Melanoma Pathology Parameters
For decades (at least since 1980), research scientists have hoped to come up with technology that will avoid tissue biopsies when "cancer" is suspected. Most technologies have ended up bringing MORE biopsies to pathologists (even though it avoids biopsies on a subset of lesions that previously would have been biopsied). MoleMap has the hope of dermatologist-directed comparative photography to help prove lack of significant interval change so as to avoid surgery. Dermatoscopy allows special magnified visualization by dermatologists of skin moles so as to discern benign 3 dimensional configurations and avoid some biopsies. In 2009, laser scanning screening is getting grant money as it stimulates the imagination of researchers & engineers hungry for research grants. In late 2011, MelApp came out for the iPhone for a nonmedical phone owner to (1) take a phone photo of his/her suspicious mole and (2) have the app calculate "riskiness" that it be melanoma (and even use the phone GPS to locate a nearby dermatologist). But, I found it not easy to take an optimal photo.
Primary tumor sites: We think of melanoma as a skin cancer; but, they can rarely originate ANYWHERE, including from node capsule nevi in various lymph node clusters (such as in the groin or axilla). ALSO, rarely, biphasic maligancies arising in non-skin locations can have a melanomatous-appearing component with, beginning in 2011, treatment implications [was melanomatous L12-8775; was not melanomatous L12-9826].
Pathology lab specimen processing: If your local pathologist has very carefully processed
your skin specimen and carefully determined the parameters, you
will be able to find out additional information on the internet
or from medical contacts around the world. Careful processing includes a system of careful "grossing" of all skin specimens so that there is assured embedding of skin such that epithelial surface is at 90 degrees to the plane of microtome sectioning...to avoid incorrect Breslow thickness measurement due to tangential increasing of thickness. A FAXed, excellently
informative pathology report contains essential information on
which experts can give additional opinions and advice (there are
usually only a few actual glass slides which could be shipped out
long distances for other expert opinions). Especially important is the application
of exact criteria to separate RGM & VGM in cases of thin level
II, see below14. All of these parameters are considered in estimating a melanoma patient's prognosis if left untreated. If it
is "bad", then various treatment measures are considered.There is developing genetic
Pre-surgical predicting of likelihood of positive SLN: One parameter for assessing prognostic risk in a melanoma patient is "node status". And there are parameters which help
to select those at risk for node positivity...tested by
sentinel lymph node or other node biopsy or dissection if liklihood of positivity warrants it. A general online calculator based on common parameters is at MSKCC. But, if the calculator produces a low risk number, a search for presence or absence of other higher-risk histology features may result in a decision to check the nodes anyhow. Especially as to melanoma "growth phase", "vertical growth phase (some think radial growth phase...RGM...
rarely if ever metastasizes17) melanoma" (VGM) has the ability to metastasize (13 % of VGMs have pos. SLN). So, RGM are extremely unlikely to metastasize. This
2006 study of 682 VGM SLN cases found 88 positive. Here are their SLN triage & prediction criteria: (1) if Breslow is 2mm or less & zero mitoses per square mm, 2.1%
have pos. SLN & if any mitoses per square mm, 9.8% pos SLN (those negative for TILs have the highest rate in this group); and, if (2) Breslow is thicker than
2mm, then absence of significant TILs actually infiltrating through melanoma cell clusters has a 40% SLN positivity rate while presence of TILs only has a 20% positivity
rate17. So any VGM [criteria] with no dermal-melanoma-cell mitoses and less than 2mm thick has only a 2% likelihood of a positive sentinel node17, 19! But, there is an on-line claulator20 for 10 year overall survival prognosis of thin (a mm or less in thickness) lesions.
Sentinel-node (SLN) status:
- Positive vs. negative SLNs: in one study21 (a follow up period of up to just over 5-year follow up), 31% of SLN positive patients recurred & 19% of SLN positives died of melanoma, while SLN negatives were 6% & 4%, respectively.
- SLN node-capsule nevus:
- False positive SLN: On finding a positive SLN, the pathologist must be careful not to interpret small node capsule melanocytic nevi (amitotic and low Ki67) as metastatic melanoma. These nevi (many being minute) may be as common as 39% of SLN encounters when using a detection system of immunohistochemistry marking and automated digital image analysis 21. They are more common in SLNs than non-SLN and in patient's with congenital melanocytic nevi or melanoma associated nevi...their coarser but practical study (also with IHC) finding a rate of 11% in melanoma cases22.
- Node-capsule primary melanoma: Likewise, it is possible that a melanoma initially diagnosed which originated as a pathological node as a capsular-nevus-derived primary [L08-3623] (if the previous history is totally negative and the patient is also currently negative for a primary melanoma of skin or mucosa).
- Metastatic volume21: less than a half cubic millimeter vs. greater than half.
LONGTERM PROGNOSIS: In spite of particular case prognosis predictions, remember that melanoma is a malignancy infamous
for NOT "playing by the rules". There are some amazing stories of long term survivors! I our one county and hospital during a 40 year career, the following came to my attention. (1) I personally knew a local professional man who was misdiagnosed about 1973 and only correctly diagnosed a year later when he had bulky axillary metastasis...he lived well until he developed a new primary melanoma & died in 2012 (39 years later). (2) Also in the early 1970s, a man in that same small town & friend of (1) had a bad melanoma diagnosis & lived maybe 25 years (both had gotten vaccine therapy at M. D. Anderson). (3) Another local man had a dark mole removed in 1974 & appeared for emergency laparotomy showing bulky stage IV melanoma in 1983. He then underwent a Christian "laying on of hands" some weeks later (the story). Some time further, he went on a macrobiotic diet; he died in early 1997. (4) In 2005, we had an 80 y/o F who presented with bone lesions suggesting myeloma who was later found to have had melanoma in 1960. (5) In 2015, a 70 y/o male had a benign FNA of a possible early pancreatic mass; hed'd had a flank melanoma removed in 1980 followed 5 years later with mets [S05-15202; T15-1...at least 35 years survival]. In 2016, we had a patient present with a cough & found to have a lung mass: melanoma (she'd had a melanoma of the face removed [where?] in 1978 & treated at Duke with some sort of immunotherapy [T16-63]).
Our group's pathology reports on the primary skin melanoma include
the following numerous parameters (basic
tumor location: extremities B vs.
trunk Intermediate vs.
( acral [volar & subungual], scalp, ears, and mucous membrane or immediately
sex of patient (survival, men W vs.
Clark's melanoma histogenetic types: lentigo
maligna B, SSMM, acral lentigenous, mucosal
lentigenous, verrucous, desmoplastic, nodular W [microscopic
diagnostic criteria & other pigmented lesions].
angiolymphatic invasion: detection of vascular invasion implies the need for chemo/immuno-therapy.
tumor ulceration (not meaning
traumatic excoriation [L05-517] or artifactual "ulceration"6)...defined
as absence of epidermis over a major portion (probably 3MM
or more [L-05-517]) of the melanoma & measurements
should be made16. See below.
surgical margin status.
perineural space invasion: one may need to perform an IHC neural marker such as S100 in order to see small cutaneous twigs obscurred by perineural tumor. Positivity implies strong consideration of local radiation because of about 25% increased risk of local recurrence in such cases.
- lymp node status:we are now working up about 1-2 sentinel lymph
node cases per week (our department is regularly involved in breast
cancer sentinel node cases and a large experience of detailed and
focused skill at lymph node dissection in search of metastatic
malignancies). It is vital to not mistake a nodal nevus for metastatic melanoma (about IHC)...even taking care to discern a nodal nevus (criteria, above, this page) in a completion
dissection in a case with positive sentinel node [L07-5254]!
A file on melanoma types and
skin lesions which might clinically be melanoma
overview page with link to melanoma on-line
Below: B=better, W=worse.
is it located on an extremity B (arm
or leg) or non-extremity W?
is it in a sun-exposed B or
covered location W?
is it small B or large W?
is it nodular W or not completely
is it pigmented B (melanotic)
or not pigmented W (amelanotic)?
is it "tumor ulcerated" W (a
scab or crust may cover the ulcer) or not ulcerated B?
[don't misdiagnose traumatic or excoriative defects...they
have hemorrhage and brightly eosinophilic fibrin exudation
on the site surface...which are not really tumor-necrosis ulcerations6]
True ulceration tends to be thick melanomas9.
is the patient young W or
could it be a cutaneous metastasis from a previous
melanoma (be sure to warn the pathologist if you previously had a melanoma)?
Predicting Metastatic Potential:
The various Clark levels, followed later by designations
of radial growth or vertical growth melanoma, are a staging attempt
to separate those which are highly unlikely (RGM & Clark
levels I & II) to metastasize from the rest of melanomas which are more likely to metastasize. The Breslow
thickness is thought to be a more reliable parameter, less subject
to inter-observer variation. Warning13: Dr.
Ackerman has collected a small group of cases of very thin melanomas
which metastasized; we have seen one which was daignosed as MIS turn up later with
brain mets [LMC-01-8112]...never guarantee
a melanoma patient of a complete cure! Once in a while, a pathologist gets pulled into a case to the point of being moved to express advice & encouragement that the patient undergo a maximum attempt to cure, based on all pathological factors [L05-517].
tumor ulceration seems related to "explosive" upward
intra-epidermal melanoma cell scattering (whereas, the epidermis
tends to bulge over non-ulcerated melanomas15).
In thin melanomas (1MM or less thick), the level of invasion
is more powerful prognostically than in thicker stage I-II
where presence of ulceration indicates a 50% 10 year survival
rate & without ulceration, a 78% survival rate.
what is the exact thickness (the Breslow
thickness3 is measured in millimeters
from the granular epidermal layer to the deepest point of
tumor penetration)...thinner B or thicker W?
A carefully interpreted marker stain such as MART-1 can help
discern vague deeper cells as well as "early" progression
of cells into the next deeper Clark level [S-01-9973;
S-01-9340]. There is greater inter-observer agreement
on thickness than on Clark level12.
|Thickness (clinical stage I)
||8-year survival rate10
||in-situ, noninvasive intraepidermal only (lentigo maligna);
MIS vs. early II can be problematic [S-03-16189]
||homogeneously widely spaced, small (<10 cells
wide) nests in papillary
dermis only...no deeper & no dominant nodule that looks "different"; MART1 may help discern microinvasion [S-01-9340]
||radial (but there are some thin, Clark II verticals, see below14)
||(a nodular is no less than
"look" because of expanding tumor plaque/nodule filling and expanding
papillary dermis; sometimes II-III problematic [S-01-13088;
LMC-01-4912; S-04-9050; L-05-1936];
sometimes III-IV problematic [S-02-433]
||active invasion of the reticular dermis15 (an IHC
melanoma marker may help to discern [S-01-9973])
||invasion of subcutaneous fat
is it radial growth phase (RGP/RGM) B or
vertical growth phase (VGP/VGM) W?
|Radial (tumorigenic) growth phase mel.
||Vertical (tumor) growth phase mel. (VGP/VGM)
cells single or small groups
a dermal nest is larger
than epidermal or DEJ
|dermal clusters smaller than epidermal clusters14
||one or more dermal clusters larger than the largest epidermal cluster14***, 17 or a dermal mitosis...either one17
|epidermal component tends pagetoid or
||at least one dermal nest looks different
than parent dermal nests
|dermal component profile horizontal
||at least one dermal nest >10 cells thick
(>25 cells thick
nearly diagnostic VGM)
|dermal and epidermal cytology similar9
||dermal & epidermal cytology variation;
especially if dermal atypia worse than epidermal9
|dermal mitoses usually absent
||usually dermal mitoses (any dermal melanocytic mitosis makes it
VGM14, 16***, 17 )
|even when heavy host response, it is usually not at tumor cells
||if host response, cells amongst and beneath tumor cells
|Clark level I-II
are Clark level III-V
Presence of this type of cluster and/or dermal mitosis...especially
presence of any dermal mitosis makes it VGP/VGM!!!
what is the mitotic
rate10, 11 (number of mitotic figures
per square millimeter of tumor tissue)...is it low B or
high W? In Clark's study of 23 variables,
6 were independently prognostic; and the mitotic rate was
the most powerful!
8-year survival if zero mitoses/mm2:
8-year survival if 0.1-6.0 mitoses/mm2:
8-year survival if >6.0 mitoses/mm2:
- What is the Schmoeckle & Braun-Falco prognostic
index10 (PI) (product of Breslow thickness
x mitotic rate)...low B or high W?
| 1.5-3.99 mm.
Host Vertical Growth (VGM) Tumor Infiltrating
Lymphocyte (TILs should surround & disrupt VGM cells15)
(1) if the lymphs are diffusely present throughout the
substance of the VGM component, or
(2) peripherally layered across the entire underneath of the VGM
||(1)one or more foci of diffuse intra-VGM, or
||no lymphocytic reaction at all, or
none infiltrates VGM15
Plasma cells: does the host inflammation contain plasma (plasmas) cells or
not (few) B? [yes (especially if clusters to sheetsW, 23
...34 of 710 melanomas23 ) is more likely to have gone to lymph nodes] 1
3-parameter likelihood for positive lymph nodes1
|upper extremity location + < 1mm + no plasmas
|>1 mm. + upper extremity with plasmas or
located elsewhere & no plasmas
|>1 mm. + elsewhere + plasmas
is there any visible venous or lymphatic embolic
lumenal tumor W or not B?
["yes" is awful2]
is there any visible perineural (neurotropism)
space invasion W or not B? If so, may be (strongly recommend consideration [L07-132],
NOTE HERE) a candidate for local control radiation.
are the surgical margins free of visible tumor B (did
the surgery seem to get all of the tumor out?) or positive W for
NODES: do sentinel or other regional nodes contain W metastatic cells or not B?
serum LDH repeatedly elevated (not just one time) is a stage independent prognostic factor for decreased survival15. serum albumin at or less than 3.5-4.0 is an independent prognostic factor for decreased survival in stage IV cases15.
- S100 is the most sensitive IHC marker7 (but it also marks nodal dendritic cells) while HMB-45 & MART-1 are more specific; HMB-45 can have
some IHC positive mononuclear cells in which the nuclei are discordantly non-melanomatous [LMC-01-6340]. Watch out for nodal nevi, present even in cases with melanoma
mets, in fibrous septae & capsule & with benign cytology & lacking nucleoli [L07-5254].
- if not, be sure to note whether the melanoma shows signs of regression6: papillary dermal deposition of loose, edematous collagen containing increased
numbers of melanophages & possibly ectatic vessels plus MAYBE some lichenoid vacuolar change in overlying basal keratinocytes8.
- it is the number of positive nodes (met = 0.2 mm or larger tumor cell cluster) and the percentage of the node occupied by the met (not the size of the met) that is better
or worse15. Therefore, watch out for nodal nevi, present even in cases with melanoma mets, in fibrous septae & capsule & with benign cytology
& lacking nucleoli [L07-5254]. Node capsule nevi have a very low Ki67 proliferation of around 1% & are HMB45 negative, while both melanoma, nevus cells,
& nodal dendritic cells are S100 positive, and nodal nevi & melanoma are MART-1 positive18.
REFERENCES: [melanoma diagnostic criteria] [skin diseases index]
- The American J. of Dermatopathology, A. B. Ackerman, editor,
6(supplement):1-352, 1984 [EBS's office]
- A Trial in Philadelphia, a combined reprint, A. B. Ackerman
(compiler), Dermatopathology: Practical & Conceptual, 6(3):236-250,
2000; 7(1):21-27, 2001; 7(2):165-170, 2001. [EBS's office]
- Principles & Practice of Surg. Path. and Cytology, [3 vol.
text] Silverberg, SC, 3rd Ed. 1997.
- Prognostic factors for Cutaneous Melanoma [editorial], Wick,
Mark R., AJCP, 110:713-717, 1998.
- Prognostic Value of Tumor Infiltrating Lymphocytes in the Vertical
Growth Phase of Primary Cutaneous Melanoma, Clemente, Mihm, et.
al., Cancer 77:1303-10, 1996.
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15 Aug. 2001 [EBS's office], Final Version of the American Joint
Committee on Cancer Staging System for Cutaneous Melanoma.
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October 2001, Malignant Melanoma, an Update.
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- Ackerman AB, 9th Annual (Pittsburgh) Seminar in Pathology,
4 May 2002.
- Relevance of Vertical Growth Pattern in Thin Level II Cutaneous
Superficial Spreading Melanomas, Lefevre M et. al., A. J. Surg.
Path. 27(6):717-724, 2003 (an excellent case-controlled study
in search of features predictive of relatively poor prognosis
in thin melanomas). Abstract also in CAP Today October 2003,
- Compton CC, et. al., Protocol for the Examination of Specimens
from Patients With Malignant Melanoma of the Skin, Arch. Path. & Lab.
Med. 127(10):1253-1262, Oct. 2003.
- McKee, Calonje, & Granter, Pathology of The Skin...
- Kruper LL, Spitz FR, Czerniecki BJ, Fraker DL, Blackwood-Chirchir A, Ming ME, Elder DE, Elenitsas R, Guerry D, Gimotty PA, "Predicting sentinel node status in AJCC stage
I/II primary cutaneous melanoma" Cancer 107(10):2436-45, 15 November 2006.
- Biddle DA, et. al., AJSP 27(5):676, 2003.
- Gimotty PA & Gerry D, "Prognostication in Thin Cutaneous Melanoma", Arch Path & Lab Med 134(12):1758-1763, Dec. 2010 (a special issue on Melanoma Update).
- Melanoma Molecular Map Project website HERE.
- Riber-Hansen R, et. al., Automated digital volume measurement of melanoma metastases in sentinel nodes predicts disease recurrence and survival, Histopathology, 59(3): 433–440, September 2011.
- Holt JB, et. al., "Nodal Melanocytic Nevi in Sentinel Lymph Nodes
Correlation With Melanoma-Associated Cutaneous Nevi", AJCP 121:58-63, 2004.
- Medscape, about plasma cells & melanoma, June 2016, HERE, via Modern Pathology 29(4):347-358, 2016.
(posted 9 February 2002; latest addition 17 June 2016)