michael t. tetzlaff md, phdemphasis on concise and accurate reporting of primary and metastatic...

Update on American Joint Cancer Committee (AJCC) staging system for primary cutaneous melanoma

Emphasis on concise and accurate reporting of primary and metastatic melanoma for effective risk stratification and prognosis

Michael T. Tetzlaff MD, PhD Associate Professor

Department of Pathology, Section of Dermatopathology Department of Translational and Molecular Pathology The University of Texas MD Anderson Cancer Center

Executive Officer

Translational Research Program The Alliance for Clinical Trials

Outline

• 8th Edition of AJCC staging system

• Parameters of the primary lesion that direct pathologic T-category • Additional informative and prognostic

parameters of the primary melanoma

• Lymph node metastases and satellitosis: criteria of pathologic N-category

• Distant metastases: M-category

• Pathology report and cancer templates

• What we report and why?

8th Edition AJCC for cutaneous melanoma

Conjunctival Vulvar Urothelial Anorectal

Does not apply to melanomas of the conjunctiva, uvea, or mucosal melanomas of the head/neck, vulva/vaginal, or anorectum.

• Improved scientific knowledge of the biology and pathogenesis of melanoma improve our capacity to stratify risk.

• Pathology reports have become more comprehensive – Diagnosis – Prognostic factors – Mutation information

• Include cancer protocol templates

• Impact clinical decisions and treatment modalities

– Earlier intervention and neoadjuvant therapy on the horizon

Pathology report for primary cutaneous melanoma

Pathology report for primary cutaneous melanoma

(A) RIGHT SHOULDER, SKIN PUNCH BIOPSY:

MELANOMA, INVASIVE, SUPERFICIAL SPREADING TYPE CLARK LEVEL, IV BRESLOW THICKNESS, 2.25 MM RADIAL (NON-TUMORIGENIC) GROWTH PHASE, PRESENT VERTICAL (TUMORIGENIC) GROWTH PHASE, PRESENT MITOTIC FIGURES/MM2, 6 ULCERATION, PRESENT (3.2 MM) REGRESSION, PRESENT VASCULAR INVASION, PRESENT PERINEURAL INVASION, PRESENT MICROSCOPIC SATELLITOSIS, PRESENT (3 X 2 MM) TUMOR-INFILTRATING LYMPHOCYTES, NON-BRISK ASSOCIATED MELANOCYTIC NEVUS, PRESENT INTRADERMAL) PREDOMINANT CYTOLOGY, EPITHELIOID SURGICAL MARGINS: INVASIVE MELANOMA PRESENT AT PERIPHERAL TISSUE EDGES

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* Required by CAP * Required by AJCC

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• Provide complete pathology report • Important information from non-required elements

• Clark level can be informative (e.g. Breslow thickness

not available) – Fragmented tissue (e.g. curettage specimens) – Maloriented specimens

• Regression

– Ongoing studies assessing depth of regression versus depth of persistent melanoma

– Considered an adverse prognostic indicator • Presence may drive subsequent management

– May have relevance to immunotherapy

Why report all 15 parameters?


• Perineural invasion

– Included in Breslow thickness by many centers – May upstage T category (e.g. change T1 to T2) – Associates with increased risk of local recurrence

• May indicate a need for adjuvant radiation therapy

• Tumor infiltrating lymphocytes – May inform subsequent immunotherapy decisions



• Associated melanocytic nevus

– Primary lesion (versus metastasis) – Associates with better survival in some studies

• Predominant cytology

– Aids in examination of excision specimens, sentinel lymph nodes and/or subsequent distant metastases

• Epithelioid, Spindle, nevoid


• T = Primary tumor – Breslow (Tumor)

thickness – Mitotic rate (7th Edition) – Ulceration

• N = Regional metastasis

– Lymph node • Microscopic/”clinically

occult” (A) • Macroscopic/”clinically

detected” (B) – Skin/subcutaneous tissue

(In-transit metastasis/satellites)

• M = Distant metastasis – Lymph node – Skin/subcutaneous

tissue – Visceral metastasis

• Pulmonary • Non-pulmonary

– Brain metastasis – Serum LDH

TNM staging

T = Primary tumor • Breslow (Tumor) thickness • Ulceration • Mitotic rate (7th Edition)

T-category driven by Breslow thickness and ulceration

Breslow (Tumor) thickness Ulceration Mitotic figures

Melanoma staging T-category: thickness and ulceration

All principle T-category

ranges are preserved in

the 8th Edition AJCC


7th Edition pT1

pT1a ≤1.00 mm NO ulceration and mitotic rate <1/mm2

pT1b ≤1.00 mm With ulceration or mitotic rate>1/mm2

8th Edition pT1

pT1a <0.8 mm NO ulceration

pT1b <0.8 mm With ulceration

pT1b 0.8-1.0 mm With or without ulceration


• Tumor thickness now recorded to the nearest 0.1 mm (instead of the nearest 0.01 mm)

– “Due to impracticality and imprecision of 0.01 mm measurements—particularly for tumors > 1 mm”

• Important pathologic staging implications:

– 0.75 mm to 0.84 mm now recorded as 0.8 mm (pT1b) – 0.95 mm to 1.04 mm now recorded as 1.0 mm (pT1b)

• Breslow thickness for pathologic staging – Includes the thickness measured in the biopsy

• If the biopsy is transected, Breslow thickness is recorded as “AT LEAST”

– Includes the thickness measured in the excision – WHICHEVER IS GREATEST (NOT ADDITIVE)


• Clarification on pTis, pT0 and pTx – pTis: Melanoma in situ – pT0: No evidence of primary tumor (“melanoma of

unknown primary”) – pTx: Tumor thickness cannot be determined

• Tangential sectioning or the epidermis is not visualized

Breslow thickness

Breslow thickness: Measured from (1) top of granular layer or (2) base of the ulcer

to the deepest point of invasion

Melanoma staging T-category: Breslow thickness

Breslow thickness: Top of granular layer to deepest point of invasion

Top of granular layer to deepest invasion

If a primary tumor lacks an intraepidermal component, the tumor thickness should still be measured in the standard manner (from the top of the granular

to the deepest point of invasion)

Top of granular layer to deepest invasion Base of ulcer to deepest invasion

Breslow thickness: Base of ulcer to deepest point of invasion

Breslow thickness pitfalls Measure only to invasive melanoma not

associated nevus

1 2

Breslow thickness pitfalls Avoid measuring around adnexal structrues

Breslow thickness pitfalls Include to perineural invasion (if deepest)

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In our practice we provide both conventional Breslow thickness and designate a thickness as measured to

PNI separately.

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• Breslow thickness measured to the deepest viable tumor cell

• Insufficient evidence yet to support measuring to regression

Impact of regression on Breslow thickness

If a tumor has undergone complete regression, then pT0.

Breslow thickness pitfalls Avoid measuring tangential sections

If a tumor cannot be measured due to tangential sectioning, then pTX.

Breslow thickness pitfalls Tumor is transected in the primary biopsy

Breslow thickness reported as “AT LEAST 1.1 MM”

Biopsy specimen 1 Biopsy specimen 2

Breslow thickness pitfalls Breslow thickness is not additive

BT1 + BT2 ≠ BT3

1 2

Breslow thickness reported as “AT LEAST BT1 mm”

Melanomas lacking an intraepidermal component: Primary or metastatic

• In melanomas lacking an intraepidermal component, consideration should be given to a cutaneous metastasis.

• Features favoring a primary origin: • (Overlying melanoma in situ) • Associated nevus • Superficial regression

• Exercise caution when diagnosing melanoma as metastatic without knowledge (e.g. is there clinical evidence of a prior melanoma?)

Melanomas lacking an intraepidermal component: Primary or metastatic

(A) PARIETAL SCALP, SKIN PUNCH: MELANOMA IN DERMIS, PRESENT AT PERIPHERAL TISSUE EDGES. SEE COMMENT.

Comment Sections reveal a proliferation of malignant epithelioid melanocytes forming an expansile nodule in the dermis, abutting the epidermis. An intraepidermal component is not identified. A primary or metastatic origin is possible. If this were interpreted as a primary melanoma at this anatomic site, the following prognostic indicators would apply….

Primary tumor ulceration Ulceration

• Defined as absence of intact epidermis overlying invasive melanoma with host reaction above the primary melanoma: – Fibrin deposition and neutrophils

• Based on microscopic examination • Must be distinguished from artifactual or traumatic

disruption of epidermis

• Transepidermal elimination of tumor • Scale crust over intact epidermis • Prior trauma or biopsy site • Detached but in tact epidermis

Pitfalls in primary tumor ulceration

Not ulcerated

Detached epidermis Not ulcerated Absent fibrin crust

Detached epidermis

Not ulcerated Ulcer likely from trauma No melanoma beneath ulcer

Pitfalls in primary tumor ulceration

Melanoma of unknown primary: pT0 • Patient presents with a regional lymph node

metastasis or distant visceral metastasis but no known primary origin

• Potential sources of primary melanoma: – Iatrogenic or non-iatrogenic procedures caused regression – Spontaneously regressed primary melanoma

• Patients with lymph node metastases should be

considered as regional stage III disease if there is not evidence of disease elsewhere. – Such patients have a prognosis and natural history similar

to—if not MORE FAVORABLE than—those same staging characteristics from a known primary cutaneous melanoma

Pathology report for primary cutaneous melanoma Other reported parameters

(A) RIGHT SHOULDER, SKIN PUNCH BIOPSY:

MELANOMA, INVASIVE, SUPERFICIAL SPREADING TYPE CLARK LEVEL, IV BRESLOW THICKNESS, 2.25 MM RADIAL (NON-TUMORIGENIC) GROWTH PHASE, PRESENT VERTICAL (TUMORIGENIC) GROWTH PHASE, PRESENT MITOTIC FIGURES/MM2, 6 ULCERATION, PRESENT (3.2 MM) REGRESSION, PRESENT VASCULAR INVASION, PRESENT PERINEURAL INVASION, PRESENT MICROSCOPIC SATELLITOSIS, PRESENT (3 X 2 MM) TUMOR-INFILTRATING LYMPHOCYTES, NON-BRISK ASSOCIATED MELANOCYTIC NEVUS, PRESENT INTRADERMAL) PREDOMINANT CYTOLOGY, EPITHELIOID SURGICAL MARGINS: INVASIVE MELANOMA PRESENT AT PERIPHERAL TISSUE EDGES

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* CAP required elements * Elements for AJCC

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* Recommended by AJCC

Primary cutaneous melanoma Histopathologic subtypes

Superficial spreading Lentigo maligna

Acral-Lentiginous Nodular

Melanoma staging and reporting Mitotic figures

Mart-1/PHH3

• Numerous studies correlate mitotic figure count with prognosis

• Use the hot spot method: • Identify the high-power field

containing the most mitotic figures and count 1 mm2.

• Do not cut additional sections “…in excess of those normally used to report and diagnose melanoma…”

• Immunohistochemical studies are not used to determine mitotic rate for staging and reporting purposes.

MiTF/D2-40

Lymphovascular invasion as a prognostic factor in melanoma. Am Surg. 2011. 77(8):992-7.

Prognostic Implication of Lymphovascular Invasion Detected by Double Immunostaining for D2-40 and MITF1 in Primary Cutaneous Melanoma. Am J Dermatopathol. 2016. 38(7): 484-91.

Melanoma staging and reporting Lymphovascular invasion

• Numerous studies correlate lymphovascular invasion by tumor cells with prognosis

• Do not cut additional sections “…in excess of those normally used to report and diagnose melanoma…”

• Immunohistochemical studies MAY BE USED to determine the presence of lymphovascular invasion for staging and reporting purposes.

Papillary dermis

Reticular dermis

I: Intra-epidermal

IV: Reticular dermis

V: Subcutaneous adipose

Melanoma reporting: Clark Levels

II: Into papillary dermis

III: Fills/expands papillary dermis

• Clark level of invasion have prognostic significance in univariate analyses, numerous studies have now confirmed that it: – Loses significance in multivariate analyses – Less reproducible among pathologists – Less robust a predictive factor than thickness

Melanoma staging and reporting

Regression Associated

nevus

• Regression viewed as an adverse prognostic indicator

• Underestimates true Breslow depth

• Correlation with response to immune checkpoint blockade?

• Important implication for staging: • Primary melanoma

• Seen more frequently in LMM and ALM with desmoplastic features

• Presence of PNI indicator for increased likelihood of local recurrence or for further adjuvant radiation therapy

Perineural invasion by tumor cells

• Include area of PNI in Breslow thickness measurement

• Nerve entrapment in central aspect of tumor is not PNI.

• Each primary melanoma is staged independently. • For those rare cases where patients present with

multiple simultaneous melanomas that drain to the same regional lymph node basin and nodal metastases are present, the tumor with the highest T-category should be assigned the origin.

Multiple primary melanomas

pT2a pT3b

Melanoma staging N-category: number, extent and satellites

Major modifications: • ‘Clinically occult’ replaces ‘microscopic’ [pNXa] • ‘Clinically evident’ replaces ‘macroscopic’ [pNXb] • Microsatellite, satellite or in-transit metastasis [pNXc]

Melanoma staging N-category: number, extent and satellites

Key points: • ‘Clinically occult [pNXa] versus clinically evident [pNXb] • Presence of a microsatellite, satellite or in-transit metastasis modifies to [NXc]

• Number of lymph nodes assessed (SLN and non-SLN)

• Number of lymph nodes containing metastasis • Tumor size

– Reported in mm – Measured on slide

• Tumor location – Subcapsular – Intraparenchymal – Currently NOT a component of the staging system but

envisioned to guide future prognostic models and possibly direct how (neo)adjuvant therapy is deployed

• Extracapsular extension

Template for reporting lymph nodes

5.3 x 1.8 mm

Sentinel lymph node evaluation Extracapsular extension

Defined as the presence of nodal metastasis extending through the lymph node capsule into adjacent tissues—usually seen as

microscopic extension of metatatic mleanoma into the perinodal adipose tissue.

• Deposit separated by normal tissue

• 8th Edition of the AJCC does not require minimum size threshold or minimum distance from the primary lesion. – Microsatellites situated close to the primary lesion

should be subjected to additional sections to exclude a connection.

N-category: Microsatellitosis, Satellitosis and in-transit metastases

N-category: Microsatellitosis, Satellitosis And in-transit metastases

• Satellite: focus of metastatic melanoma in the skin or subcutis detected clinically within 2 cm but discontinuous from the primary tumor.

• In transit metastasis: clinically evident metastasis in the skin or subcutis located > 2 cm from the primary tumor in the region between the tumor and the regional lymph node basin.

• Microsatellite: focus of metastatic melanoma in the skin or subcutis adjacent to or deep to the primary melanoma. • The tumor cells are discontinuous

from the primary tumor and separated from the primary lesion by normal tissue (rather than fibrosis or inflammation)

• All thought to occur via lymphatic spread of tumor (pNXc)

Primary Melanoma

Microsatellite

Satellite

In transit Metastasis

N-category: Microsatellitosis, Satellitosis And in-transit metastases

• Intravascular deposit (IHC informative) • Lesion contiguous on deeper sections • Incidental nevus

Pitfalls of satellitosis

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Mart-1/K-67

Melanoma staging M-category: site and LDH

Thank you! Victor G. Prieto MD, PhD

Carlos A. Torres-Cabala MD Jonathan L. Curry MD

Priya Nagarajan MD PhD Phyu Aung MD, PhD

Jeff Gershenwald MD Michael A. Davies MD, PhD

Jennifer A. Wargo MD

• Sentinel lymph nodes in melanoma – Positive in ∼20% of patients

• 15% > 1.0 mm • 5% < 1.0 mm • 16% detected on initial H&E • 4% detected with additional

sections/IHC – <5% with extracapsular extension

N-category determined by sentinel node evaluation in most cases

• If at least one node is detected clinically and others are detected microscopically, then [pNXb]

michael t. tetzlaff md, phdemphasis on concise and accurate reporting of primary and metastatic...

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