Brooke- Spiegler syndrome Autosomal dominant Mutation in CYLD Cylindroma Microscopic features Nests of basaloid tumor cells surrounded by dense basement membrane material Tumor lobules have complex pattern Jigsaw puzzle pattern Small basaloid cells and larger pale cells Small basaloid cells Basement membrane Larger pale cells Spiradenoma Clinical features Most common in young adults Presents on upper half of body 75% on ventral surface Dermal mass, often painful Multiple lesions associated with Brooke-Spiegler syndrome Spiradenoma Microscopic features Basophilic nodules in dermis Fibrous capsule sometimes present Less complex pattern than cylindroma Two cell types: small basaloid cells and larger polygonal cells Focal duct lumen formation Eosinophilic globules within tumor lobules often present May have thick basement membrane May have areas indistinguishable from cylindroma 15

16 Ducts Polygonal cells Hyaline globules Basaloid cells Brooke-Spiegler syndrome Inherited in an autosomal-dominant fashion Consists of multiple spiradenomas associated with multiple trichoepitheliomas, cylindromas, BCC & benign & malignant tumours of the parotid gland Responsible gene is CYLD located at 16q12-q13 shows sequence mutations or loss of heterozygosity at 16q typical of a tumour suppressor gene Spiradenoma/cylindroma: Key points Similar cellular composition (basaloid & larger polygonal cells) Spiradenoma less complex growth pattern Often features of both in the same tumor Multiple lesions a marker of Brooke-Spiegler syndrome Rare malignant variants described (carcinoma ex cylindroma & spiradenoma) Basal cell carcinoma most practical DDx Search for additional features of BCC 16

17 62-year-old male with firm nodule of right index finger Diagnosis? Digital papillary adenocarcinoma Digital Papillary Adenocarcinoma Formerly divided in digital papillary adenoma and digital papillary adenocarcinoma Now recognized that there is no difference in behavior based on histology Both considered low-grade adenocarcinomas 17

18 Digital Papillary Adenocarcinoma Clinical features Middle aged adults M>F (7:1) Fingers, toes, palms, and soles Often painful Behavior: Frequent recurrence and metastasis Have a high index of suspicion for any adnexal tumor at acral site Digital Papillary Adenocarcinoma Microscopic features Deep dermis to subcutis, relatively circumscribed Cystic spaces Back to back glands Papillary structures Mitoses & necrosis often encountered Squamous metaplasia and clear cell change common (but not predominant) Immunophenotype: Positive for keratin, S100, CEA (not diagnostically useful) Squamous metaplasia Cystic spaces Clear cell change Papillary projections Back to back glands 18

19 Differential: Digital papillary adenocarcinoma Hidradenoma Both have solid and cystic areas Clear cell change common in both Not papillary Lacks back to back glands Uncommon on digits Key points: Digital papillary adenocarcinoma Deceptively low-grade adenocarcinoma with recurrence in 50% and metastasis in 14% of cases, respectively Have a high index of suspicion for the Dx for any adnexal tumor arising at an acral site Complete excision with free margins, sometimes requires amputation Long term follow-up Usefulness of adjuvant therapy and SLNBx have not been defined 63-year-old male with a lesion on the neck

20 MSH2 Diagnosis? Low-grade cystic sebaceous neoplasm 115 Sebaceous Hyperplasia Middle aged and older patients Usually presents on central face Clinically resembles BCC Hyperplasia of normal sebaceous glands Increased number of glands Lobules of sebaceous glands grouped around follicle DDx: Sebaceous adenoma, nevus sebaceus Sebaceous Adenoma Clinical features Middle-aged and older patients Usually on head and neck Clinically resembles basal cell carcinoma Usually sporadic but may be hereditary and multiple Most common tumor associated with Muir-Torre syndrome Sebaceous neoplasms, SCC & visceral carcinomas (laryngeal & GI) Sebaceous Adenoma Abnormal sebaceous gland that connects to epidermis Not associated with follicle Predominantly composed of mature sebocytes Lobules of peripheral basaloid cells ( 50%) & central mature sebocytes No or little cytologic atypia No or rare mitotic figures DDx: Sebaceous hyperplasia, BCC with sebaceous differentiation Superficial biopsy may be difficult to distinguish from sebaceous carcinoma Epidermal connection 20

21 Sebaceoma Basaloid cells 50% Sebaceous adenoma variant Clinically similar to sebaceous adenoma Most common on head and neck Microscopic features Predominantly composed of basaloid cells (>50%) rather than mature sebocytes Basaloid cells intermingled with mature sebocytes No to mild atypia Mitotic figures often present but no atypical mitotic figures Basaloid cells admixed with sebocytes >50% basaloid cells 21

22 Differential: Sebaceoma Basal cell carcinoma with sebaceous differentiation BCC has peripheral palisading Retraction spaces Positive for Ber-EP4, unlike sebaceoma Sebaceous carcinoma Clinical: Sebaceous carcinoma Middle aged to older patients Two clinical locations: ocular (75%) and non-ocular (25%) Non-ocular associated with Muir-Torre syndrome Behavior Local recurrence 30-40% Metastasis 20-25% Mortality 10-20% Pathologic features: Sebaceous carcinoma Basaloid cells > sebocytes Microscopic features Nodular or infiltrative growth pattern Basaloid cells > sebocytes Nuclear atypia and mitotic figures Atypical mitotic figures common Squamous metaplasia and pagetoid spread common Especially ocular tumors Immunophenotype: Androgen receptor (AR) and EMA usually positive Infiltrative Nuclear atypia Atypical mitoses 22

23 Sebaceous carcinoma of eyelid with pagetoid growth pattern High-grade sebaceous carcinoma Sebocytic differentiation difficult to appreciate 133 Note: cytoplasmic vacuoles indenting nuclei Differential: Sebaceous carcinoma Basal cell carcinoma with sebaceous differentiation Retraction spaces and peripheral palisading Androgen receptor positivity less prominent Clear cell squamous cell carcinoma Clear cells result of glycogen not lipid (PAS+) Negative for androgen receptor, negative or weak positivity for EMA Melanoma Melanin often present Lacks cytoplasmic vacuoles that indent nuclei Muir-Torre Syndrome (MTS) Heritable cancer syndrome associated with hereditary nonpolyposis colorectal cancer (HNPCC) MTS definition: heritable cancer syndrome with at least one sebaceous neoplasm and one underlying visceral malignancy Associated visceral malignancies: GI (47%), GU (21%), and breast (12%), most common Skin tumors in MTS: sebaceous adenoma (most common), sebaceous carcinoma and keratoacanthoma Muir-Torre Syndrome (MTS) ~ 40% of patients with sebaceous tumors have MTS Mean age sebaceous neoplasm in MTS: 63 yrs Range: yrs. Cutaneous tumors may be concurrent with diagnosis of visceral malignancy (9-22%) subsequent to visceral malignancy (56-59%) precede diagnosis of visceral malignancy (>6%) Muir-Torre Syndrome (MTS) Due to defects in DNA mismatch repair enzymes, usually MSH2 (90%) or MLH1 If sebaceous neoplasm encountered, consider screening for MTS Can screen with immunostains Loss of nuclear staining suggests MTS Not 100% specific If immunostains not available, correlate with family history. If there is family history of colon cancer or other cancer, or the patient is relatively young (<60), consider early screening for colon cancer 23

24 MSH2 PPV of lack of mismatch repair gene by IHC for diagnosis of Muir-Torre syndrome Gene that is lacking by IHC Positive predictive value (PPV) MSH2 55% MLH1 88% MSH6 67% Loss of staining in tumor cells MLH1 & MSH6 100% MSH2, MLH1 & MSH6 100% MLH, MutL Homolog; MSH, MutS Homolog. V. Chhibber, K. Dresser, M. MahalingamMSH-6: extending the reliability of immunohistochemistry as a screening tool in Muir-Torre syndrome. Mod Pathol, 21 (2008), pp Canned comments for sebaceous neoplasms 1. Initial biopsy with sebaceous neoplasm: Sebaceous neoplasms may arise sporadically or in association with the Muir-Torre syndrome. Immunohistochemical stains for mismatch repair proteins (MSH2, MSH6, MLH1 and PMS2) are available and can be performed upon the clinician s request. 2. Reporting of positive MMR results: Immunohistochemical stains against the mismatch repair proteins show loss of expression for and retained expression for within the sebaceous neoplasm. These results are not diagnostic but may be seen in Muir-Torre syndrome. Correlation with clinical findings and family history is required. Molecular testing (microsatellite instability and/or gene mutation analysis) may be performed to confirm germline mutation if clinically indicated. 3. Reporting of negative MMR results: Immunohistochemical stains against the mismatch repair proteins show intact expression for MSH2, MSH6, MLH1 and PMS2 within the sebaceous neoplasm. These results speak against but do not entirely exclude Muir-Torre syndrome. Correlation with clinical findings and family history is required. Molecular testing (microsatellite instability and/or gene mutation analysis) may be considered if clinical concern for Muir-Torre syndrome persists Key points: Sebaceous neoplasms & MT Precise classifications of sebaceous neoplasms may not be possible in limited biopsies In this case a dx of low-grade or atypical sebaceous neoplasm with a recommendation for complete excision appropriate May be sporadic or associated with MT Screening for MSI by IHC is reliable & cost effective Results suggesting MSI should be followed up with definitive genetic testing and counseling year-old male with multiple papules on the nose 24

25 Diagnosis? Fibrofolliculoma 145 Clinical: Fibrofolliculoma/trichodiscoma Flesh-colored papules on face, neck Indistinguishable clinically Favored to be follicular hamartomas Multiple in Birt-Hogg-Dube syndrome Pathology: Fibrofolliculoma/trichodiscoma Fibrofolliculoma Central distorted hair follicle Thin anastomosing strands of follicular epithelium centered around infundibular portion of follicle Pale fibrotic stroma Trichodiscoma Mainly fibrous Often only with surrounding collarette of epithelium Birt-Hogg-Dube: Trichodiscoma Fibrofolliculoma/trichodiscoma: Central distorted follicle with surrounding fibrosis and a surrounding network of thin anastomosing strands of follicular epithelium. Predominantly fibrous stroma surrounded by epidermal collarette 25

26 Birt-Hogg- Dube: Trichodiscomas Birt-Hogg-Dube Autosomal Dominant Follicular hamartomas (Fibrofolliculomas, Perifollicular fibromas, trichodiscomas) and acrochordons Renal tumors Oncocytoma, chromophobe RCC and clear cell RCC Pulmonary symptoms Emphysema, cysts, spontaneous pneumothoraces Less frequently thyroid CA Predominantly fibrous stroma surrounded by epidermal collarette Birt-Hogg-Dube Mutation in folliculin (FCLN) on 17p 11.2 Thought to be a tumor suppressor acting as a regulator of mtor pathway Encodes folliculin which interacts with FNIP1 and FNIP2 Differential: Fibrofolliculoma/trichodiscoma BCC Retraction artifact, mucinous stroma, palisading nuclei, atypia Neurofolliular hamartoma Spindle cell rich trichodiscoma S100 & CD34+ Perifollicular fibroma Form of fibrofolliculoma Perifollicular fibrosis surrounds normal follicles rather than the epithelial strands seen in fibrofolliculoma Differential: Fibrofolliculoma/trichodiscoma Fibrofolliculoma Perifollicular fibroma Neurofollicular hamartoma Spindle cell trichodiscoma with atypia and fatty metaplasia

27 Key points: Fibrofolliculoma/trichodiscoma Fibrofolliculoma & trichodiscoma represent the opposite ends of a spectrum of the same lesion Multiple lesions are a marker for Birt-Hogg-Dube syndrome, which is associated with renal tumors, pulmonary symptoms & rarely thyroid carcinoma Neurofollicular hamartoma, perfollicular fibroma and spindle cell predominant trichodiscoma are histologic variants These lesions are benign 62-year-old female with a solitary exophytic lesion on the scalp, present for many years Diagnosis? Proliferating pilar tumor

28 Clinical: Proliferating pilar tumor (PPT) Usually older individuals Females > males Scalp most common site (90%) Often large exophytic tumors measuring 10cm in diameter Recurrence after excision infrequent 2% of pilar tumors will develop into PPT Rare instances of transformation into malignant PPT Metastasis to regional lymph nodes may occur Complete excision with margin of normal tissue Pathology: Proliferating pilar tumor (PPT) Lobular proliferation of squamous epithelium with trichilemmal (pilar) abrupt keratinization (lacks granular layer), hylanized membrane at periphery, peripheral palisading Well-demarcated peripheral margin Remnant pilar cyst usually present Epithelium often demonstrates: Variable clear cell change Disordered proliferation Nuclear pleomorphism Prominent nucleoli Mitoses DDx: SCC= More atypical, infiltrative boarders, rapid evolution Well-demarcated Abrupt keratinization Disordered growth Central cystic area SCC Atypia Pilar cyst Mitosis

29 Key features distinguishing PPT from SCC Preexisting simple pilar cyst Good circumscription Smooth peripheral margins Trichilemmal (abrupt) keratinization Lack of significant cytologic atypia & minimal mitotic activity Presence of peripheral palisading Presence of hyaline basement membrane Acknowledgements Thank you to my colleagues: May Chan & Steve Billings for sharing PPT slides used in this talk