Cutaneous melanoma: Detecting it earlier, weighing management options

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Cutaneous melanoma: Detecting it earlier, weighing management options

J Fam Pract. 2007 January;56(1):18-28

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References

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TABLE 1
Using the TNM staging system to determine prognosis for melanoma

T CLASSIFICATION		BRESLOW THICKNESS (MM)					ULCERATION
T1		≤1.0					a: no ulceration and Clark’s level II/III
T1		≤1.0					b: ulceration or Clark’s level IV/V
T2		1.01–2.0					a: no ulceration
T2		1.01–2.0					b: with ulceration
T3		2.01–4.0					a: no ulceration
T3		2.01–4.0					b: with ulceration
T4		>4.0					a: no ulceration
T4		>4.0					b: with ulceration
N CLASSIFICATION		METAST ATIC NODES					NODAL METASTATIC MASS
N1		1 node					a: micrometastasis*
N1		1 node					b: macrometastasis^†
N2		2–3 nodes					a: micrometastasis*
N2		2–3 nodes					b: macrometastasis^†
N3		≥4 metastatic nodes, or matted nodes, or in transit metastases/satellites with metastatic node(s)
M CLASSIFICATION		METASTASES (SITE)					SERUM LDH^‡
M1a		Distal skin, subcutaneous/nodal					Normal
M1b		Lung					Normal
M1c		All other visceral					Normal
M1c		Any visceral					Elevated
*Micrometastases diagnosed after sentinel or elective lymphadenectomy.
^‡Macrometastases defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.
^‡LDH, lactate dehydrogenase.
Once the TNM classification has been determined, the combined findings, as shown below, can help you determine a patient’s relative prognosis.
	Clinical Staging			Pathologic Staging			5-year survival (%)
0	Tis	N0	M0	Tis	N0	M0	96–100
IA	T1a	N0	M0	T1a	N0	M0	95
IB	T1b	N0	M0	T1b	N0	M0	90
	T2a	N0	M0	T2a	N0	M0
IIA	T2b	N0	M0	T2b	N0	M0	78
	T3a	N0	M0	T3a	N0	M0
IIB	T3b	N0	M0	T3b	N0	M0	65
	T4a	N0	M0	T4a	N0	M0
IIC	T4b	N0	M0	T4b	N0	M0	45
III	Any T	Any N	M0
IIIA	T1-4a	N1a	M0	66
	T1-4a	N2a	M0
IIIB	T1-4b	N1a	M0	52
	T1-4b	N2a	M0
	T1-4a	N1b	M0
	T1-4a	N2b	M0
	T1-4a	N2c	M0
	T1-4b	N2c	M0
IIIC	T1-4b	N1b	M0	26
	T1-4b	N2b	M0
	Any T	N3	M0
IV	Any T	Any N	Any M	Any T	Any N	Any M	7.5–11

Preferred management and contingencies

Primary treatment for cutaneous melanoma is wide local excision of the primary site.

How wide should excision margins be? The appropriate margin of normal skin (measured from the biopsy scar or lateral border of residual melanoma) varies with Breslow tumor thickness.¹⁷ With thin and intermediate thickness, a surgical margin encompassing 1 cm of normal skin is the consensus.¹⁷ For thicker lesions, many authorities recommend a 2-cm margin. A 1-cm margin may be inadequate due to the risk of local recurrence; however, whether a 2 cm or 3 cm margin is optimal remains unclear.^18,19TABLE 2 reviews treatment guidelines for surgical excision of primary cutaneous melanoma.^20-24

Biopsied tissue submitted as permanent sections. The planned primary excision site should be oriented and submitted to pathology in formalin for permanent section examination. Frozen sections are generally not recommended; when the pathologist assesses surgical margin status, scattered melanocytes in adjacent sun-damaged skin may lead to uncertainty. Moreover, artifacts from the freezing process make interpretation difficult.

2 qualifiers for the above advice: immunostains have increased the utility of frozen sections, and frozen sections were not used in the clinical trials from which current treatment options were derived. These considerations apply particularly to the use of frozen section analysis in Mohs micrographic surgery (see below).

FAST TRACK

Even with a negative biopsy result, repeat the biopsy if you remain suspicious of a lesion’s clinical appearance

The wide local excision specimen can be examined by multiple surgical pathology orientation methods. In many cases, if the primary lesion was completely excised by the initial biopsy, the pathologist will examine the area of the biopsy scar for residual melanoma and select portions of the lateral margins for examination. Alternatively, the entire lesion, all of the margins, or even the entire specimen may be submitted for examination depending on the clinical circumstances and concerns of the pathologist and surgeon, such as incomplete removal at the time of initial biopsy or close deep or lateral margins. Communication between surgeon and pathologist must be clear and unambiguous.

Immunohistochemical techniques and antibody testing

Examining multiple sections from the tissue block and adding immunohistochemical stains greatly increase sensitivity for metastatic melanoma.^37-40 Cochran et al⁴¹ originally demonstrated the importance of immunohistochemistry in the pathology examination of lymph nodes. From 2227 lymph nodes removed from 100 patients, they found that 16 additional lymph nodes in 14 patients contained metastatic melanoma when examined with S-100 immunohistostains. Using additional antibodies more recently (see below), these authors reported that up to 12% of metastatic melanoma deposits can be missed by experienced pathologists without the aid of immunohistochemistry.⁴²

Though no antibody is both highly sensitive and specific for malignant melanoma (versus normal melanocytes), the antibodies most commonly used in immunohistochemistry include S-100 (a neuroectodermal tissue maker expressed in nerves, melanocytes, histiocytes and dendritic cells in lymph nodes), HMB 45 (recognizes an oligosaccharide side chain present in immature melanosomes), Melan-A (recognizes the MART-1 protein), and tyrosinase (recognizing the enzyme tyrosinase required for melanin synthesis). S-100, although very sensitive, is not a melanocyte-specific antibody. The remaining antibodies, though melanocyte specific, are non-reactive in 5% to 15% of cutaneous malignant melanoma.⁴²

Using polymerase chain reaction (PCR) and reverse transcriptase polymerase chain reaction (RTPCR) for MRNA for melanocyte-associated proteins further increases sensitivity, detecting positive nodal cells when routine hematoxylin/eosin and immunohistochemical methods do not. The clinical utility of molecular methods for diagnosis and patient management has not been established; these techniques are the subject of ongoing clinical trials.⁴³

In retrospect, it is clear that the standard techniques used to examine lymph nodes taken from regional lymph node dissections underestimate the presence of micrometastatic disease. one could argue, in fact, that the sole advantage of lymphatic mapping and sentinel lymph node biopsy has been to allow the pathologist to perform a focused, extensive examination on 1-3 lymph nodes – an examination that would be impractical (and prohibitively expensive) on a standard regional lymph node dissection specimen. Interestingly, the idea that additional sections from lymph nodes will increase the detection rate of metastatic tumor is not new and was well-known to the surgeons and pathologists involved in the pioneering work on sentinel lymph node biopsy.⁴¹