Thomas, Md Associate Professor Section of Dermatopathology Valencia Thomas, Md Ut Houston School of Medicine Associate Professor Mohs and Dermasurgery Unit M.D

11/7/2016

HISTOPATHOLOGY OF SQUAMOUS CELL CARCINOMA

VALENCIA THOMAS, MD ASSOCIATE PROFESSOR SECTION OF DERMATOPATHOLOGY VALENCIA THOMAS, MD UT HOUSTON SCHOOL OF MEDICINE ASSOCIATE PROFESSOR MOHS AND DERMASURGERY UNIT M.D. ANDERSON CANCER CENTER DERMATOPATHOLOGY, UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON DIRECTOR, MOHS SURGERY, M.D. ANDERSON CANCER CENTER

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Actinic Squamous Invasive Keratosis cell squamous Do carcinoma in- cell situ carcinoma

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ACTINIC KERATOSIS ATYPICAL KERATINOCYTIC PROLIFERATIONS

• Actinic keratosis (AK) • “precancer” • Partial-thickness keratinocytic atypia • “squamous cell carcinoma grade 1/2” • Squamous cell carcinoma in-situ • “SCC – AK type” • Full-thickness keratinocytic atypia • Invasive squamous cell carcinoma • “keratinocytic intraepithelial neoplasia = KIN” • Well-differentiated • Does not need Mohs surgery • Moderately-differentiated • Poorly-differentiated • AK and squamous cell carcinoma are often • Other modifiers multifocal with field effects in margins • Depth of invasion, perineural invasion, lymphovascular • 1/20 develop into a skin cancer invasion,

Duplicate KERATINOCYTIC INTRAEPITHELIAL AK: PARTIAL-THICKNESS ATYPIA NEOPLASIA = KIN 1, 2, 3 or • Analogous to CIN, PIN, VIN 1,2,3 • Really in SKIN with most popular system, we don’t have a “2”: AK = KIN-1 SCC in situ (Bowen’s) = KIN-3

Distribute ACTINIC KERATOSIS RX AK: PARTIAL-THICKNESS ATYPIA • Treating AKs is beyond this lecture • Trying to eradicateNot totally is like playing “whack a mole” so goal is to eradicate most significant areas • Cryo, curettage, laser, imiquimod, fluorouracil, Dodiclofenac, etc

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AK BUDDING INTO THE PAPILLARY DERMIS AK

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Hyperkeratotic “hypertrophic” AK = HAK, not invasive SCC Acantholytic actinic keratosis Distribute

SQUAMOUS CELL CARCINOMA IN-SITU (SCCIS, BOWEN’S DISEASE)) Not

• Full-thickness atypia • Disordered epidermis Do • Cannot tell which way is “up” • Loss of the entire granular layer

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Bowen’s disease = SCC in situ

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Clear cell Bowen’s disease – Pagetoid cells Bowen’s disease = SCC in situ resemble Paget’s disease or Melanoma Distribute Not Do

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INFLAMMATORY LESIONS

• May have reactive atypia

Duplicate Lichenoid keratosis or

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Unzipping of the dermal-epidermal junction INTERFACE DERMATITIS Parakaratosis

Wedge-shaped hypergranulosis • Interface dermatitis • Lichenoid

Lichen Planus

Duplicate SPONGIOTICorDERMATITIS

• Intercellular edema • Lymphocytes • Eosinophils may be present

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PSORIASIFORM DERMATITIS

• Psoriasiform epidermal acanthosisNot • Suprapapillary plate thinning • Neutrophils • DoConfluent parakeratosis

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PERI-INFUNDIBULITIS

• Rosacea • Dilated vessels throughout the reticular dermis • Perivascular and peri-infundibular lymphocytes with some plasma cells • Slight spongiosis

Duplicate INVASIVE SQUAMOUS CELL CARCINOMA SCC or • 200,000 to 300,000 in the United States yearly • Surgical excision is the recommended • Seventy-five percent of these tumors occur on the head and neck treatment for uncomplicated cutaneous SCCs • Risk factors for the development of SCCs • Cure rates above 95 to 98 % with Mohs • Excessive ultraviolet radiation, older age, male sex, chemical exposure (arsenic), chronic ulcers, fair skin, blond Micrographic Surgery (MMS) or red hair, blue eyes and chronic scarring conditions

Distribute INVASIVE SCC HISTOLOGY TYPES SCC

Not • Well-differentiated • Metastatic rate: 3% to 5% usually to • Moderately-differentiated regional lymph nodes • Poorly-differentiated • 10 to 20% of high-risk SCC metastasize Do • Adenoid (acantholytic) • Spindle cell

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 Nests of squamous epithelial cells  Abundant eosinophilic cytoplasm  Large, vesicular nucleus  Prominent intercellular bridges Duplicate or

Distribute SQUAMOUS CELL CARCINOMA: Not CYTOLOGY • Nests, sheets and strands of squamous epithelial cells • Abundant eosinophilic cytoplasm • Large, often vesicular, nucleus • Prominent intercellular bridges Do • Variable keratinization

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INTERCELLULAR BRIDGES (SPINES)

• Cohesive aggregates of tumor • Keratinization

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Distribute  Irregular chromatin (dark and light) HISTIOCYTES  Cords of cells  High nuclear/cytoplasmic ratio Not Absence of lumens

Do • Note the even chromatin • Absence of spines • Multinucleated cells SQUAMOUS CELL CARCINOMA • Low nuclear/cytoplasmic ratio

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Well- Poorly differentiated differentiated SCC SCC

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Acantholyic or pseudoglandular SCC Distribute Spindle cell SCC Not Do

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Spindle cell (sarcomatoid) SCC

Duplicate SINGLE CELL SEEDING or • Single dyscohesive squamous cells in dermis indicate poor prognosis and high chance of metastasis

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Distribute MOHS MICROGRAPHIC SURGERY (MMS)

Not  Tissue-sparing excision technique  Evaluation of 100% of the peripheral and deep margin  Employed only for certain tumors displaying Do contiguous growth

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PERMANENT PROCESSING AGGRESSIVE TUMORS AND MOHS MICROGRAPHIC SURGERY (MMS) The specimen is sectioned vertically (breadloafed) and placed in paraffin • 2% to 5% of tumors recur after MMS due to Depth of invasion may be measured aggressive behavior or residual disease Nerves/Vessels can be evaluated • Post- or preoperative therapy with radiation therapy or chemotherapy may be indicated

Duplicate HIGH-RISK CUTANEOUS SCC : GREATER THAN 5% CHANCE OF SUBCLINICAL METASTASES

or • Aggressive histologic features • Poorly-differentiated • Recurrence tumor histology • Involvement of deep tissues • Perineural invasion • Greater than 2mm in depth • Host immunosuppression • Occurrence in prior scars • Solid-organ transplant • Large tumor size greater than 2 patients cm • Leukemia or lymphoma • Location in high-risk areas • Human Immunodeficiency Virus)

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Farasat et al. J Am Acad Dermatol. 2011 Jan 19. [Epub ahead of print]

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METASTASIS FROM SQUAMOUS CELL CARCINOMA

• Sun-exposed 0.5% • Lower lip 10% • Chronic leg ulcers20% • Burn scars 20% • Irradiated sites 20% • Osteomyelitis 30%

Duplicate HIGH-RISKor SCC • Metastatic rates of tumors larger than 2 cm may be triple those of lesions less than 2 cm • Invasion of the tumor greater than 4mm and beyond the subcutis also independently correlates with an increased risk of GREATER THAN 2 MM, MAY BE OF CLINICAL subclinical metastases CONCERN IF ONE OTHER HIGH RISK FEATURE IS PRESENT

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HIGH-RISK FEATURES CLARK LEVEL GREATER THAN IV

• Breslow depth > 2 mm thickness • Clark level greaterNot than IV • Clark Level IV • Cancer in the • Perineural invasion reticular dermis • Greater than Clark • Primary location on the ear or nonglabrous lip Level IV • Cancer in the • Poorly differentiated or undifferentiated fat and beyond Do• Patient immunocompromise

• Locally recurrent tumors http://www.cancer.gov/images/cdr/live/CDR630443-571.jpg

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CLARK LEVEL > IV

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NERVE CYTOLOGYor

PERINEURAL INVASION

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IDENTIFYING NERVES Not Artefactual split between nerve layers on frozens Do

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PERINEURAL Epineurium PERINEURAL INVASION (PNI) DEFINITION Around the nerve Perineurium

• Tumor cell invasion in, around, and through nerves1 Endoneurium • Tumor cells within any of the 3 layers of the nerve sheath or tumor foci outside of the nerve with involvement of 33% of the nerve’s circumference2

1. Batsakis JG. Nerves and neurotropic carcinomas. Ann Otol Rhinol Laryngol 1985;94(4 Pt 1):42. 2. Liebig C, Ayala G, Wilks JA, et al. Perineural invasion in cancer: a review of the literature. Cancer 2009;115:3379-91. http://www.conncad.com/gallery/myelin.html Duplicate

or Endoneurium Endoneurium

Epineurium Epineurium

PERINEURAL Around the nerve Distribute

ESTIMATING 0.1 MM (100 MICRONS) GENERAL CONSIDERATIONS

• Tumor incidentally • Identify normal, Not engulfing a nerve adjacent nerves under (Incidental PNI) the central mass of • Tumors that seek-out tumor • Eccrine coils have an outer diameter of 50 – 80 microns nerves (clinically- • Look at the significant PNI) morphology of the entire mass (bird’s eye Do view)

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CLUES TO ASSESS PNI

• Inflammation • Tears in the deep dermis/subcutis • Small-caliber nerve invasion (SCNI) of nerves • Levels (additional sections) less than 0.1mm in diameter was associated with significantly lower risks of disease- specific death, local recurrence, nodal metastasis, distant metastasis, and all-cause death • PNI defined as tumor cells within the nerve sheath Dermatol Surg 2009;35:1859–1866

Duplicate ESTIMATING NERVE DIAMETER WITH ECCRINE Nerve Engulfment COIL DIAMETER • Diameter ranges from or 50 to 80 microns • Small caliber nerves (less than 0.1 mm) are about the same size or SCC

smaller than the NERVE dermal eccrine coil (outer diameter)

Dermatol Surg. 2014 May;40(5):497-504.

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Neurotropic tumor SKULL BASE Not

NERVE Do

J Neurosurg. 2015 Apr 24:1-8

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SKULL BASE TUMORS

• Median overall survival (n=24) 43.2 months • 82% 1-year • 37% 5-year

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SCCor

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ADJUNCTIVE THERAPY FOR HIGH-RISK, INVASIVE SCC AFTER EXCISION:

• Radiation therapy (RT) • Positive surgical margins • Multiple recurrences • Perineural/intraneural invasion • Invasion of the cartilage • Invasion of the bone • Systemic chemotherapeutic agents for metastatic disease • Intralesional therapies • 5-fluorouracil • Standard dosing regimens and duration have yet to be clarified

Duplicate GRANULOMATOUS INFLAMMATION GRANULOMATOUSor INFLAMMATION

Palisaded Sarcoidal/ Naked Tubercle Tuberculoid

Interstitial Suppurative

Distribute KERATOACANTHOMAS USUALLY ARE SQUAMOUS CELL CARCINOMAS Not • Exception: Multiple KA syndromes • tendency toward spontaneous resolution – not often seen! • Rapid growth: not always present, and can occur with DoSCC too! • Keratin-filled crater – not specific • If lots of atypia, never call it KA! Keratoacanthoma • Eosinophils, more with KA, per Dr Ackerman

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Keratoacanthoma IATROGENIC INDUCTION OF CUTANEOUS MALIGNANCIES

• BRAF inhibitors in the treatment of melanoma

• Immunosuppression (solid organ transplant)

Duplicate CHARACTERIZATION OF THERAPY-ASSOCIATED CUTANEOUS NEOPLASMS (PLX 4032) BRAF INHIBITOR EXAMPLE VEMUAFENIBor(PLX4032) Wild • KA type SCC (n = 19) RAF Normal - • SCC suggestive of KA (n = 8) Activation Type of Extracellular Signal- • SCC with some KA features (n = 4) Related Kinase (ERK) Mutant Mutant BRAF • SCC (n = 1)

• Verruca-like lesions (nLacouture = 3), M.E., McArthur, G.A., Chapman, P.B., Ribas, K., Increase activation in Flaherty, K.T., Lee, R.J., et al., 2010. PLX4032 (RG7204), Decrease activation in a selective mutant RAF inhibitor: clinical and histologic melanomas with mutant normal cells or wild-type characteristics of therapy-associated cutaneous neoplasms in a Phase I trial. J. Clin. Oncol. 28 (15 Suppl.) (Abstract No. 8592). BRAF mutations via MAPK Distribute Not Do

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INFUNDIBULOCYSTIC SCC

• Term coined to encompass KA-like SCCs with keratin cystic areas • Supposed to be follicular differentiation

Kossard et al: Am J Dermatopath 2008;30:127.

Duplicate BASOSQUAMOUS CELL CARCINOMA (METATYPICAL BCC) or • Features of both SCC and BCC • Probably has intermediate prognosis • Use the term sparingly • Some cases are a “collision” • BCCs will keratinize under ulcers and those are just BCCs – not true basosquamous Basosquamous carcinoma Distribute Not Do

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Duplicate or

Distribute VERRUCOUS CARCINOMA • Pale and glassy with minimal atypia • Pushing border rather than infiltrative Not • Mainly is a huge wart (HPV) • Does not metastasize • Epithelioma cuniculatum - sole • Buschke-Lowenstein tumor of genitals Do • Oral florid papillomatosis of mouth

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Verrucous carcinoma

Duplicate Verrucous Verrucous carcinoma carcinoma resembles giant or wart, even with koilocytes

Distribute Verrucous carcinoma – Rx intralesional bleomycin, one unit/one ml weekly SCC LOOK-ALIKES Not • Hypertrophic lichen planus • Hypertrophic lupus erythematosus • Healing wounds • Prurigo nodularis and LSC • Granular cell tumor Do • Deep fungus and AFB preRx, one month, three months

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SCC VS PSEUDOCARCINOMATOUS Re-excision of HYPERPLASIA Spitz nevus with pseudo- • Mainly distinguished by the clinical carcinomatous situation (healing wound, fungus hyperplasia or AFB found, etc) • PEH (pseudoepitheliomatous hyperplasia) tends to have jagged irregular edges with fibrosis in dermis and no atypia

Duplicate PSEUDOCARCINOMATOUS HYPERPLASIA MUSCLE DEGENERATION (PSEUDOEPITHELIOMATOUS HYPERPLASIA) or • Weird looking nuclei in damaged or degenerating • Can be nearly impossible to muscle can closely resemble distinguish from well-differentiated SCC squamous cell carcinoma unless you have history Distribute Not Do

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ADNEXAL METAPLASIA Sweat duct metaplasia • Sweat duct metaplasia or hair resembling follicle metaplasia is most SCC SCC common in previous biopsy sites • Damaged or regenerating adnexal structures look atypical and keratinize, resembling carcinoma

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• 70 year old man with myelodysplastic syndrome • History of Sweet's syndrome • Rapidly-growing lesion on the left thumb • Biopsy-proven squamous cell carcinoma

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SWEETS SYNDROME Not • Neutrophilic dermatosis • Sheets of neutrophils • Pseudoepitheliomatous hyperplasia Do • Absence of infection

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DEGRANULATED NEUTROPHILS SHEETS OF NEUTROPHILS

Duplicate MANY EPITHELIOID HOW TO ASSESS: IDENTIFY THE EPIDERMIS AS A HISTIOCYTES NORMAL CONTROLor

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IDENTIFY NORMAL STRUCTURES Not Do A PATTERN OF THE PATIENT’S Normal eccrine duct SWEET’S WAS OBTAINED IN AN epithelium: usually 2 AREA REMOTE FROM TUMOR. cell layers thick

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IDENTIFY ATYPIA

Abnormally-thickened eccrine ducts

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Distribute Not Do Huge meningioma Warty dyskeratoma attacked by Mohs

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PROLIFERATING PILAR CYST (PILAR TUMOR)

• A pilar cyst (trichilemmal cyst, follicular isthmus-catagen cyst) in which the wall proliferates • Usually scalp • Ackerman feels they are all SCC, but most feel they just mimic SCC • Metastases have been reported

Duplicate Prolif pilar or cyst

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Do Abrupt (“trichilemmal”) keratinization in proliferating pilar cyst

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Trichoadenoma

Duplicate TANGENTIAL SECTIONING OF EPIDERMIS BEWAREor • Can resemble SCC • In Mohs, when you section • But there usually is no atypia and tangentially, an AK can look like no inflammatory reaction superficial invasive SCC • You can see dermal islands

Distribute Tangential sectioning – NOT SCC Not Do

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MALIGNANT FOLLICULAR TUMORS: PILOMATRIX CARCINOMA TRICHILEMMOCARCINOMA

• Possible squamous cell carcinomas with follicular differentiation

Trichilemmocarcinoma

Duplicate SCC IN TRANSPLANT POPULATIONS or

• Solid organ transplant recipients have a risk up to 250-fold greater than that of the general population • Overall metastatic rate between 3% to 5% • Mortality rate of 8%

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SCC IN TRANSPLANT POPULATIONS Not • Solid organ transplant recipients have a risk up to 250-fold greater than that of the general population • Overall metastatic rate between 3% to 5% Do• Mortality rate of 8%