Amino [13]-macrodilactones: Synthesis, derivatization, and structural motifs

Article abstract of DOI:10.1016/j.tetlet.2020.152579

Macrocycles draw their usefulness from an ability to balance size, shape, and functionality according to general principles. These structural parameters manifest as the conformations of macrocycles and ultimately their functions. Reported here are results of an investigation on [13]-macrodilactones that take up unique folded conformations based on the interplay of multi-atom planar units and sterics. The defining feature of this group of [13]-macrodilactones is the pendant amine group attached to the ring. Amidation of the ring generated analogs that were designed to imitate features of the macrocyclic natural product Teixobactin. We also show that intramolecular interactions, and the A-value of an acylated amine can explain the conformational preferences in macrocycles.

Full text of DOI:10.1016/j.tetlet.2020.152579

See related Commentary on page v
Increasing Incidence of Lentigo Maligna Melanoma Subtypes:
Northern California and National Trends 1990–2000
Ã
Susan M. Swetter, w Jennifer C. Boldrick,w Sandy Y. Jung,w Barbara M. Egbert,wz and Jeff D. Harvell,y1
Ã
Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA; wDepartment of Dermatology, Stanford University Medical
Center, Stanford, California, USA; zPathology Services, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA; yDepartment of Pathology,
Stanford University Medical Center, Stanford, California, USA
Worldwide, lentigo maligna melanoma (LMM) comprises 4%–15% of cutaneous melanoma and occurs less com-
monly than superficial spreading or nodular subtypes. We assessed the incidence of melanoma subtypes in
regional and national Surveillance, Epidemiology, and End Results (SEER) cancer registry data from 1990 to 2000.
Because 30%–50% of SEER data were not classified by histogenetic type, we compared the observed SEER trends
with an age-matched population of 1024 cases from Stanford University Medical Center (SUMC) (1995–2000). SEER
data revealed lentigo maligna (LM) as the most prevalent in situ subtype (79%–83%), and that LMM has been
increasing at a higher rate compared with other subtypes and to all invasive melanoma combined for patients aged
45–64 and X65 y. The SUMC data demonstrated LM and LMM as the only subtypes increasing in incidence over the
study period. In both groups, LM comprised X75% of in situ melanoma and LMM X27% of invasive melanoma in
men 65 y and older. Regional and national SEER data suggest an increasing incidence of LM and LMM, particularly
in men Xage 65. An increased incidence of LM subtypes should direct melanoma screening to heavily sun-exposed
sites, where these subtypes predominate.
Key words: epidemiology/histopathology/incidence/melanoma
J Invest Dermatol 125: 685–691, 2005
Separation of cutaneous melanoma into distinct ‘‘histo-
genetic’’ subtypes was first proposed by Clark et al in the
1960s, and resulted in the classification of melanoma into
four main subtypes: superficial spreading melanoma (SSM),
nodular melanoma (NM), lentigo maligna (LM) melanoma
(LMM), and acral lentiginous melanoma (ALM) (Clark et al,
1969; Arrington et al, 1977; Coleman et al, 1980). World-
wide, the superficial spreading subtype predominates, fol-
lowed by nodular, LM, and acral lentiginous subtypes
(Elwood et al, 1987; English et al, 1987; Castel et al, 1990;
Vazquez-Botet et al, 1990; Carmichael et al, 1992; Jelfs
et al, 1994; Oumeish, 1997; Jones et al, 1999). Exceptions,
however, have occurred in Asian countries where most
cases were of the acral lentiginous subtype (Kuno et al,
1996; Chen et al, 1999; Ishihara et al, 2001), and in some
reported series of head and neck cases, in which LM and
LMM have shown a higher incidence, but remained less
common than superficial spreading and nodular growth
patterns (Ringbord et al, 1993; Cox et al, 1996).
Prior studies have shown an increased age-specific in-
cidence of both LM and LMM (Little et al, 1980; Newell et al,
1988; Jones et al, 1999), although the LM subtype (whether
in situ or invasive) is still recognized as comprising only a
small percentage of cutaneous melanoma (Little et al, 1980;
Langley et al, 1998). Based on analysis of the Swedish
Cancer Registry from 1961 to 1998 (Hemminki et al, 2003),
LM was reported as the most common in situ histogenetic
type, occurring almost three times more frequently than
SSM. In a regional analysis of incidence trends from 1976 to
˚
1994 in the Stockholm–Gotland area (Mansson-Brame et al,
2002), however, SSM far outnumbered LMM for invasive
cases, although LMM incidence increased significantly in
both men and women. Recent characterization of the Unit-
ed States Surveillance, Epidemiology, and End Results (SE-
ER) cancer registry of the National Cancer Institute (NCI) for
incidence of in situ and invasive melanoma subtypes has
not been reported. Furthermore, confirmation of trends re-
ported in the regional/national SEER data has not been un-
dertaken at the local level where complete and precise
reporting of melanoma subtype may be more feasible (Hall
et al, 2003).
We assessed melanoma subtype incidence according to
the four main histogenetic types in national and northern
California SEER data from 1990 to 2000, and compared it
with an age-matched population at Stanford University
Medical Center (SUMC). We believe that LM/LMM subtypes
account for a larger proportion of in situ and invasive me-
lanoma than reported previously.
Abbreviations: ALM, acral lentiginous melanoma; APC, annual
percentage change; LM, lentigo maligna; LMM, lentigo maligna
melanoma; MM, millimeters; NCI, National Cancer Institute; NM,
nodular melanoma; SEER, Surveillance, Epidemiology, and End
Results; SSM, superficial spreading melanoma; SUMC, Stanford
University Medical Center; UV, ultraviolet
Presented in part at the Society of Investigative Dermatology
63rd Annual Meeting, May 2002, Los Angeles, CA.
1Present address: Bethesda Dermatopathology Laboratory,
1730 Elton Road, Ste. 11, Silver Spring, Maryland 20903, USA.
Copyright r 2005 by The Society for Investigative Dermatology, Inc.
685

686 SWETTER ET AL
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Results
The proportion of LM compared with all subtyped cases
increased from 41% in 1995 to 61% in 2000, and LMM
increased from 10% to 16% over the same period. All other
subtypes (in situ and invasive) decreased over the same
time period.
SEER data analysis Analysis of the SEER melanoma in-
cidence data for subtyped tumors diagnosed from 1990
through 2000 revealed significant, previously unreported
trends for both LM and LMM. Over this 10-y period, LM
comprised 83% of all subtyped in situ melanoma, and LMM
accounted for 12% of all subtyped invasive melanoma in
the northern California region. Nationwide results were sim-
ilar, with LM comprising 79% and LMM 12% of subtyped
tumors (Table I). Notably, the incidence of the LM/LMM
subtypes increased nearly every year during this time pe-
riod: 73% of all subtyped in situ melanomas were classified
as LM in 1990 compared with 81% in 2000. Similarly, 8.4%
of all subtyped invasive melanomas were classified as LMM
in 1990 compared with 14% in 2000. These trends were
most prominent in older males. For men aged 65 y or
greater, the incidence of LMM increased from 20% in 1990
to 27% in 2000, when compared with all subtyped invasive
tumors.
In both men and women aged 45–64, diagnosis of LM
(compared with all melanoma) increased by 52% between
1990 and 2000 (actual rate increase 3.8–5.8 per 100,000),
with an increase of 96% for individuals X65 y at the time of
diagnosis (actual increase 12.1–23.7 per 100,000) (Table II).
Both these trends were significant at p-values of less than
0.05, with annual percentage changes (APC) of 3.9 and 6.8,
respectively (Table II). In comparison, SSM in situ showed a
smaller, but significantly increased APC (3.7) only in the 65 y
and older age group.
Comparison of regional and national data Melanoma
subtype data from SUMC were compared with the NCI
SEER cancer registry for comparable years of diagnosis
and age range (Table IV). Males comprised 56% of patients
in the SEER data and 57% of SUMC cases, and gender
similarities were maintained when the SEER data was ex-
amined according to region, comparing the San Francisco–
Oakland, CA registry with the other national registry sites.
The SEER patient population was predominantly diagnosed
with invasive tumors (63% in California and 69% in non-
California sites), as was 58% of the SUMC population. The
anatomic site of melanoma was also consistent between
the California and non-California SEER sites and the SUMC
data, with SEER data revealing 68% of LM and 64% of
LMM located on the head or neck.
Our analysis of melanoma subtypes in the SEER data
revealed that the LM/LMM subtypes were diagnosed at a
higher incidence than previously reported, and that this in-
crease was most notable in the older male segment of the
population. Although the size of the patient population in our
regional data from SUMC was too small to perform trend
analysis, we were able to observe the incidence of LM/LMM
subtypes over the entire time period and in specific sub-
groups.
During this time period, the incidence of LMM also in-
creased significantly. LMM incidence increased by 88%
(0.8–1.5 per 100,000) in the 45–64 y old age group (APC 6.0,
po0.05) and by 105% (3.9–8.0 per 100,000) in the X65 y
old group (APC 5.5, po0.05). In comparison, the incidence
of all invasive melanoma during this time period increased
by only 21% (24.5–29.7 per 100,000) for the 45–64 y age
group (APC 2.3, p40.05) and by 53% (38–58 per 100,000)
for the ꢀ 65 y age group (APC 4.2, po0.05). Incidence
trends for invasive SSM, NM, and ALM over the decade are
listed in Table II. Significant, but smaller increases in APC
values were noted only for SSM (3.7) and NM (2.8) in the 65
y and older age group. As the trends were independently
significant using the same incidence data and standardiza-
tion, the higher APC for LMM represented a true difference
between the subtypes over the time period.
The proportion of LM in men aged 65 y or older, com-
pared with all subtyped in situ melanomas, was 91% in the
SEER data and 75% in the SUMC data (Table IV). Similarly,
LMM occurred in 27% of men in this age group in the SEER
data and 30% in the SUMC data, when compared with all
subtyped invasive melanomas. Among subtyped in situ
melanoma in men aged 45–64 y, LM comprised 79% and
49% in the SEER and SUMC data, respectively, and of
subtyped invasive tumors, LMM accounted for 11% and
10% (SEER and SUMC, respectively).
Discussion
In the late 1960s, Clark et al initially proposed three main
variants of melanoma (SSM, LMM, and NM), which were
believed to demonstrate distinct clinical, histopathological,
and biological features (Clark et al, 1969). ALM was added
as a fourth major clinicopathologic type in the 1970s (Ar-
rington et al, 1977; Coleman et al, 1980). Molecular analysis
has demonstrated different patterns of cell death, oncogene
expression (Miracco et al, 1998), gene amplification (Bastian
et al, 2000), and BRAF mutation frequency (Sasaki et al,
2004) among the four main subtypes. But, the practice of
subtyping cutaneous melanoma has been criticized over
whether distinction among subtypes is based on anatomic
site alone, or whether melanoma subtype affects overall
prognosis (Ackerman, 1980, 2000; Ackerman and David,
1986). Likewise, the lack of uniformly agreed upon histo-
logic criteria for classification of the four major types has
resulted in moderate to significant interobserver variability in
SUMC data analysis The SUMC population consisted of
1024 primary cutaneous melanomas classified into the four
main histogenetic subtypes (Table III). Forty-eight additional
melanoma variants were identified including 18 desmoplas-
tic, 19 spindle cell type, three minimal deviation, three ne-
void, four Spitzoid, and one small cell variant. In addition, 34
in situ and 48 invasive tumors (8% of total cases) could not
be subtyped. Fifty-two percent (220 of 420) of in situ cases
were LM, and 11% (67 of 604) of invasive melanomas were
LMM, which represented a greater proportion than NM
(5%). The median age at diagnosis in the SUMC population
was 54 (range 17–99), with LM and LMM occurring mainly in
older patients (median ages 69 and 71, respectively), and on
heavily sun-exposed sites (85% of LM and 77% of LMM).

125 : 4 OCTOBER 2005
INCREASING INCIDENCE LENTIGO MALIGNA SUBTYPES 687
Table I. National Cancer Institute SEER program registry data regarding melanoma subtype incidence by region, 1990–2000,
patient age range 20–99 y
San Francisco–Oakland
Non-Californiaa
Combined data including NOS/other casesb
In situ subtypes
Lentigo maligna in situ (%)
Superficial spreading melanoma
Nodular melanoma
1598 (83)c
304 (16)
0 (0)
7436 (79)c
1937 (20)
4 (0.04)
9034 (43)
2241 (11)
4 (0.02)
Acral lentiginous melanoma
Total in situ tumors
17 (1)
90 (1)
107 (5)
1919 (37)d
9467 (31)d
11386 (54)
Invasive subtypes
Lentigo maligna melanomac
393 (12)c
2308 (72)
2634 (12)c
15367 (72)
3027 (7)
17675 (39)
Superficial spreading melanoma
Nodular melanoma
435 (14)
72 (2)
2883 (14)
393 (2)
3318 (8)
465 (1)
Acral lentiginous melanoma
Total invasive tumors
3208 (63)d
21277 (69)d
24485 (55)
aNon-California regions include Hawaii; Utah; Connecticut; Detroit, Michigan; Iowa; New Mexico; Seattle-Puget Sound, Washington; and Atlanta,
Georgia.
bPercentage calculated as total subtyped in situ or invasive tumors divided by total in situ or invasive tumors, including subtyped, unsubtyped (NOS),
and subtypes not included in the four major categories (Other). Other subtypes (desmoplastic, spindle cell, amelanotic, Spitzoid, etc.) accounted for
o5% of the total cases.
cNumber displayed represents the total subtyped cases within study group as described in Material and Methods. Percentage calculated as individual
subtype divided by total subtyped cases of in situ or invasive melanoma and displayed in parentheses.
dPercentage calculated as total subtyped in situ or invasive tumors per northern California or non-California SEER regions divided by total subtyped
cases per region(s) and displayed in parentheses.
SEER, Surveillance, Epidemiology, and End Results; NOS, not otherwise specified.
subtyping in some studies (Heenan et al, 1984; Krieger et al,
1994; Corona et al, 1996).
Cohen, 1995). Two distinct categories have been proposed
based on this division: (1) the term ‘‘LM’’ for the melanoma
precursor in the setting of atypical melanocytic hyperplasia
alone and (2) the term ‘‘melanoma in situ, LM type’’ repre-
senting the true in situ melanoma defined by melanocytic
hyperplasia, pagetoid spread, confluence of melanocytes
replacing the basilar region, uniformity of cytological atypia,
and nesting of uniformly atypical melanocytes (Flotte and
Mihm, 1999; Tannous et al, 2000). Slow progression from
the precursor lesion to obvious melanoma in situ may ex-
plain this dichotomy. We were careful to include only cases
definitively diagnosed as melanoma in situ, LM type and to
exclude cases of junctional atypical melanocytic hyperpl-
asia, even when ‘‘early LM’’ was suggested by the der-
matopathologist.
Most of the worldwide melanoma subtype incidence da-
ta do not distinguish between in situ and invasive cutaneous
melanoma. Globally, LM/LMM is estimated to account for
4%–15% of all melanomas, and 10%–26% of all head and
neck melanomas (McGovern, 1970; Donnellan et al, 1972;
Little et al, 1980; McGovern et al, 1980; Popescu et al, 1985;
Langford et al, 1993; Ringbord et al, 1993). In their study of
invasive melanoma incidence in New Zealand, Jones et al
(1999) reported increased age-specific rates for LMM and
NM, most notably after age 70 y, with SSM showing de-
creased incidence after this age. In this analysis, though,
SSM far outnumbered NM and LMM cases overall, with an
age-specific annual rate of 36.3 of 100,000 compared with
2.8 of 100,000 for NM and 2.4 of 100,000 for LMM. In the
US, the best evidence for an increased incidence of LM
is based on unpublished 1995 data from a large private
Worldwide melanoma data have also shown conflicting
results in terms of the impact of subtype on prognosis, and
most multivariate analyses have shown that histogenetic
type is not an independent prognostic variable for survival
after controlling for tumor thickness (Ringbord et al, 1993;
Cox et al, 1996; Kuno et al, 1996). Major exceptions have,
however, arisen in the settings of ALM and LMM (Urist et al,
1984; O’Brien et al, 1991; Kuchelmeister et al, 2000).
LMM differs markedly from SSM and NM in that it has no
nevus precursor, is linked to cumulative, rather than inter-
mittent sun exposure, occurs in older individuals, and has a
significantly longer period of intraepidermal growth com-
pared with SSM (Clark and Mihm, 1969; Clark et al, 1975;
McGovern et al, 1980; Sagebiel, 1996). Long-term ultravi-
olet (UV) radiation exposure is believed to be the most im-
portant risk factor for the development of LM/LMM (Holman
et al, 1983; Holman and Armstrong, 1984; Elwood et al,
1987). In some series, LMM has been associated with im-
proved prognosis compared with SSM and NM (Urist et al,
1984; O’Brien et al, 1991), whereas other studies have
shown no significant difference in disease-free or overall
survival compared with other histologic subtypes, when
matched for tumor thickness (Koh et al, 1984; Langford
et al, 1993; Cox et al, 1996).
Further controversy has arisen in the setting of the LM
subtype itself. Whereas some authors have considered LM
as only a precursor to melanoma (Clark and Mihm, 1969;
Barnhill and Mihm, 1993), whereas, others have classified
LM as a true melanoma in situ (Dubow and Ackerman, 1990;

688 SWETTER ET AL
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Table II. National Cancer Institute SEER program registry data,
rate of melanoma incidence, 1990–2000, patient age range
20–99 y
Furthermore, this publication highlighted the potential
bias in interpreting subtype incidence because of the large
proportion of melanoma not classified according to histo-
logic subtype in the SEER registry, which accounted for
452% of cases analyzed in both men and women. But,
no differences were apparent when age-specific incidence
curves for the unclassified melanoma cases were compared
with those of the classified melanomas according to an-
atomic site. The authors concluded that the similarity of the
curves provided reassurance that patients with classifiable
melanoma were likely representative of the non-classifiable
cases, at least for the major variables of age and gender.
Incomplete subtype data are an unavoidable limitation of
the SEER registry, and as with other reports of melanoma
subtypes (Newell et al, 1988; Carmichael et al, 1992; Ring-
borg et al, 1993), we can only draw conclusions from the
subtyped cases. There are clearly a small percentage of
melanomas in any dermatopathology practice that cannot
be accurately classified into a specific histogenetic type.
This factor certainly contributes to the large percentage of
unclassified melanomas in the SEER data (30%–50% per y)
along with other probable factors, e.g., non-dermatopa-
thologist interpretation of cutaneous melanoma, lack of be-
lief in the concept of melanoma subtyping, or failure to
report the subtype data at the local registry level. The ad-
vantage of using our hospital-based analysis to confirm the
trends in the SEER data lies in greater precision in reporting
of histologic subtype (only 8% SUMC melanoma unclassi-
fied) as well as more complete reporting of both in situ and
invasive melanoma.
Hospital-based reporting to the SEER registries has gen-
erally shown a high case ascertainment rate (497%), al-
though this rate may be much lower for melanoma (Koh
et al, 1992; Zippin et al, 1995; Merlino et al, 1997). Under-
reporting of melanoma may be related to treatment admin-
istered in outpatient, non-hospital settings, particularly for
early-stage, localized disease (Koh et al, 1992). The most
accurate calculation of national incidence rates of me-
lanoma would combine SEER data and information from
additional state cancer registries. Recent analysis compar-
ing melanoma incidence rates between SEER registries and
National Program of Cancer Registries (NPCR) has sug-
gested increased case ascertainment and reporting in the
NPCR registries, which provide information for cancer con-
trol at the local level (Hall et al, 2003). Likewise, calculation
of SEER incidence rates tends to include only invasive me-
lanoma (Hall et al, 1999) without specific attention to trends
in the more common in situ cases.
Age
group
Actual rate
changea
Confidence
APCb interval of APC
Lentigo maligna
In situ
20–44
45–64
X65
0.4–0.5
3.8–5.8
12.1–23.7
0.1–0.1
0.8–1.5
3.9–8.0
2.0
3.9c
6.8c
ꢁ0.4
6.0c
5.5c
ꢁ0.6–4.6
1.7–6.2
5–8.7
Invasive
20–44
45–64
X65
ꢁ5.7–5.2
2.7–9.3
3.4–7.5
All melanoma
In situ
20–44
45–64
X65
2.9–5.1
8.3–18.7
17.4–43.9
11.7–11.8
24.5–29.7
38–58
6.6c
8.7c
9.8c
0.5
5.3–7.9
7.3–10.1
8.8–10.8
ꢁ0.4–1.5
1.3–3.2
Invasive
20–44
45–64
X65
2.3c
4.2c
ꢁ0.6
0.7
3.4–5.0
SSM (invasive)
NM (invasive)
ALM (invasive)
20–44
45–64
X65
6.0–5.7
11.3–12
11.2–17
1.0–0.6
1.8–1.8
4.4–4.7
0.0–0.1
0.2–0.2
1.1–0.8
ꢁ1.5–0.3
ꢁ0.6–2.0
2.4–5.2
3.7c
ꢁ4.2c
ꢁ0.2
2.8c
8
20–44
45–64
X65
ꢁ6.2 to ꢁ2.3
ꢁ2.9–2.6
0.3–5.3
20–44
45–64
X65
ꢁ3.8–21.3
ꢁ3.2–9.7
ꢁ5.9–4.2
3.1
ꢁ0.1
aActual change of incidence rate per 100,000 persons.
bThe annual percentage change was calculated by fitting a least
squares regression line to the natural logarithm of the rates.
cTrend is statistically significant with a p-valueo0.05.
SEER, Surveillance, Epidemiology, and End Results; APC, annual per-
centage change; SSM, superficial spreading melanoma; NM, nodular
melanoma; ALM, acral lentiginous melanoma.
dermatopathology laboratory in which 54% of in situ me-
lanomas were reported to be of the LM subtype (Cohen,
1999).
To our knowledge, there has been no recent character-
ization of SEER data regarding incidence of invasive and
in situ melanoma according to histogenetic subtype. Newell
et al (1988) reported histological subtype incidence rates for
SSM, NM, and LMM based on 1973–1981 SEER data and
according to four anatomic sites (face, trunk, arm/shoulder,
and leg/hip). Not surprisingly, analysis of over 1300 cuta-
neous melanomas revealed that age-specific incidence for
melanoma of the face steadily increased with age, with
LMM rates being higher in SEER geographic locations with
higher UV indices and SSM rates being higher in areas with
lower UV indices. When all anatomic and geographic loca-
tions were combined, however, SSM remained the subtype
with the highest incidence, although the incidence of LMM
and NM was similar in both males and females.
Underreporting of cutaneous melanoma to the SEER
registry in northern California was reported to increase from
4% in 1973 to 16% in 1985 (Seiffert, 1992) with larger num-
bers of in situ cases missed, as they were more likely to be
diagnosed and treated solely in private physicians’ offices.
This issue is particularly relevant given the prevalence and
availability of Mohs surgery in northern California for treat-
ment of LM, where similarly, these melanomas in situ may
not be evaluated by a hospital-based pathology service,
and thus may not reported to the regional SEER registry.
The increased incidence of LM and LMM in the regional
and national SEER data from 1990 through 2000 was con-
firmed in the hospital-based SUMC analysis. But, there

125 : 4 OCTOBER 2005
INCREASING INCIDENCE LENTIGO MALIGNA SUBTYPES 689
Table III. Stanford University Medical Center melanoma subtype data, 1995–2000
In situ subtypes
Number (%)a
Median age (range)
Predominant site (%)
Gender
Lentigo maligna (in situ)
220 (52)
Superficial spreading melanoma in situ
Acral lentiginous melanoma in situ
196 (47)
4 (1)
69 (25–94)
51 (24–99)
Trunk (48)
67 (39–78)
Foot (100)
Head/Neck (69)
Male
140
80
95
2
2
Female
101
Lentigo maligna
melanoma
Superficial spreading
melanoma
Nodular
melanoma
Acral lentiginous
melanoma
Invasive subtypes
Number (%)a
67 (11)
490 (81)
29 (5)
18 (3)
Median age (range)
Median breslow depth (range)b
Predominant site (%)
Gender
71 (36–96)
48 (17–96)
0.55 (0.1–10)
Trunk (50)
58 (25–81)
3.0 (1.0–16)
Trunk (35)
63 (19–84)
2.0 (0.3–9.0)
Foot (72)
0.52 (0.16–5.0)
Head/Neck (66)
Male
48
19
273
217
18
11
9
9
Female
aPercentage calculated as individual subtype divided by the total cases of in situ or invasive melanoma. Median age and range are displayed in y.
bBreslow depth is displayed in millimeters (mm).
were slightly more invasive tumors diagnosed in the SEER
population compared with SUMC. This may be related to
improved health care access or closer follow-up within the
SUMC population compared with sites participating in the
SEER registry, but is more likely because of underreporting
of in situ tumors in the SEER database. Despite the smaller
number of SUMC cases, the Stanford data accurately re-
flect current US melanoma incidence trends (Geller et al,
2002), and both datasets revealed notably similar LM/LMM
incidence in the cohort of middle-aged and older men.
Analysis of the trends of melanoma incidence in the SE-
ER data revealed that age-adjusted rates of both LM and
LMM significantly increased from 1990 to 2000 in people
aged 45–64 y and those 65 y and older. For both age
groups, the LMM incidence rate demonstrated a higher an-
nual percent change than individual SSM, NM, and ALM
subtypes and in comparison with all invasive melanoma
combined. The reported dramatic rise in melanoma inci-
dence over the past three decades does not appear to be
simply a result of increased surveillance and early detection
of thin tumors, but seems to represent a true increase in
melanoma rates, in part because of changes in lifestyle that
have led to increased UV exposure (Armstrong, 1988; Bur-
ton and Armstrong, 1988; Rigel, 1997; Dennis, 1999). This is
especially relevant for the LM and LMM subtypes that typ-
ically arise on chronically sun-damaged skin. A true in-
crease in the proportion of LMM compared with all invasive
melanomas, however, may have a favorable effect on me-
lanoma mortality rates as LMM tends to be thinner at the
time of diagnosis than other histogenetic patterns (nodular
and desmoplastic) and may be associated with reduced risk
of metastasis compared with other subtypes (Urist et al,
1984; O’Brien et al, 1991).
Table IV. General characteristics and proportion of LM and
LMM subtypes in the SEER and SUMC patient populations
SEER
SUMC
Median age, all cases (range)
60 (20–99)
54 (17–99)
Percentage in each age group (number) (y)
20–44
23 (8326)
29 (292)
37 (376)
34 (347)
57 (585)
43 (439)
45–64
35 (12465)
42 (15080)
56 (20054)
44 (15817)
X65
Percentage male (number)
Percentage female (number)
Proportion of LM in malesa (y, %)
45–64
79
91
49
75
X65
Proportion of LMM in males (y, %)
45–64
11
27
10
30
Although opinions vary as to whether subtyping me-
lanoma into distinct morphologic growth patterns is valid
(Weyers et al, 1999) or has prognostic import, there is no
question that early detection of thinner melanomas leads to
improved prognosis (Clark et al, 1989; Balch et al, 2001).
Our northern California hospital-based data show increased
incidence for both LM and LMM over the study period and
X65
aThe number of tumors identified as LM or LMM was divided by the
total number of in situ or invasive subtyped tumors within the specified
age group and expressed as a percentage.
SEER, Surveillance, Epidemiology, and End Results; LM, lentigo
maligna; LMM, lentigo maligna melanoma; SUMC, Stanford University
Medical Center.

690 SWETTER ET AL
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
above, with the exception that ‘‘all melanomas’’ were selected for
comparison with LM/LMM and other subtypes using the ICD-O
codes 8720–8790, which included tumors designated ‘‘Melanoma,
NOS’’ in addition to those specified as a particular subtype.
Following Human Subjects approval at SUMC, a retrospective
review of the Stanford Department of Pathology dermatopathology
database was conducted from January 1995 through June 2000.
Archived SUMC data regarding melanoma subtype and individual
histology slides were not accessible before January 1995. Infor-
mation regarding melanoma subtype (SSM, NM, LMM, ALM) for
both in situ and invasive cutaneous melanomas was obtained
along with Breslow depth, patient age at the time of diagnosis,
melanoma location, and gender. Chronically sun-exposed anatom-
ic sites were defined as the head, neck, arms, and shoulders.
Histopathological diagnosis of melanoma subtype was made
by one of three dermatopathologists at SUMC over the 5-y period
using established histologic criteria (Elder and Murphy, 1991).
Cases of mucosal melanoma and other rare melanoma variants,
i.e., malignant blue nevus, melanoma arising from large congenital
nevi, melanoma of the soft parts, and metastatic melanoma, were
excluded as were cases in which primary cutaneous melanoma
was diagnosed synchronously with widespread metastasis. The
number of desmoplastic, spindle cell, Spitzoid, minimal deviation,
and nevoid melanoma cases was noted at each institution, but not
further analyzed.
correlate with the 1990–2000 SEER data. Health care pro-
viders should be alerted to the need for routine examination
of chronically sun-exposed skin in older, fair-complexioned
individuals for detection of LM, now the most common
in situ melanoma subtype in middle-aged and older men in
the US, and for its invasive counterpart, LMM. As a pro-
gressively larger proportion of the US population ages, the
incidence of these melanoma subtypes may continue to
rise. Ultimately, LM and LMM must receive greater public
and health care attention.
Materials and Methods
Permission was granted by the Surveillance Research Program of
the NCI to obtain incident cases of melanoma from the SEER Da-
Ã
tabase (www.seer.cancer.gov) (SEER Stat database, 2003). Data
were obtained from the nine regions included in the SEER data-
base, including: San Francisco–Oakland, California; Hawaii; Utah;
Connecticut; Detroit, Michigan; Iowa; New Mexico; Seattle-Puget
Sound, Washington; and Atlanta, Georgia. Stanford reported reg-
istry information to the Northern California Cancer Center, which is
responsible for the Greater Bay Area Cancer Registry and provides
information to the NCI SEER program. Registry information from
Stanford was incorporated into the San Francisco–Oakland region
in the SEER database.
DOI: 10.1111/j.0022-202X.2005.23852.x
SEER data were compiled for those patients diagnosed from
1990 through 2000, and from ages 20 to 99 y. Individuals of all
races and both genders were included with in situ or invasive me-
lanoma of the skin [International Classification of Diseases for
Oncology (ICD-O) morphology codes 8721 (NM), 8742 (LMM),
8743 (SSM), and 8744 (ALM), and topography codes C44.0
through C44.9]. For comparison with SUMC data, cases with
widely metastatic disease on presentation and those with non-
cutaneous primary tumors (i.e., ocular, mucosal) were excluded, as
were unclassified cases of ‘‘melanoma, histology not otherwise
specified’’ (NOS). A total of 35,871 cases fulfilled the inclusion cri-
teria.
Manuscript received August 10, 2004; revised May 6, 2005; accepted
for publication May 14, 2005
Address correspondence to: Susan M. Swetter, MD, Department of
Dermatology, Stanford University Medical Center, 900 Blake Wilbur
Drive, W0069, Stanford, California 94305, USA. Email: sswetter@
stanford.edu
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