Malignant melanoma

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
Site	skin, others
Syndromes	familial melanoma
Signs	ABCDE = asymmetrical, border irregular, colour (black), diameter (>6 mm), evolving (growing)
Prevalence	common

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

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 transist 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

Metatstatic/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.
• Other 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:

• WC:
  • Melanoma in situ - intermed. mag. (WC).
  • Melanoma in situ - very high mag. (WC).
• www:
  • Malignant melanoma - several images (upmc.edu).

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.
  • History/clinical is important for differentiation.

Breslow thickness

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

Clark level

• AKA anatomic level.
• Not as reproducible as Breslow thickness - not used.

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.

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. Tease try to apart melanoma cells from benign melanocytes.
   • Use 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.

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.
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.
• S-100 marks melanocytes and follicular dendritic cells.

Threshold panel

When one it sure it is melanocyte... but unsure 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.

Others

• SOX10 +ve -- useful for differentiate from excision scar.
  • SOX-10 = pan-schwannian and melanocytic marker.

• Melanoma cocktail (HMB-45, MART-1).
• Microphthalmia (MITF) - easy to interpret as it is a nuclear stain.
• Tyrosinase.

Sign out

Melanoma in situ

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 (MELANOMA IN SITU AND SOLAR ELASTOSIS), MARGIN CLEARANCE < 0.1 MM.

COMMENT:
This lesion should be re-excised.

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).

See also

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