Invasive melanoma of the skin

Author: Mikael Häggström
Melanoma of the skin generally presents as a dark skin focality.

Fixation

Generally 10% neutral buffered formalin.

  See also: General notes on fixation

Gross processing

Gross examination

Note:

• Color
• Well-defined or diffuse border
• Size
• Any elevation

Tissue selection

Tissue selection from suspected malignant skin lesions, by lesion size:

<4 mm	4 - 8 mm	9 - 15 mm

In table above, each top image shows recommended lines for cutting out slices to be submitted for further processing. Bottom image shows which side of the slice that should be put to microtomy. Dashed lines here mean that either side could be used. Further information: Gross processing of skin excisions

Microscopic evaluation

Differential diagnoses

• 

  Melanoma in situ, where melanoma cells are limited to the epidermis.

Dermal nevus

Comparison of dermal nevus and suspected invasive melanoma  

Parameter		Non-dysplastic dermal nevus	Low-grade dysplastic dermal nevus		High-grade dysplastic dermal nevus	Suspected invasive melanoma
			Mild dysplasia	Moderate dysplasia	Severe dysplasia
Macroscopic	Lateral circumscription	Sharp	Slightly diminished	Moderate		Poor
	Symmetry	Good			Often broken	Rare
Structural (Low mag.)	Micrograph
	Delimitation		Rarely diffuse	Sometimes diffuse	Often diffuse
	Confluent nests		Rarely	Sometimes	Often	Often widespread
	Pigment distribution	Regular		Irregular
	Concentric fibrosis	Regressive (see below table)	Yes			Occasional
	Lamellar fibrosis		Rarely	Often	Often pronounced	Occasional
	Lymphocytic infiltrate		Mild, perivascular	Mild or moderate, perivascular	Varying	Varying
Cellular (high mag.)	Micrographs
	Nuclear size		Small	Medium	Large	Medium or large. Pleomorphic
	Nuclear pleomorphism	Slight superficial	Slight	Prominent
	Chromatin pattern	Uniform	Condensed	Partically expanded	Expanded, coarse in some cells	Expanded, hyperchromatic, coarse. Usually granular.
	Nucleoli		Small	Medium	Large	Usually large
	Mitoses	Few superficial				Superficial and deep
	Histological regression (see below table)		Usually		Usually not
	Percentage of atypical melanocytes		<10%	About 10 - 50%	about 50-90%	Usually> 90%

Histological regression is one or more areas within a tumor in which neoplastic cells have disappeared or decreased in number. In this case, it means complete or partial disappearance of neoplastic cells from areas of the dermis (and occasionally from the epidermis), which have been replaced by fibrosis, accompanied by melanophages, new blood vessels, and a variable degree of inflammation.

In suspected but not certain nevus or melanoma, generally perform immunohistochemistry with SOX10 (which stains cell nuclei of melanocytes), whereby melanocyte proliferation and nuclear pleomorphism is easier to see:

• 

  SOX10 showing dermal nevus nests.

Further workup

In case a diagnosis of invasive melanoma of the skin can be made, the following are generally mandatory:

• Margins
• Depth
• Any ulceration
• Histopathologic type.
• Presence of mitoses in the intradermal component.

The following aspects are mandatory in some regions:

• Clark's level (not mandatory in the US)

Margins

Determine if the distance to any margin is greater or lesser than 3 mm. If a margin is closer, measure it at an exactness of 0.1 mm.

If margins are difficult to determine, consider immunohistochemistry with SOX10 (staining the nuclei of melanocytes), to better visualize melanoma nests.

Depth and ulceration

For invasive melanoma, measure the depth and whether there is ulceration or not, so as to be able to classify the T stage (following table by AJCC, 8th edition):

T Category	Thickness	Ulceration status
TX: primary tumor thickness cannot be assessed (e.g., diagnosis by curettage)	Not applicable	Not applicable
T0: no evidence of primary tumor (e.g., unknown primary or completely regressed melanoma)	Not applicable	Not applicable
Tis (melanoma in situ)	Not applicable	Not applicable
T1	≤1.0 mm	Unknown or unspecified
T1a	<0.8 mm	Without ulceration
T1b	<0.8 mm	With ulceration
	0.8–1.0 mm	With or without ulceration
T2	>1.0–2.0 mm	Unknown or unspecified
T2a	>1.0–2.0 mm	Without ulceration
T2b	>1.0–2.0 mm	With ulceration
T3	>2.0‐4.0 mm	Unknown or unspecified
T3a	>2.0–4.0 mm	Without ulceration
T3b	>2.0–4.0 mm	With ulceration
T4	>4.0 mm	Unknown or unspecified
T4a	>4.0 mm	Without ulceration
T4b	>4.0 mm	With ulceration

Histopathologic type

If needing to evaluate, the main types of invasive melanoma are:

Type	Features	Relative incidence (in comparison to all melanomas)	Photograph	Micrograph
Superficial spreading melanoma	Melanoma cells with nest formation along the dermo-epidermal junction.	70%
Nodular melanoma	Grows relatively more in depth than in width.	15% - 20%
Lentigo maligna melanoma	Atypical epidermal melanocytes as well as invasion into the dermis.	5% - 10%
Acral lentiginous melanoma	Continuous proliferation of atypical melanocytes at the dermoepidermal junction.	7% - 10%

Clark's level

Skin layers.

If needing to evaluate, Clark's levels are:

• Level 1: Melanoma confined to the epidermis (melanoma in situ)
• Level 2: Invasion into the papillary dermis
• Level 3: Invasion to the junction of the papillary and reticular dermis
• Level 4: Invasion into the reticular dermis
• Level 5: Invasion into subcutaneous tissue.

Tumor‐infiltrating Lymphocytes (TILs)

Classify as either of the following:

• Absent TIL infiltrate: no lymphocytes present or, if present, they do not interact with tumor cells.
• Non-brisk TIL infiltrate: focal areas of lymphocytic infiltration in the tumor.
• Brisk TIL infiltrate: TIL infiltration of the entire base of the tumor, or diffuse permeation of the tumor.

Lymph nodes

Cells that stain for melan-A but are nevus-like may be a capsular nevus

If negative on H&E stain, generally use immunohistochemistry for melanoma markers (such as a combination of melan-A and HMB-45) to exclude micrometastasis:

• 

  Melanoma micrometastases on melan-A stain.

Other parameters

Optionally, the following parameters can be given:

• 
• 

• histological regression, with complete or partial disappearance from areas of the dermis (and occasionally from the epidermis), which have been replaced by fibrosis, accompanied by melanophages, new blood vessels, and a variable degree of inflammation.

Further information: Evaluation of tumors

Report

Report when evaluated (as per mandatory vs. optional in Further workup above):

• Melanoma area dimensions (width x width)
• Radicality, mainly into either of the following:

• >3 mm : "Clear margins" (or: "Clear margins at over __ mm")((or the exact distance thereof)).))
• <3 mm but not continuous with edge: "Close margins at __ mm at (location). [[Locations are mainly the deep edge, or the (superior/inferior/medial/lateral) radial edge.]]." Numbers are generally given at an exactness of 0.1 mm.
• Continuous with margin: "Not radically excised at (location)."

• Depth or most distant invasion of melanoma cells.
• Ulceration or not, and maximum dimension if present
• Stage as per AJCC
• Clark's level
• Histopathologic type
• Mitotic rate, as amount per mm²
• Significant signs of regression
• Cytoplasmic pigmentation
• Melanoma cell shapes

US example

Skin, mid upper back, excision: Malignant melanoma, nodular type, Clark level IV, Breslow thickness 10mm. Surgical margins are negative for melanoma. See synoptic report. SYNOPTIC REPORT: Specimen Procedure:  Excision Specimen Laterality:  Midline Tumor Tumor Site:  Skin of trunk Histologic Type:  Nodular melanoma Maximum Tumor (Breslow) Thickness (Millimeters): 10 mm Macroscopic Satellite Nodule(s): Not identified Ulceration: Present Extent of Ulceration (Millimeters):  12 mm Anatomic (Clark) Level: IV (Melanoma invades reticular dermis) Mitotic Rate:  18 mitoses / mm2 Microsatellite(s):  Not identified Lymphovascular Invasion:  Not identified Neurotropism:  Not identified Tumor-Infiltrating Lymphocytes:  Present, nonbrisk Tumor Regression:  Not identified Margins Peripheral Margins:  Negative for invasive melanoma Distance of Invasive Melanoma from Closest Peripheral Margin (Millimeters):  5 mm Location:  3 o'clock and 9 o'clock Status of melanoma in situ at peripheral margins: Negative for melanoma in situ Distance of melanoma in situ from closest peripheral margin (millimeters):  Cannot be determined - Ulcerated surface and no in-situ noted in the remaining surface Location:  Lateral Deep Margin:  Negative for invasive melanoma Distance of Invasive Melanoma from Deep Margin (Millimeters):  2 mm Status of Melanoma in situ at Deep Margin: Negative for melanoma in situ Distance of Melanoma in situ from Deep Margin (Millimeters):  Cannot be determined (negative for melanoma in situ) Lymph Nodes Regional Lymph Nodes:  No lymph nodes submitted or found Pathologic Stage Classification (pTNM, AJCC 8th Edition) Primary Tumor (pT):  pT4b Regional Lymph Nodes (pN):  pNX

European example

Sun-damaged skin with central diffusely delimited proliferation of melanocytic cells having polymorphic cell nuclei, distinct nucleoli and uneven light brown pigmentation. An area of pagetoid migration is seen. There is ulceration of a smaller area. The radial margin is over 3.0 mm and the deep margin is 2.0 mm. Free margin: Yes Margin in mm: 2.0 mm Tumor depth: 1.2 mm Ulceration: Yes Stage: T2b Clark's level: IV Histopathologic type: Superficial spreading melanoma Presence of mitoses: Yes Significant signs of regression: No

  See also: General notes on reporting

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