Malignant melanoma

Malignant melanoma, also melanoma, is an aggressive type of skin cancer that can be diagnostically challenging for pathologists.

Malignant melanoma
Diagnosis in short
Malignant melanoma. H&E stain.
LM	melanocytic differentiation (e.g. pigment), abnormal architecture, lack of maturation, +/-nuclear atypia - esp. nucleoli, +/-upward scatter of melanocytes, +/-asymmetry of pigmentation
LM DDx	dysplastic nevus, Spitz nevus, common nevus (nevoid melanoma), atypical fibroxanthoma, (spindle cell) squamous cell carcinoma, leiomyosarcoma, serous carcinoma, clear cell sarcoma, others
Stains	melanin
IHC	S-100, Melan A, HMB-45, MITF, tyrosinase
EM	melanosomes
Molecular	+/-BRAF mutation
Site	skin (usu. sun exposed areas), oral mucosa, others
Syndromes	familial melanoma
Signs	ABCDE = asymmetrical, border irregular, colour (black), diameter (>6 mm), evolving (growing)
Prevalence	common
Prognosis	good to very poor (dependent on stage)
Clin. DDx	pigmented skin lesions, esp. melanocytic lesions
Treatment	wide excision if possible

Melanoma in situ
External resources
EHVSC	10171

It fits into the larger category of melanocytic lesions which includes many benign entities, a number of which can be difficult to distinguish from melanoma.

General

• Known as the great mimicker in pathology; it may look like many things.

Pathologic prognostic factors

Pathologic predictors for a poor prognosis:

• Tumour thickness (Brewslow thickness) > 1 mm.
• Mitotic rate >1/mm^2.
• Ulceration.
• Regression - >75% of tumour.
• Microsatellitosis - nest of tumour cells > 0.05 mm size, separated from primary tumour >=0.3 mm and <= 2 cm.
• In transit metastasis.
• Lymphovascular invasion.
• Perineural invasion.
• Lack of tumour infiltrating lymphocytes (TILs).^{[citation needed]}

Clinical

Serologic predictors of a poor prognosis:

• Lactate dehydrogenase (LDH) > 200-225 U/L.
• Alumin < 35 g/L.

Epidemiology:

• Strong association with sun exposure.
• Typically Caucasians.
  • Blacks rarely get melanoma. When they do it is often on the palms or soles.

Gross

Memory device ABCDE:

• Asymmetric.
• Borders (irregular).
• Colour (black - variable in lesion).
• Diameter (larger than 6 mm).
• Evolving (change with time).

Microscopic

Metastatic/non-skin

Features (non-skin):

• Classic appearance of melanoma:
  • Loosely cohesive; mix of small nests of cells, single cells.
    • Nests often have clefting with surrounding tissue.
  • Mix of spindle cells and epithelioid cells:
    • +/-Occasional large binucleated cells.
    • Cytoplasm with brown pigment (melanin).
    • Prominent (large) red nucleoli (like in serous carcinoma of the ovary).
    • Marked nuclear pleomorphism - variation in cell size, shape & staining (like in serous carcinoma of the ovary).
    • Nuclear pseudoinclusions (like in papillary thyroid carcinoma).

Notes:

• Can look almost like anything.
  • Like it is said that sarcoidosis is in every internal medicine DDx... melanoma is every pathologic DDx
• May have no nuclear atypia.
  • Diagnosis is based on architecture (upward spread in the epidermis, single cells, asymmetry).

DDx

• Carcinoma.
  • Serous carcinoma - both serous carcinoma and melanoma have a large nucleolus.
• Sarcoma - as may have spindle cells.
  • Clear cell sarcoma (AKA melanoma of the soft parts).
  • Metaplastic carcinoma.
  • Spindle cell squamous carcinoma.
  • Epithelioid angiosarcoma.
• Lymphoma.
• Nodal nevus - benign nevus in lymph node.
• Other (benign) melanocytic lesions.

Images:

• Desmoplastic melanoma - several images (upmc.edu).

Skin

Features (skin):

1. Melanocytic differentiation:
   • Pigmentation (melanin).
   • Nuclear pseudoinclusion.
   • Gray cytoplasm.
   • Clear (artefactual) halo around cells.
2. Architecture:
   • Sheeting - diagnostic.
   • Asymmetry of architecture - as judged from low power magnification.
3. Lack of maturation - see below.
4. +/-Nuclear atypia - esp. nucleoli.
   • May be seen in a Spitz nevus.
5. +/-Upward scatter of melanocytes AKA intraepidermal ascent - "cannonball" appearance.
   • No diagnostic significance in the following cases:
     • Acral sites - see: Acral nevus.
     • Histologic evidence of trauma.
       • Thick dense stratum corneum.
6. +/-Asymmetry of pigmentation.

Maturation - with depth:

• Cells get smaller.
• Mitoses decrease.
• Pigmentation decreases.
• Nests get smaller.

Memory device CMPA: Cells, Mitoses, Pigment, Aggregates of cells (nests).

DDx:

• Epithelioid cell forms:
  • Spitz nevus - especially difficult.
    • Key differences: maturation and symmetry.
  • Melanocytic nevus - especially:
    • Dysplastic nevus.
• Spindle cell forms:
  • Spindle cell squamous carcinoma.
  • Atypical fibroxanthoma.
  • Leiomyosarcoma.
  • Dermal scar.
  • Blue nevus.

Images

www

• Malignant melanoma - several images (upmc.edu).

MIS

• 

  MIS - very low mag. (WC/Nephron)

• 

  MIS - low mag. (WC/Nephron)

• 

  MIS - intermed. mag. (WC/Nephron)

• 

  MIS - high mag. (WC/Nephron)

• 

  MIS - very high mag. (WC/Nephron)

Regression of melanoma

Main article: Tumour regression

General

• Complete regression without metastases estimated to be 10-20%.
  • Common ~25% of cases.
• Complete regression and partial regression >75% of the lesion are a poor prognostic feature.

Note:

• Melanocytic lesions in general, not only melanoma, may regress.

Microscopic

Features - all required:

• No melanocytes.
• Melanophages.
• Fibrosis.
• Thinned epidermis.
• Telangiectatic vessels.
• Lymphocytes.

Metastatic versus primary

Primary lesions should have:

• Epidermal involvement.

Metastatic lesions classically have:

• Tumour angiotropism (tumours cells cluster around vessels).
• Intravascular invasion.
• No epidermal component.

Note:

• Histology is not definitive for metastatic melanoma vs. primary melanoma; epidermal involvement may be seen in mets.
  • IHC (like histology) is not definitive.
  • History/clinical is important for differentiation.

Margin assessment

Main article: Surgical margin

General

• Adequate distance dependent on tumour stage - see surgical margin article.
• Margin assessment is notoriously difficult as there are numerous mimics of melanoma in situ:
  1. Melanocytic hyperplasia (considered to be on a continuum with melanoma) may be due to:
     • Light exposure.
     • Peritumoral-effect.
     • Previous biopsy.
  2. Solar lentigo.
  3. Lichenoid reactions.

Microscopic

Features of MIS:

1. Pagetoid spread of melanocytes.
2. Junctional or intraepidermal melanocytic nests.
3. Three of more contiguous melanocytes in the basal layer.
4. Increased numbers of basal melanocytes ( > 25 melanocytes / 0.5 mm of basal layer).
5. Marked cytologic atypia - multinucleated cells.
6. Adenxal involvement.

Lame mnemonic MARGIN:

• Marked cytologic atypia.
• Adnexal involvement.
• Row of melanocytes.
• Gravity defying melanocytes (Pagetoid spread).
• Increased basal melanocytes.
• Nests of melanocytes.

Assessment/reporting of margins

• There is no general agreement on how to report margins in melanoma.

It is suggested that one should:

1. Try to tease apart melanoma cells from benign melanocytes.
   • Use the MARGIN mnemonic above.
     • Melanocytes with nuclear atypia = melanoma cells.
2. Report the clearance of the nearest melanoma cell to the margin.
   • Positive margin = melanoma cell is touching ink.
   • Very close is reported as "clearance < 0.1 mm".
3. Use immunostains to assist the assessment of difficult cases:
   • MiTF is considered the preferred marker.
   • MART-1 (Melan A) is considered to overestimate melanocytes; it should not be used.
   • S-100 also marks follicular dendritic cells; it is not a preferred marker.

Breslow thickness

• AKA maximum tumour thickness.
• Depth measured from stratum granulosum to deepest intradermal tumour cell - predictive of survival.

Tumour stage

Melanoma staging is based primarily on the Breslow thickness:

• pT1 ≤ 1.0 mm.
  • pT1a: ≤ 0.8 mm, no ulceration.
  • pT1b: ulceration present or 0.8 mm < thickness ≤ 1.0 mm (with or without ulceration).
• pT2 1.01 mm to 2.0 mm.
  • pT2a: no ulceration.
  • pT2b: ulceration present.
• pT3 2.01 mm to 4.0 mm.
  • pT3a: no ulceration.
  • pT3b: ulceration present.
• pT4 >4.0 mm.
  • pT4a: no ulceration.
  • pT4b: ulceration present.

Clark level

• AKA anatomic level.
• Not as reproducible as Breslow thickness. It is not used for this reason.

Anatomic level - definition:

• I = epidermis only (AKA melanoma in situ).
• II = extends into papillary dermis but does not fill or expand.
• III = fills and expands papillary dermis.
• IV = extends into reticular dermis.
• V = extends into subdermis.

Subtypes

Subtype name	Key feature	Microscopic additional	DDx	Image	Notes/other
Melanoma in situ	confined to epidermis, nuclear atypia	melanocyte enlargement, nuclear hyperchromasia, +/- melanocytes above suprapapillary plate (above basal layer) = "Pagetoid spread"	melanocytic hyperplasia, pagetoid Spitz nevus, dysplastic nevus	(upmc.edu), (WC)	lentigo maligna (LM) is melanoma in situ on sun damaged skin; LM should not be confused with lentigo maligna melanoma (LMM)
Malignant melanoma - superficial spreading type	atypical melanocytes at all levels of epidermis + dermis	atypical dermal melanocytes single, in cluster or sheets	compound melanocytic nevus	Image?	Notes/other?
Malignant melanoma - lentiginous type	atypical melanocytes prominent along basal keratinocytes + in dermis	nuclear atypia	melanoma in situ	Image?	lentigo maligna melanoma (LMM) = lentiginous malignant melanoma with sun damage[citation needed]
Malignant melanoma - nodular type	dermal large nodule/sheet	nuclear atypia; may not be prominent in epidermis	metastatic melanoma	Image?	Notes/other?
Malignant melanoma - desmoplastic-neurotropic type AKA desmoplastic melanoma	large atypical spindle cells, between collagen	predominantly dermal, +/-lymphocytes (nodules or infiltrating)	pleomorphic undifferentiated sarcoma (MFH), scar, dermatofibroma, DFSP, leiomyosarcoma, desmoplastic Spitz nevus, sclerosing blue nevus	(upmc.edu)	IHC: rarely S100-, generally Melan A- & HMB-45-; subdivided into mixed desmoplastic melanoma and pure desmoplastic melanoma
Malignant melanoma - nevoid type	prominent nucleoli, deep mitoses - high power diagnosis	mimics nevus at low power; "push" elastic fibers downward (unlike benign nevi)	(benign) nevus	Image?	deep HMB-45+
Malignant melanoma - spitzoid type	nested pattern, nuclear atypia, no maturation (large deep cells)	NC ratio increased (vs. Spitz)	Spitz nevus	Image?	Notes/other?

Subtypes in short

Subtype name	Key feature
in situ	confined to epidermis, unlike all others
superficial spreading	above basal layer
lentiginous	along basal keratinocytes
nodular	nodular dermal lesion
desmoplastic-neurotropic	atypical dermal spindle cells
nevoid	nevus-like at low power
spitzoid	mimics Spitz nevus (at DE junction)

Electron microscopy

• Melanosomes.

Image(s):

• Melanosomes (nature.com).

Stains

• Fontana-Masson stain, stains melanin.
  • May be useful to differentiate melanin from other brown stuff (e.g. lipofuscin, hemosiderin).

IHC

Standard panel

1. S-100 +ve.
   • Negative staining pretty much excludes the diagnosis.
2. HMB-45 +ve -- especially deep, often patchy.
3. Melan A (MART-1) +ve.

Notes:

• The standard panel above (S100, HMB-45, MART-1) is also positive in other lesions, e.g. cellular blue nevus.
• Melan A tends to overestimate the number of melanocytes.
  • Counting the cell bodies may give an accurate result.^{[citation needed]}
• S-100 marks melanocytes and follicular dendritic cells.

Threshold panel

When one it sure it is melanocytic... but unsure whether it is melanoma:

• HMB-45 +ve deep melanocytes.
  • In benign lesions deep (mature) melanocytes are negative.
• Ki-67.

Sentinel lymph node panel

Main article: Sentinel lymph node

Three sets of the following (12 slides in total):

• H&E.
• S-100.
• MART-1.
• HMB-45.

Notes:

• Positive in approximately 20% of cases - based on one series.
  • Strongly dependent on T-stage (T1 ~5%, T2 ~11%, T3 ~28%, T4 ~47%).

Others

• SOX10 +ve -- useful for differentiate from excision scar.
  • SOX10 = pan-schwannian and melanocytic marker.
• CD99 +ve.

• Melanoma cocktail (HMB-45, MART-1).
• Microphthalmia transcription factor (MITF) - easy to interpret as it is a nuclear stain.
• Tyrosinase.
• WT1 usually +ve - not commonly used.

Molecular

• Commonly have BRAF mutations.
• Desmoplastic melanoma has the highest number of mutations (62 per megabase).
  • The high number of (C>T) transitions suggest UV radiation as main cause.
  • Approx. 15% of the cases have NFKBIE amplifications.

Sign out

Melanoma in situ

Skin Lesion, Left Upper Back, Re-excision:
- Melanoma in situ, completely excised.
-- Surgical clearance 8 millimetres.
- Dermal scar.
- Solar elastosis.

Comment:
The case was partially reviewed with Dr. X; he agrees melanoma in situ is present.

Block letters

SKIN LESION, MID-MIDDLE BACK, PUNCH BIOPSY:
- MELANOMA IN SITU, NEAREST (LATERAL) MARGIN APPROXIMATELY 1 MM -- WIDE RE-EXCISION SHOULD BE DONE.

COMMENT:
The lesion is characterized by mild nuclear atypia and marked architectural complexity.  
It has lamellar fibrosis and multiple foci of complex rete ridge bridging and pagetoid 
spread of melanocytes. Mitotic activity is seen focally.

SKIN LESION, MID BACK, EXCISION:
- LENTIGO MALIGNA (SOLAR ELASTOSIS AND MELANOMA IN SITU), MARGIN CLEARANCE < 0.1 MM.

COMMENT:
This lesion should be re-excised.

SKIN LESION, MID BACK, EXCISION:
- MELANOMA IN SITU AND SOLAR ELASTOSIS (LENTIGO MALIGNA), MARGIN CLEARANCE 2 MM.

COMMENT:
The presence of melanoma in situ is confirmed with immunostaining (HMB-45, MITF).

This lesion should be re-excised.

At least MIS

LEFT THUMB NAIL, AVULSION AND NAIL MATRIX BIOPSY:
- AT LEAST MALIGNANT MELANOMA IN SITU.

COMMENT:
The quantity of diagnostic material is suboptimal.

The limited number of lesional cells stain as follows:
POSITIVE: S-100, HMB-45, MITF, Melan A.

An internal review confirms the impression of at least melanoma in situ.

Micro

The sections show hair-bearing skin with atypical melanocytes confined to the epidermis. The melanocytes scatter upwards (focally), have confluent growth and nucleoli, and involve the adnexal structures. Occasional large multi-nucleated melanocytes, with their nuclei arranged around the cell periphery, are present. Mitotic activity is not apparent. Extensive solar elastosis is present.

The lesion is very close to the margin (<0.1 mm clearance).

Alternate

The sections show skin with pigmented atypical melanocytes confined to the epidermis. The melanocytes scatter upwards, and have focal confluent growth and nucleoli. Mitotic activity is not apparent. Solar elastosis is present in the background. The lesion extends to the edge of the tissue; it is incompletely excised.

Invasive melanoma

SKIN LESION, LEFT LOWER BACK, SHAVE BIOPSY:
- INVASIVE MALIGNANT MELANOMA.
-- AT LEAST pT3a.
-- 6 MITOSES/MM*MM.
-- DEEP AND LATERAL MARGINS POSITIVE, WIDE RE-EXCISION SHOULD BE DONE.
-- PLEASE SEE TUMOUR SUMMARY.
-- PLEASE SEE COMMENT.

COMMENT:
The morphologic impression is confirmed by immunostains; the tumour is POSITIVE for 
S-100, HMB-45, and MART-1.

See also

• Dermatopathology.
• Dermatologic neoplasms.
• Cytopathology.
• Melanocytic lesions.

External links

• Dear 16-year-old me - DCMFCanada (youtube.com).