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The spectrum of minimal deviation melanoma: A clinicopathologic study of 21 cases
Original Contributions The Spectrum of Minimal Deviation Melanoma: A Clinicopathologic
Study of 21 C a s e s
MILDRED E. PHILLIPS, ME),* RANDALL J. MARGOLIS, MD, t YVES MEROT, MD: ARTHUR J. SOBER, MD, wRICHARD J. REED, ME),# JAN E. MUHLBAUER, MD,82 AND MARTIN C. MIHM, JR, MD t A retrospective study of 21 patients with the histopathologic diagnosis of minimal deviation melanoma (MDM; n = 18) and borderline melanoma (BM; n = 3) was undertaken to determine the prognosis for these patients compared with that for patients with other types of malignant melanoma. The findings indicate that the prognosis for these uncommon nevomelanocytic tumors is somewhat better than that for other malignant melanomas. Follow-up periods in this series ranged from 18 to 96 months (mean, 57 months). Primary lesions ranged in tlfickness from 1.6 to 10.4 mm. The histopathologic subtypes included the Spitz variant (nine patients), the spindle cell variant (six patients), the combined spindle and epithelioid cell type (three patients), and the small epithelioid cell type (three patients). Only t~'o of the patients died of widespread metastatic disease. Comparison of the histologic and clinical prognostic indicators of mortality in patients who have malignant melanoma with the clinical and pathologic features seen in this series of 21 patients would appear to indicate a diminished tendency toward metastatic or recurrent disease in patients with MDM and BM. HUM PATIIOL17: 796-806, 1986.
An u n c o m l n o n n e v o m e l a n o c y t i c t u m o r , the minimal deviation melanoma (MDM), has been purported to have a less assauhive clinical course than o t h e r m o r e c o m m o n t y p e s o f m a l i g n a n t inelan o m a ) -~ T h e MDM is characterized histologically by expansile growth of uniformly atypical nevomelanocytes, with e x t e n s i o n into the r e t i c u l a r d e r m i s (Clark's level IV). The borderline melanoma (BM) exhibits similar vertical growth characteristics but is confined vertically to a widened papillary dermis (Clark's level III). In either case, the vertical growth phase has cytologic atypia (lfistologic variance) less pronounced than that observed in tile other malignant melanomas. Clinical inspection reveals both pigmented and nonpigmented lesions, which are commonly diagnosed as Spitz nevi, llemangiomas, or malignant melanomas. A retrospective stud)' examining the outcome of patients with BM and MDM has sug-
gested tlmt these lesions are less virltlent than other more commonly seen melanomas. ~ Using this same patient population, we undertook tile current study to propose a tnore definitive classification of the subtypes of MDM, as well as to contrast tile clinical outlook for these lesions with that for other types of malignant melanoma. MATERIALSAND METHODS
The tissue sections and clinical information for tiffs series of cases were obtained from the private constthation files of one of tile authors (M.C.M.) and the pathology files of tile Massachusetts General Hospital. The initial biopsies were performed during tile period fronl 1973 to 1978. All lesions in this series were more than 1.6 mm thick (Breslow measurement). For tile current report, tire slides were again reviewed i n d e p e n d e n t l y by three of the authors (M.E.P., M.C.M., and R.J.M.). Follow-up periods, with data obtained by physical examination or telephone call, for 21 patients (10 males, 11 females), ranged fi'om 18 to 96 months (mean, 57 months) througll the middle of 1983. RESULTS
Received from the *Department of Pathology, State Universit)' of New York, Stony Brook, New York; tThe Dermatology Unit, Massachusens General Hospital and Harvard Medical School, Boston, Massachusens; the ~Clinique de Dermatologie, tt6pital Cantonal Universitaire, Geneva, Switzerland; w Department of Dermatology, Massachusetts General ttospital a,ld Harvard Medical School, Boston, Massachusetts; the #Department of Pathology, Tulane University of Medicine and Touro Infirmary, New Orleans, Louisiana; and the 82 of Dermatology, University of Rochester Medical Center, Rochester, New York. Revision accepted for publicationJanuary 9, 1986. Address correspondence and reprint requests to Dr. l'lfillips: Department of Pathology, Heahh Sciences Center, State University of New York, Stony Brook, NY 11794.
796
Tile 21 patients included 18 patients with MDM and three with tile borderline variant. Clinical information and histologic features of these lesions are shown in table 1. Pritnary lesions ranged in thickness from 1.6 to 10.4 ram. Tile histologic subtypes, according to the classification proposed by Muldbauer et al. l (table 2), included the Spitz variant (nine patients), the spindle cell variant with and without pigmentatioxl (six patients), tile combined spindle and epithelioid cell type (three patients), and tile small epithelioid cell type (three patients). The histologic subtypes are illustrated in figures 1 to 5. Histologic signs of regression were not observed in any of the lesions. Surface ulceration measuring 0.8 to 3.2 mm was present in four cases. Satellitosis was observed in two patients, one of whom died of metastatic disease. Mitotic figures r a n g i n g froth 1 to 6/ram 2 were present in 11 of tile 21 cases (table 2). Twelve of the lesions showed lymphocytic infiltration at the base of the tumor. The lesions from the two patients who died of metastatic disease exlfibited mild to moderate lymphocytic infiltration. T u m o r cells in general had enveloped rather than displaced the adnexal struc-
MINIMAL DEVIATIONMELANOMA (Phillips et al.]
tures. Adnexal involvement, in the form of perineural space invasion or permeation of the arrector pill nmscle, was demonstrated in five cases; two of these patients died of metastatic disease. As reported previously, 1 recurrent disease developed in three o f the patients with MDM, two o f whom died o f widespread metastatic disease. O f these two patients, one had a pigmented spindle cell lesion of the back (upper back, posterior arm, posterior neck, posterior scalp [BANS?]) with a measured depth of 8.24 ram. The lesion from the other patient exhibited the small epithelioid cell pattern, had a measured depth of 4.31 mm, and was located in the posterior neck (BANS+) region. The third patient had a local recurrence and subsequently died of a myocardial infarction 53 months after initial diagnosis of the tumor. DISCUSSION
Recognition of the BM and MDM requires understanding and appreciation of the maturation and histologic appearances of both the common acquired nevi and the fully evolved malignant melanoma. 1-4 In the former lesion, the characteristic nevus cells first appear in nests at the tips of rete ridges. They then begin to descend into the dernfis. Junctional and dermal components present together within the same lesion characterize the usual compound nevus. The jtmctional component is eventually lost, and, at that point, the nevomelanocytes are present only within the dermis. The migration of nevus cells into the dermis is characterized by differentiation into a variety of patterns, wtfich, in general, is characterized by increased fibrogenesis, leading to nesting of the cells, and decreased melanogenesis. When the nevus cells first appear at the dermoepidermal junction, they resemble epithelial cells. They are polygonal, dendritic, and melanized, and they have an abtmdance of cytoplasm. Their nuclei are small and uniform. In this superficial location, they are referred to as type A nevus cells. During the maturation process, as the nevus cells penetrate the dernfis, they no longer have dendrites and cytoplasmic melanin is no longer present, except in the most superficial areas. T h e cells, located in the superficial papillary dermis, are now rotmded, have less cytoplasm than type A nevus cells, and resemble lymphocytes. T h e y have a more orderly arrangement, usually in nests and strands, and are now referred to as type B nevus cells. In the lower papillary dermis and in the upl)er retictflar dermis, the nevomelanocytes again undergo transformation. The cells become smaller and elongated, resembling spindle cells. They proliferate as single cells or in fascicles and are referred to as type C cells. In some areas, the fascicles of type C nevus cells may undergo neurotization, wtfich may be accompanied by the appearance of histochemically demonstrable cholinesterase. T h e cells may also organize in such a way as to simulate normal neural structures, such as Meissner's corpuscles.
Tile other form of common acquired nevus is the spindle and epithelioid cell nevus, also known as the Spitz nevus. Clinically, these minors are reddish and rounded, and they are frequently diagnosed as hemangiomas. Tile), are found primarily in children but can be observed in individuals of any age group. T h e architecture is usually that o f a c o m p o u n d nevus, with proliferation of nevomelanocytes along the dermoepidermal junction and extension into the reticular dermis and, sometimes, into the subcutaneous fat. At the d e r m o e p i d e r m a l junction, the nevus cells proliferate in nests. The long axis of the cells witlfin these nests is usually perpendicular to the overlying epidermis. Because of the orientation perpendicular to the skin surface, which is frequently hyperplastic, these clusters of nevomelanocytes have been a h e r n a t e l y d e s c r i b e d as having a "raining down" appearance or resembling a cluster o f bananas. The tumor cells within the Spitz nevus may be predonfinantly spindle-shaped, epithelioid, or a nfixture of the two. Cytologically, the spindle-shaped cells are elongated cells with oval vesicular nuclei, dark nuclear membranes, and finely, evenly dispersed cbromatin around the nuclear membrane. These cells may contain one or more small, prominent basophilic nucleoli, and they are associated with variable anmunts of aml)hophilic or slightly basoplfilic cytoplasm. The cytoplasm has a wispy appearance and is usually nonpigmented. Within the papillary dermis, the nevomelanocytes proliferate in fascicles and nests. At the base of the lesion, the cells most commonly infihrate as single cells or small aggregates. However, t h e r e is increasing maturation with depth, with the cells becoming smaller and looking more like the cells of the common melanocytic nevus. The epithelioid cells that are commonly seen in spindle and epithelioid cell nevi are usually round to polygonal, and they are associated with g r e a t e r amotmts of cytoplasm than is the spindle cell variant. However, the nuclear and cytoplasnfic characteristics are essentially the same as in the spindle cell type. Althougla b i n u c l e a t e d or m u l t i n u c l e a t e d forms, which can sometimes be cytologically atypical, may be present, the overall appearances of the individual nuclei are qtfite bland and sinfilar to those in the spindle-shaped cell. T h e malignant tumors of melanocytic origin generally are subdivided into four categories: lentigo maligna melanoma, acral lentiginous melanoma, superficial spreading melanoma, and nodular melanoma. These lesions exhibit two distinct patterns of growth: monophasic and biphasic. 4,~ T h e monophasic pattern, or vertical growth phase, is characterized by downward or vertical proliferation of neoplastic cells from the epiderm!s into the dermis and, sometimes, into the subcutaneous fat. The biphasic pattern is characterized by an initial radial or horizontal, predonfinantly intraepidermal growth phase, wtfich is followed by a vertical growth phase. Lentigo maligna melanoma, superficial spreading melanoma, 797
HUMAN PATHOLOGY
Volume 17, No. 8 [August 1986) TABLE I.
Case
Patient's Age at Diagnosis (yr)/Sex
Site
BANS
Histologic Type
1
53/F
Calf
-
MDM
2
16/F
Achiles (right)
-
BM
3 4
8/F 2 I/F
Back Thigh (right)
~ -
5
20/M
Forearm
6
13/F
7
Clinical and Histologic Features of Minimal
Histologic Subtype
Thickness (mm)
Co-existent Lesions
1.60
--
! .62
--
BM MDM
Pigmented spindle Combined spindle and epithelioid Spitz Spitz
~
*|DM
Spitz
1.82
Back
;
MDM
2.15
Spitz relnnant
30/F
Ear (right)
-
MDM
Combined spindle and epithelioid Combined spindle and epithelioid
2.42
Residual lentiginous coml)ound nevus
8 9
?/M 73/M
Knee (right) Ear
-
MDM MDM
Spindle Pigmented spindle
2.47 2.74
10
44/M
-
bIDM
Spitz
2.9
--
11
28/F
Thigh Posterior Arm
?
MD*I
2.9
Remnant of type B nevus at periphery of lesion
12
17/F
Arm
~
MDM
Small epithelioid with type A&B patterns Spitz
2.9
13 14 15
5/F 20/M 63lM
Vulva Thigh (left) Eyelid
-
MD*I MDM BM
Remnant of nevus cells at periphery of lesion --Residual dermal nevus
16
26/F
Nose (side)
-
MDM
17
14/M
Neck (posterior)
+
18 19
24/M 20/M
Trunk Neck (right)
20
53/F
21
18/M
1.70 1.75
Spitz Spitz Small epithelioid (malignant dermal nevns variant) Pigmented spindle
3.55 3.6 3.66
MD.X,I
Small eptithelioid
4.31
-
MDM MDM
4.5 6.2
Back
~
MDM
Spitz Pigmented spindle Pigmented spindle
Elbow
-
MDM
Spitz
4.23
8.24
-Remnant of type B nevus cells Remnant of benign pigmented nevus
Residual type B nevus in papillary dermis; atypical --
-Remnant of nevus cells --
10.4
ABBREVIATIONS:BANS, upper back, posterior arm, posterior neck, posterior scalp; A & W, alive and well; MI, myocardial infarction. * - , = none present; 1 + = mild; 2+ = moderate; 3+ = marked. a n d acral l e n t i g i n o u s m e l a n o m a e x h i b i t t h e b i p h a s i c pattern of growth. Lent!go maligna melanoma, w h i c h is associated with t h e best p r o g n o s i s , 6 o c c u r s o n visible, e x p o s e d sites a n d has t h e m o s t p r o l o n g e d radial growth phase. Superficial spreading melan o m a a n d acral l e n t i g i n o u s m e l a n o m a , o c c u r r i n g o n t h e p a l m s a n d soles, a r e c h a r a c t e r i z e d b y t h e e a r l y onset of a biphasic growth pattern. Nodular melan o m a s exhibit only the m o n o p h a s i c pattern. With the
d e v e l o p m e n t of the vertical growth phase, a malign a n t m e l a n o m a a c q u i r e s i n c r e a s e d p r o p e n s i t y to m e tastasize a n d l e a d to t h e p a t i e n t ' s d e a t h . I n t h e f u l l y e v o l v e d m a l i g n a n t m e l a n o m a , tlle t u m o r cells c o n s t i t u t i n g t h e lesions, w h e t h e r s p i n d l e cells, e p i t h e l i o i d cells, o r a m i x t u r e o f t h e two, e x h i b i t m a r k e d cytologic a t y p i a i n t h e f o r m o f n u c l e a r pleom o r p h i s m , i n c r e a s e d n u c l e a r / c y t o p l a s m i c ratios, a n d increased mitotic indices. I n addition, failure of mat798
MINIMAL DEVIATIONMELANOMA[Phillips et
ol.)
Deviation Melanoma (MDM) a n d Borderline Melanoma (BM)
Ulceration (mm)
B
+,0.7 -
Vascular or Neural Invasion
Satellitosls
Lymphocytic Infiltration*
-
-
I+
3 yr/8 mo
A & W
4
-
-
5 yr/5 mo
A&W
2 3
+
4 yr/4 mo 6 yr
A &W A&W
5 yr/2 mo
A&W
8 yr
A&W
4 yr/3 mo
A&W
1+ 1+
5 yr 4 yr/5 m o
2+
3 yr/5 mo
A & W Local recurrence, d i e d o f MI 53 m o a f t e r biopsy A &W
4 yr/l m o
A & W
4 yr
A & W
7 yr/6 mo 5 yrl5 m o 4 yr/3 m o
dysplastic nevi A & W A&W A&W
+ , Perineural sheath
3 yr
A & W
+, Permeation o f arrector pili m u s c l e
Died approximately 1 }r a f t e r initial diagnosis with widespread nletaslases 5 yr/5 m o 5 yr/1 m o
A&W A & W
M e t a s t a s e s to lungs, liver; d i e d 6 yr/2 m o after initial diagnosis of metastatic melanoma 4 yr/4 m o
A & W
I+ 3+
m
+, Permeation o f arrector pili m u s d e 2+
Not m e a s u r a b l e d u e to sloughing of cells + , 2.8
Follow-u p Period
Mitoses/ mm z
?, V a s c u l a r invasion
3
-
1+
+ , Perineural sheath
Outcome
n t l m e r o u s
+ , 0.8 + , 3.2
6
-
-
-
1
-
3+
-
2+
2
-
R
m
_
m
-
1
+
1+
+, Perineural sheatll
4
-
2+
-
moderately atypical type A, B, or C nevonmlanocytes or spindle and epithelioid cells. T h e MDM is similarly characterized by the formation o f an expansile n o d u l e in the papillary dermis, but with progression from level III to levels IV or V ) ,3 The level IV component im'ades the reticnlar dermis in the form o f broad fascicles and tongues rather than as single cells. As in the BM, within the nodule and fascicles slight to moderate
uration or failure of diminution in nuclear size characterizes the tumor cells with increasing depth. In contrast to the fully evolved malignant melanoma, the BM is characterized by the formation within the papillary dermis o f all expansile nodule o f nevomelanocytes, which may extend to the level of the papillary reticular dermal interface, the equivalent of level III invasion) ,3 These nodules are composed of relatively uniform populations of slightly to 799
TABLE 2.
Histologic Variance in the Vertical Growth Phase*
Small epithelioid cell (includes halo nevns-like variant, minimal deviation melanoma in premalignant dysplasia, and malignant dermal nevus) Predominance of type A patterns Predominance of type B patterns Predominance of type C patterns Small, plump spindle cells in ribbons and festoons Vertical growth pattern in spindle cell nevus of Spitz type With remnant of benign pigmented spindle cell nevus De novo Minimal deviation pigmented spindle cell melanoma With remnant of benign pigmented spindle cell nevus With remnant of pigmented spindle cell melanocytic dysplasia De novo Vertical growth of lentigo maligna melanoma Desmoplastic melanoma (minimal deviation) De novo Lentigo maligna melanoma Acral lentiginous melanoma Neurotropic melanoma (minimal deviation) Lentigo maligna melanoma Acral lentiginous melanoma De novo Minimal deviation melanoma of small, epithelioid nevocytic cell type Combined spindle and epithelioid cell (atypical combiued nevus) * From Muhlbauer et al. I
TABLE 3.
Factors Associated with Mortality in Clinical Stage I Malignant Melanoma (MM),* Minimal Deviation Melanoma [MDM], and Borderline Melanoma [BM]
Prognostic Factor Thickness (3.65 ram) Level of invasion (Clark's) II III IV V Location Acral BANS Non-BANS, trunk Non-BANS, head and neck Extremities, excluding hands and feet Histologic ulceration >3 mm wide Microscopic satellites Absent Present More than 6 mitoses/ram 2 Lymphocytic response Nearly absent Moderate or marked Types of metastases Visceral Other recurrence No other recurrence Histologic type Nodular Superficial spreading Lentigo maligna Other Spitz Combined spindle and epithelioid cell type Small epithelioid Spindle, pigmented and nonpigmented Sex Female ,Male Age (yr) 40 40-60
Stage I MM (n = 428): Deaths/Occurrence (% Dying) 19145
(42%)
MDM (n = 18): Deaths/Occurrence
BM (n = 3): Deaths/Occurrence
217
0/1
1/117 0%) 6/150 (4%) 371146 (25%) 4/15 (27%)
3/187
6123 211120 16198 3/36 2115 22/67
0/0 212 0/6 1/4 0/8 0/1
(26%) (18%) (16%) (8%) (1%) (33%)
0/3
0/1 0/1 0/1 0
30/373 (8%) 18155 (33%) 31/41 (32%)
1/17 112 0/1
012
271134 (20%) 211294 (7%)
12118 6/18
313 0/3
17/17 (100%) 26/35 (74%) 51376 (1%)
212 1/1 0/15
0/3 0/3 0/3
0/8 012 1/2 2/6t
0/1 0/1 0/1 0/0
15/224 (7%) 33/204 (16%)
1/9 2/9
0/2 0/1
101123 (8%) 171183 (13%)
1/13 113
012
15/61 (25%) 221316 (7%) 0113 (0%) 11/38 (29%)
800
TABLE3.
Prognostic Factor 60 Unknown Nevtls Absent Nevus with congenital features
Continued
Stage I MM (n = 428): Dcatlls/Occurrc.cc (V, Dying)
MDM (n = 18): Deaths/Occurrence
BM (n = 3): Deaths/Occurrence
11/84
(12c~)
1/1 0/1
0/1
35/306 7/33
(11'7c) (21c~)
? 0/0
0/2
0/0
ABBREVIATION: BANS, u p p e r back, posterior arm, posterior neck, posterior scalp. * From Sober et al. l~ t Included is 1 patient with local recurrence who died of a myocardial infarction 53 m o n t h s after local excision.
FIGURE 1. Case 1. Minimal deviation melanoma, pigmented spindle cell type. Top, irregular nests of uniformly atypical cells in the epidermis with extension into the reticular dermis. (Hematoxylin-eosin stain, x79.} Bottom left, plump spindle cells with v a r i a b l e amounts of pigmented pale cytoplasm and uniformly atypical oval vesicular nuclei. The nucleoli are large and basophilic. (Hematoxylin-eosin stain, x 500.] Bottom right, high-power view of cells at the base of the lesion revealing moderate cytologic atypia. The tumor cells exhibit failure of maturation, as evidenced by their similarity to the cells in the superficial portion of the lesion with respect to size, abundant cytoplasm, and large nuclei. (Hematoxylin-eosin stain, x 788.]
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HUMAN PATHOLOGY
Volume ~L No. 8 [August '1986)
FIGIJl/I~2. Case ~6. Minimal deviation melanoma, pigmented spindle cell type, Left,polypoid nodule of tumor ceils extending into the deep reticular dermis, level IV. [Hematoxylin--eosin stain, • ~4.] Right,,tumor cells exhibiting marked fosciculation.The pigmentation end spindle cell character of these cells are apparent. Residual type B nevus ceils in the papillary dermis [arrow} ore markedly atypical at higher magnification [inset}.[Hematoxylin-eosin stain. • 3~; inset, • 500.]
shown a stead)' and significant increase in incidence during the last decade. 8 In approximately one third of individuals with malignant melanomas, the co-existence o f benign nevomelanocytics tumor is demonstrated tfistologically. However, despite the common association of these two lesions, there is convincing evidence that the large majority of nevomelanocytic tumors remain benign throughout their natural history and proceed to complete clinical regression in late adulthood. 9 T h e MDM and BM are now more frequently detected by routine diagnostic procedures. 4 This is due in part to the increasing incidence and detection of malignant m e l a n o m a as well as to the increased awareness of tile histologic variants. Although the MDM and BM have clinical and histologic features suggestive of malignant melanoma, such features fail to meet the criteria used for tile diagnosis of the usual type of malignant melanoma and, therefore, preclude an unequivocal diagnosis of malignant melanoma. Histologically, lesions of this type are nevomelanocytic tumors with mild to moderate atypia, 2"3 as o p p o s e d to benign acquired nevomelanocytic tumors on the one hand and fully evolved malignant melanomas on the other. Sober et al. 1~ assessed 13 prognostic factors related to mortality in 428 patients with clinical stage I malignant melanoma who had been followed up for 24 to 60 months after the initial diag/nosis. Eleven per cent of the patients (48 of 428) died during this period. The deaths of two of our patients with MDM (9 per cent) were attributable to metastatic disease. More revealing information can be obtained by comparing factors associated with mortality and metastatic disease in clinical stage I m e l a n o m a versus MDM and BM (table 3). Tile risk factors associated
atypia characterizes a uniform population of either type A, B, and C nevus cells, or spindle and epithelioid cells. BM may recur. MDM may recur and/or metastasize. Although these lesions exhibit variable atypia in the form of nuclear pleonmrphism and increased mitotic indices, the atypia is mild to moderate within a relatively uniform population of ceils that lack the marked cytologic atypia demonstrated in the fiflly evolved malignant melanoma. Two other features of the MDM should be emphasized. First, the diagnosis of MDM excludes level II melanoma, i.e., by definition, in MDM an expansile nodule of nevomelanocytes fills the papillary dermis and progresses from level III to level IV. Second, a diagnosis of MDM also excludes the presence of a fully evolved radial growth component. Although radial growth phase equivalents may be present, usually in the form of a surrounding lentiginous spindle cell component exhibiting mild to moderate atypia, they are often not seen. Thus, at times, a fully evolved radial growth phase may be associated with a vertical growth phase that exhibits the pattern and histologic features o f MDM. In our opinion, such lesions should be diagnosed as malignant melanoma, subtyped according to the radial growth phase characteristics, and assigned an appropriate level of invasion and measured depth. In addition, we append a note indicating that the vertical growth phase has features of MDM. We recommend this descriptive note bcause we do not know, on the basis of a very small number of cases, whether the behavior of such lesions is different from that of lesions with a fiflly evoh'ed vertical growth phase. Benign nevomelanocytic tumors are very common. Most individuals have one or m o r e of them. 7 Malignant melanomas, although rare, have 802
FIGURE 3. Case 6. Minimal deviation melanoma, combined spindle and epithelioid cell lype, exhibiting dual character in the infiltrating nodule. Top, in one area the cells are in tightly cohesive nests and sheets, whereas in other areas clusters of cells are separated by hyalinized stroma and large ectatic vessels. [Hematoxylin-eosin stain, x 31.) Middle, higher magnification of the areas shown in figure 3, top, illustrating that the tumor cells in the deeper portions of the specimen [hyalinized areas, left of field; cohesive cell clusters, right of field] constitute a relatively uniform p o p u l a t i o n of slightly a t y p i c a l spindle and epithelioid cells. (Hem a t o x y l i n - e o s i n stain, x 200.] Bottom, high-power view of the epithelioid cells [left] a n d the spindle cells [right] revealing a fairly uniform cytologic a p p e a r ance with some atypia. The cells have rather prominent nuclei, and the nuclear chromatin, while finely dispersed along the nuclear memb r a n e in g e n e r a l , a p p e a r s clumped in some cells. (Hematoxylin-eosin stain, x788.)
dl
HUMAN PATHOLOGY
Volume '17,No. 8 [August 1986]
FIGURE 4. Case 10. Minimal deviation m e l a n o m a , Spitz type. Top, the lesion is entirely intradermal and without junctional activity. Telangiectasia is seen In the papillary dermis, and slight epidermal hyperplasia overlies the tumor. [Hematoxylin-eosin stain, x79.) Bottom left, small nests of uniformly atypical tumor ceils predominate in a sclerotic stroma. ( H e m a t o x y l i n - e o s i n stain. x3~3.] Bottom right, higher magnification showing tumor ceils of fairly uniform size with single and multiple nuclei. The nuclei are irregular and ovoid and contain coarse reticulated chromatin granules. Nucleoli are prominent in most cells. The cytoplasm Is wispy, a m p h o philic, and finely vesiculated. ( H e m a t o x y l i n - e o s i n stain. x 788.]
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ram2--13 of 41 patients (32 per cent) died; location of lesion--acral, six of 23 patients (26 per cent) died. The presence of visceral metastases at two years in clinical stage I melanoma was associated with the poorest prognosis for survival (17 of 17 patients died, 100 per cent mortality). Survival in patients with recurrent lesions was not much improved (26 of 35 patients died, 74 per cent mortality). In each case of BM and MDM, these risk factors were assessed and con-
with mortality in clinical stage I malignant melanoma include thickness--l.70 to 3.64 mm, 20 of 102 patients (20 per cent) died; more than 3.65 ram, 19 of 45 patients (42 per cent) died; level of invasion-level IV, 37 of 146 patients (25 per cent) died; level V, four of 15 patients (27 per cent) died; histologic ulceration--more than 3 ram, 22 of 67 patients (33 per cent) died; presence of microscopic satellites-- 18 of 55 patients (33 per cent) died; six or more mitoses/ 804
MINIMAL DEVIATION MELANOMA (Phillips et al.]
+
.~
-'
, . .,. +, _...
o
.q
o
-
d
A
+
Q..
ae
o,
FIGURE 5. Case '15.Borderline melanoma, small epithelioid cell type [malignant dermal nevus variant]. Left,, well-circumscribed expansile mass of focally pigmented tumor cells present within the dermis without epidermal involvement. [Hematoxylin-eosin stain, x 28.} Right, the tumor cells overall are cytologically uniform but exhibit some atypia in that they have rather prominent nuclei and overall hyperchromasia. Pigmentation is variable. Inset, the cytoplasm is rather uniform from cell to cell, except that of some balloon cells. [Hematoxylin-eosin stain. x 500; inset, x 788.)
trasted with the mortality in clinical stage I melanoma. As shown in table 3, two of the seven patients (29 per cent) with lesions more than 3.65 mm thick died. The one patient who died with a lesion in the thickness range of 0.85 to 1.69 mm had a local recurrence but died of a myocardial infarction. The three patients with BM had level I l l lesions. All were alive and well at the time of the last follow-up examination, from 51 to 65 months after the initial diagnosis. By definition, the lesions of MDM are at least level IV; two o f 18 patients (11 per cent) died. No deaths were seen in patients with histologic ulceration measuring more than 3 ram, while one of 18 patients (6 per cent) with microscopic satellites died 74 mon"~hs after the initial diagnosis. T h e lesions from the two patients who died in our series had fewer than six mitoses/ruraL The two patients (9 per cent) in this series who died both had lesions on the back; however, only one of these lesions was clearly known to be in the BANS region of the back. Both of the patients with MDM and metastases died, while one patient with local recurrent lesions died of an apparently unrelated myocardial infarction 53 months after excision. Metastases or recurrent disease did not develop in any of the three patients with BM.
805
Minimal deviation melanoma, while patently related to other malignant melanomas histologically, exhibits a divergent and, perhaps, muted metastatic metamorphosis. This small study sample does not permit statistically significant extrapolation of the risk of morbidity and mortality in this group. However, crucial prognostic elements related to mortality in clinical stage I malignant melanomas generally were absent in these patients. 1~ One factor that seems to differentiate MDM and BM from other melanomas would be the earlier onset (before the age of 40 years). Additionally, it would appear from our small sample that BANS localization of lesions may carry an increased risk for the development of metastases. Unlike clinical stage I malignant melanoma, our investigation would suggest that sex is not a determinant for the development of metastases. However, the time between diagnosis and death was one year or less for males and more than six years for females, which is consistent with observations o f more conventional metastatic melanonms. Histologically, BM and MDM are too atypical to be ordinary nevi, and yet they do not show the degree of cytologic atypia or the celhdar pleomorphism associated with conventional malignant melanomas. Although the number of cases in this retrospective
HUMAN PATHOLOGY
Volume 1L No. 8 (August 1986)
stud)' is small, the findings indicate that the clinical behavior o f these lesions differs from that of the usual malignant melanoma at each level of invasion as well as for the other risk factors. The increased awareness and follow-up studies of patients with the various subtypes of these lesions should resuh in better understanding of their clinical behavior, providing stronger evidence for a conservative approach to therapy.
4.
5. 6. 7. 8.
REFERENCES
9.
1. Muldbauer JE, Margolis RJ, Mihm MC Jr, et al: Minimal deviation melanoma: a histologic variant of cutaneous malignant melanoma in its vertical growth phase. J Invest Dermatol 80:063s, 1983 2. Reed RJ, Ichinose H, Clark WIt Jr, et al: Common and uncommon melanocytic nevi and borderline melanomas. Semin Oncol 2:119, 1975 3. Merot Y, Mihm MG Jr: Aspect inhabituel et meconnu du melanome malin cutane: le melanome malin a deviation
10.
11. 12.
minime. Etude retrospective de 45 cas. Ann Dermatot Venereal (Dermatol) 112:325, 1985 Elder DE, Greene MH, Bondi EE, et al: Acquired melanocytic nevi and melanoma. The dysplastic nevus syndrome. In Ackerman AB (ed): Pathology of Malignant Melanoma. New York, Masson, 1981 McGovern VJ, Mihm MCJr, Bailly C, et al: The classification of malignant melanoma and its histologie reporting. Cancer 32:1446, 1973 Clark WH Jr, Mihm MCJr: Lentigo maligna and lentigo maligna melanoma. Am J Pathol 55:39, 1969 Pack GT, Lenson N, Gerber DM: Regional distribution of moles and melanomas. Arch Surg 65:862, 1952 Elwood JM, LeeJAtt: Recent data on the epidemiology of malignant melanoma. Semin Oncol 2:149, 1975 Stegmaier OC: Natural regression of the pigmented nevus. J Invest Dermatol 32:413, 1959 Sober AJ, Day CL, Fitzpatrick TB, et al: Factors associated with death from melanoma from 2 to 5 years following diagnosis in clinical stage I patients. J Invest Dermatol 80:053s, 1983 Day CLJr, Harrist TJ, Gorstein F, et al: Malignant melanoma. Prognostic significance of microscopic satellites in the reticular dermis and subcutaneous fat. Ann Surg 194:108, 1981 Sober AJ, Day CL, Fitzpatrick TB, et al: Earl)' death from clinical stage I melanoma. J Invest Dermatol 80:053s, 1983
ADDENDUM
In tile article entitled "Immtmohistologic Detection of Estrogen Receptors in P a r a f f i n - e m b e d d e d Breast Cancers: Correlation with Cytosol Meastlrements" by Pascal et al. (HuM PATHOL 17:370, 1986), the source o f tile Eolyestradiol p h o s p h a t e used in tile p r o c e d u r e was i n a d v e r t e n t l y omitted. It was kindly s u p p l i e d by Ayerst Laboratories, New York, New York.
806
Study of 21 C a s e s
MILDRED E. PHILLIPS, ME),* RANDALL J. MARGOLIS, MD, t YVES MEROT, MD: ARTHUR J. SOBER, MD, wRICHARD J. REED, ME),# JAN E. MUHLBAUER, MD,82 AND MARTIN C. MIHM, JR, MD t A retrospective study of 21 patients with the histopathologic diagnosis of minimal deviation melanoma (MDM; n = 18) and borderline melanoma (BM; n = 3) was undertaken to determine the prognosis for these patients compared with that for patients with other types of malignant melanoma. The findings indicate that the prognosis for these uncommon nevomelanocytic tumors is somewhat better than that for other malignant melanomas. Follow-up periods in this series ranged from 18 to 96 months (mean, 57 months). Primary lesions ranged in tlfickness from 1.6 to 10.4 mm. The histopathologic subtypes included the Spitz variant (nine patients), the spindle cell variant (six patients), the combined spindle and epithelioid cell type (three patients), and the small epithelioid cell type (three patients). Only t~'o of the patients died of widespread metastatic disease. Comparison of the histologic and clinical prognostic indicators of mortality in patients who have malignant melanoma with the clinical and pathologic features seen in this series of 21 patients would appear to indicate a diminished tendency toward metastatic or recurrent disease in patients with MDM and BM. HUM PATIIOL17: 796-806, 1986.
An u n c o m l n o n n e v o m e l a n o c y t i c t u m o r , the minimal deviation melanoma (MDM), has been purported to have a less assauhive clinical course than o t h e r m o r e c o m m o n t y p e s o f m a l i g n a n t inelan o m a ) -~ T h e MDM is characterized histologically by expansile growth of uniformly atypical nevomelanocytes, with e x t e n s i o n into the r e t i c u l a r d e r m i s (Clark's level IV). The borderline melanoma (BM) exhibits similar vertical growth characteristics but is confined vertically to a widened papillary dermis (Clark's level III). In either case, the vertical growth phase has cytologic atypia (lfistologic variance) less pronounced than that observed in tile other malignant melanomas. Clinical inspection reveals both pigmented and nonpigmented lesions, which are commonly diagnosed as Spitz nevi, llemangiomas, or malignant melanomas. A retrospective stud)' examining the outcome of patients with BM and MDM has sug-
gested tlmt these lesions are less virltlent than other more commonly seen melanomas. ~ Using this same patient population, we undertook tile current study to propose a tnore definitive classification of the subtypes of MDM, as well as to contrast tile clinical outlook for these lesions with that for other types of malignant melanoma. MATERIALSAND METHODS
The tissue sections and clinical information for tiffs series of cases were obtained from the private constthation files of one of tile authors (M.C.M.) and the pathology files of tile Massachusetts General Hospital. The initial biopsies were performed during tile period fronl 1973 to 1978. All lesions in this series were more than 1.6 mm thick (Breslow measurement). For tile current report, tire slides were again reviewed i n d e p e n d e n t l y by three of the authors (M.E.P., M.C.M., and R.J.M.). Follow-up periods, with data obtained by physical examination or telephone call, for 21 patients (10 males, 11 females), ranged fi'om 18 to 96 months (mean, 57 months) througll the middle of 1983. RESULTS
Received from the *Department of Pathology, State Universit)' of New York, Stony Brook, New York; tThe Dermatology Unit, Massachusens General Hospital and Harvard Medical School, Boston, Massachusens; the ~Clinique de Dermatologie, tt6pital Cantonal Universitaire, Geneva, Switzerland; w Department of Dermatology, Massachusetts General ttospital a,ld Harvard Medical School, Boston, Massachusetts; the #Department of Pathology, Tulane University of Medicine and Touro Infirmary, New Orleans, Louisiana; and the 82 of Dermatology, University of Rochester Medical Center, Rochester, New York. Revision accepted for publicationJanuary 9, 1986. Address correspondence and reprint requests to Dr. l'lfillips: Department of Pathology, Heahh Sciences Center, State University of New York, Stony Brook, NY 11794.
796
Tile 21 patients included 18 patients with MDM and three with tile borderline variant. Clinical information and histologic features of these lesions are shown in table 1. Pritnary lesions ranged in thickness from 1.6 to 10.4 ram. Tile histologic subtypes, according to the classification proposed by Muldbauer et al. l (table 2), included the Spitz variant (nine patients), the spindle cell variant with and without pigmentatioxl (six patients), tile combined spindle and epithelioid cell type (three patients), and tile small epithelioid cell type (three patients). The histologic subtypes are illustrated in figures 1 to 5. Histologic signs of regression were not observed in any of the lesions. Surface ulceration measuring 0.8 to 3.2 mm was present in four cases. Satellitosis was observed in two patients, one of whom died of metastatic disease. Mitotic figures r a n g i n g froth 1 to 6/ram 2 were present in 11 of tile 21 cases (table 2). Twelve of the lesions showed lymphocytic infiltration at the base of the tumor. The lesions from the two patients who died of metastatic disease exlfibited mild to moderate lymphocytic infiltration. T u m o r cells in general had enveloped rather than displaced the adnexal struc-
MINIMAL DEVIATIONMELANOMA (Phillips et al.]
tures. Adnexal involvement, in the form of perineural space invasion or permeation of the arrector pill nmscle, was demonstrated in five cases; two of these patients died of metastatic disease. As reported previously, 1 recurrent disease developed in three o f the patients with MDM, two o f whom died o f widespread metastatic disease. O f these two patients, one had a pigmented spindle cell lesion of the back (upper back, posterior arm, posterior neck, posterior scalp [BANS?]) with a measured depth of 8.24 ram. The lesion from the other patient exhibited the small epithelioid cell pattern, had a measured depth of 4.31 mm, and was located in the posterior neck (BANS+) region. The third patient had a local recurrence and subsequently died of a myocardial infarction 53 months after initial diagnosis of the tumor. DISCUSSION
Recognition of the BM and MDM requires understanding and appreciation of the maturation and histologic appearances of both the common acquired nevi and the fully evolved malignant melanoma. 1-4 In the former lesion, the characteristic nevus cells first appear in nests at the tips of rete ridges. They then begin to descend into the dernfis. Junctional and dermal components present together within the same lesion characterize the usual compound nevus. The jtmctional component is eventually lost, and, at that point, the nevomelanocytes are present only within the dermis. The migration of nevus cells into the dermis is characterized by differentiation into a variety of patterns, wtfich, in general, is characterized by increased fibrogenesis, leading to nesting of the cells, and decreased melanogenesis. When the nevus cells first appear at the dermoepidermal junction, they resemble epithelial cells. They are polygonal, dendritic, and melanized, and they have an abtmdance of cytoplasm. Their nuclei are small and uniform. In this superficial location, they are referred to as type A nevus cells. During the maturation process, as the nevus cells penetrate the dernfis, they no longer have dendrites and cytoplasmic melanin is no longer present, except in the most superficial areas. T h e cells, located in the superficial papillary dermis, are now rotmded, have less cytoplasm than type A nevus cells, and resemble lymphocytes. T h e y have a more orderly arrangement, usually in nests and strands, and are now referred to as type B nevus cells. In the lower papillary dermis and in the upl)er retictflar dermis, the nevomelanocytes again undergo transformation. The cells become smaller and elongated, resembling spindle cells. They proliferate as single cells or in fascicles and are referred to as type C cells. In some areas, the fascicles of type C nevus cells may undergo neurotization, wtfich may be accompanied by the appearance of histochemically demonstrable cholinesterase. T h e cells may also organize in such a way as to simulate normal neural structures, such as Meissner's corpuscles.
Tile other form of common acquired nevus is the spindle and epithelioid cell nevus, also known as the Spitz nevus. Clinically, these minors are reddish and rounded, and they are frequently diagnosed as hemangiomas. Tile), are found primarily in children but can be observed in individuals of any age group. T h e architecture is usually that o f a c o m p o u n d nevus, with proliferation of nevomelanocytes along the dermoepidermal junction and extension into the reticular dermis and, sometimes, into the subcutaneous fat. At the d e r m o e p i d e r m a l junction, the nevus cells proliferate in nests. The long axis of the cells witlfin these nests is usually perpendicular to the overlying epidermis. Because of the orientation perpendicular to the skin surface, which is frequently hyperplastic, these clusters of nevomelanocytes have been a h e r n a t e l y d e s c r i b e d as having a "raining down" appearance or resembling a cluster o f bananas. The tumor cells within the Spitz nevus may be predonfinantly spindle-shaped, epithelioid, or a nfixture of the two. Cytologically, the spindle-shaped cells are elongated cells with oval vesicular nuclei, dark nuclear membranes, and finely, evenly dispersed cbromatin around the nuclear membrane. These cells may contain one or more small, prominent basophilic nucleoli, and they are associated with variable anmunts of aml)hophilic or slightly basoplfilic cytoplasm. The cytoplasm has a wispy appearance and is usually nonpigmented. Within the papillary dermis, the nevomelanocytes proliferate in fascicles and nests. At the base of the lesion, the cells most commonly infihrate as single cells or small aggregates. However, t h e r e is increasing maturation with depth, with the cells becoming smaller and looking more like the cells of the common melanocytic nevus. The epithelioid cells that are commonly seen in spindle and epithelioid cell nevi are usually round to polygonal, and they are associated with g r e a t e r amotmts of cytoplasm than is the spindle cell variant. However, the nuclear and cytoplasnfic characteristics are essentially the same as in the spindle cell type. Althougla b i n u c l e a t e d or m u l t i n u c l e a t e d forms, which can sometimes be cytologically atypical, may be present, the overall appearances of the individual nuclei are qtfite bland and sinfilar to those in the spindle-shaped cell. T h e malignant tumors of melanocytic origin generally are subdivided into four categories: lentigo maligna melanoma, acral lentiginous melanoma, superficial spreading melanoma, and nodular melanoma. These lesions exhibit two distinct patterns of growth: monophasic and biphasic. 4,~ T h e monophasic pattern, or vertical growth phase, is characterized by downward or vertical proliferation of neoplastic cells from the epiderm!s into the dermis and, sometimes, into the subcutaneous fat. The biphasic pattern is characterized by an initial radial or horizontal, predonfinantly intraepidermal growth phase, wtfich is followed by a vertical growth phase. Lentigo maligna melanoma, superficial spreading melanoma, 797
HUMAN PATHOLOGY
Volume 17, No. 8 [August 1986) TABLE I.
Case
Patient's Age at Diagnosis (yr)/Sex
Site
BANS
Histologic Type
1
53/F
Calf
-
MDM
2
16/F
Achiles (right)
-
BM
3 4
8/F 2 I/F
Back Thigh (right)
~ -
5
20/M
Forearm
6
13/F
7
Clinical and Histologic Features of Minimal
Histologic Subtype
Thickness (mm)
Co-existent Lesions
1.60
--
! .62
--
BM MDM
Pigmented spindle Combined spindle and epithelioid Spitz Spitz
~
*|DM
Spitz
1.82
Back
;
MDM
2.15
Spitz relnnant
30/F
Ear (right)
-
MDM
Combined spindle and epithelioid Combined spindle and epithelioid
2.42
Residual lentiginous coml)ound nevus
8 9
?/M 73/M
Knee (right) Ear
-
MDM MDM
Spindle Pigmented spindle
2.47 2.74
10
44/M
-
bIDM
Spitz
2.9
--
11
28/F
Thigh Posterior Arm
?
MD*I
2.9
Remnant of type B nevus at periphery of lesion
12
17/F
Arm
~
MDM
Small epithelioid with type A&B patterns Spitz
2.9
13 14 15
5/F 20/M 63lM
Vulva Thigh (left) Eyelid
-
MD*I MDM BM
Remnant of nevus cells at periphery of lesion --Residual dermal nevus
16
26/F
Nose (side)
-
MDM
17
14/M
Neck (posterior)
+
18 19
24/M 20/M
Trunk Neck (right)
20
53/F
21
18/M
1.70 1.75
Spitz Spitz Small epithelioid (malignant dermal nevns variant) Pigmented spindle
3.55 3.6 3.66
MD.X,I
Small eptithelioid
4.31
-
MDM MDM
4.5 6.2
Back
~
MDM
Spitz Pigmented spindle Pigmented spindle
Elbow
-
MDM
Spitz
4.23
8.24
-Remnant of type B nevus cells Remnant of benign pigmented nevus
Residual type B nevus in papillary dermis; atypical --
-Remnant of nevus cells --
10.4
ABBREVIATIONS:BANS, upper back, posterior arm, posterior neck, posterior scalp; A & W, alive and well; MI, myocardial infarction. * - , = none present; 1 + = mild; 2+ = moderate; 3+ = marked. a n d acral l e n t i g i n o u s m e l a n o m a e x h i b i t t h e b i p h a s i c pattern of growth. Lent!go maligna melanoma, w h i c h is associated with t h e best p r o g n o s i s , 6 o c c u r s o n visible, e x p o s e d sites a n d has t h e m o s t p r o l o n g e d radial growth phase. Superficial spreading melan o m a a n d acral l e n t i g i n o u s m e l a n o m a , o c c u r r i n g o n t h e p a l m s a n d soles, a r e c h a r a c t e r i z e d b y t h e e a r l y onset of a biphasic growth pattern. Nodular melan o m a s exhibit only the m o n o p h a s i c pattern. With the
d e v e l o p m e n t of the vertical growth phase, a malign a n t m e l a n o m a a c q u i r e s i n c r e a s e d p r o p e n s i t y to m e tastasize a n d l e a d to t h e p a t i e n t ' s d e a t h . I n t h e f u l l y e v o l v e d m a l i g n a n t m e l a n o m a , tlle t u m o r cells c o n s t i t u t i n g t h e lesions, w h e t h e r s p i n d l e cells, e p i t h e l i o i d cells, o r a m i x t u r e o f t h e two, e x h i b i t m a r k e d cytologic a t y p i a i n t h e f o r m o f n u c l e a r pleom o r p h i s m , i n c r e a s e d n u c l e a r / c y t o p l a s m i c ratios, a n d increased mitotic indices. I n addition, failure of mat798
MINIMAL DEVIATIONMELANOMA[Phillips et
ol.)
Deviation Melanoma (MDM) a n d Borderline Melanoma (BM)
Ulceration (mm)
B
+,0.7 -
Vascular or Neural Invasion
Satellitosls
Lymphocytic Infiltration*
-
-
I+
3 yr/8 mo
A & W
4
-
-
5 yr/5 mo
A&W
2 3
+
4 yr/4 mo 6 yr
A &W A&W
5 yr/2 mo
A&W
8 yr
A&W
4 yr/3 mo
A&W
1+ 1+
5 yr 4 yr/5 m o
2+
3 yr/5 mo
A & W Local recurrence, d i e d o f MI 53 m o a f t e r biopsy A &W
4 yr/l m o
A & W
4 yr
A & W
7 yr/6 mo 5 yrl5 m o 4 yr/3 m o
dysplastic nevi A & W A&W A&W
+ , Perineural sheath
3 yr
A & W
+, Permeation o f arrector pili m u s c l e
Died approximately 1 }r a f t e r initial diagnosis with widespread nletaslases 5 yr/5 m o 5 yr/1 m o
A&W A & W
M e t a s t a s e s to lungs, liver; d i e d 6 yr/2 m o after initial diagnosis of metastatic melanoma 4 yr/4 m o
A & W
I+ 3+
m
+, Permeation o f arrector pili m u s d e 2+
Not m e a s u r a b l e d u e to sloughing of cells + , 2.8
Follow-u p Period
Mitoses/ mm z
?, V a s c u l a r invasion
3
-
1+
+ , Perineural sheath
Outcome
n t l m e r o u s
+ , 0.8 + , 3.2
6
-
-
-
1
-
3+
-
2+
2
-
R
m
_
m
-
1
+
1+
+, Perineural sheatll
4
-
2+
-
moderately atypical type A, B, or C nevonmlanocytes or spindle and epithelioid cells. T h e MDM is similarly characterized by the formation o f an expansile n o d u l e in the papillary dermis, but with progression from level III to levels IV or V ) ,3 The level IV component im'ades the reticnlar dermis in the form o f broad fascicles and tongues rather than as single cells. As in the BM, within the nodule and fascicles slight to moderate
uration or failure of diminution in nuclear size characterizes the tumor cells with increasing depth. In contrast to the fully evolved malignant melanoma, the BM is characterized by the formation within the papillary dermis o f all expansile nodule o f nevomelanocytes, which may extend to the level of the papillary reticular dermal interface, the equivalent of level III invasion) ,3 These nodules are composed of relatively uniform populations of slightly to 799
TABLE 2.
Histologic Variance in the Vertical Growth Phase*
Small epithelioid cell (includes halo nevns-like variant, minimal deviation melanoma in premalignant dysplasia, and malignant dermal nevus) Predominance of type A patterns Predominance of type B patterns Predominance of type C patterns Small, plump spindle cells in ribbons and festoons Vertical growth pattern in spindle cell nevus of Spitz type With remnant of benign pigmented spindle cell nevus De novo Minimal deviation pigmented spindle cell melanoma With remnant of benign pigmented spindle cell nevus With remnant of pigmented spindle cell melanocytic dysplasia De novo Vertical growth of lentigo maligna melanoma Desmoplastic melanoma (minimal deviation) De novo Lentigo maligna melanoma Acral lentiginous melanoma Neurotropic melanoma (minimal deviation) Lentigo maligna melanoma Acral lentiginous melanoma De novo Minimal deviation melanoma of small, epithelioid nevocytic cell type Combined spindle and epithelioid cell (atypical combiued nevus) * From Muhlbauer et al. I
TABLE 3.
Factors Associated with Mortality in Clinical Stage I Malignant Melanoma (MM),* Minimal Deviation Melanoma [MDM], and Borderline Melanoma [BM]
Prognostic Factor Thickness (3.65 ram) Level of invasion (Clark's) II III IV V Location Acral BANS Non-BANS, trunk Non-BANS, head and neck Extremities, excluding hands and feet Histologic ulceration >3 mm wide Microscopic satellites Absent Present More than 6 mitoses/ram 2 Lymphocytic response Nearly absent Moderate or marked Types of metastases Visceral Other recurrence No other recurrence Histologic type Nodular Superficial spreading Lentigo maligna Other Spitz Combined spindle and epithelioid cell type Small epithelioid Spindle, pigmented and nonpigmented Sex Female ,Male Age (yr) 40 40-60
Stage I MM (n = 428): Deaths/Occurrence (% Dying) 19145
(42%)
MDM (n = 18): Deaths/Occurrence
BM (n = 3): Deaths/Occurrence
217
0/1
1/117 0%) 6/150 (4%) 371146 (25%) 4/15 (27%)
3/187
6123 211120 16198 3/36 2115 22/67
0/0 212 0/6 1/4 0/8 0/1
(26%) (18%) (16%) (8%) (1%) (33%)
0/3
0/1 0/1 0/1 0
30/373 (8%) 18155 (33%) 31/41 (32%)
1/17 112 0/1
012
271134 (20%) 211294 (7%)
12118 6/18
313 0/3
17/17 (100%) 26/35 (74%) 51376 (1%)
212 1/1 0/15
0/3 0/3 0/3
0/8 012 1/2 2/6t
0/1 0/1 0/1 0/0
15/224 (7%) 33/204 (16%)
1/9 2/9
0/2 0/1
101123 (8%) 171183 (13%)
1/13 113
012
15/61 (25%) 221316 (7%) 0113 (0%) 11/38 (29%)
800
TABLE3.
Prognostic Factor 60 Unknown Nevtls Absent Nevus with congenital features
Continued
Stage I MM (n = 428): Dcatlls/Occurrc.cc (V, Dying)
MDM (n = 18): Deaths/Occurrence
BM (n = 3): Deaths/Occurrence
11/84
(12c~)
1/1 0/1
0/1
35/306 7/33
(11'7c) (21c~)
? 0/0
0/2
0/0
ABBREVIATION: BANS, u p p e r back, posterior arm, posterior neck, posterior scalp. * From Sober et al. l~ t Included is 1 patient with local recurrence who died of a myocardial infarction 53 m o n t h s after local excision.
FIGURE 1. Case 1. Minimal deviation melanoma, pigmented spindle cell type. Top, irregular nests of uniformly atypical cells in the epidermis with extension into the reticular dermis. (Hematoxylin-eosin stain, x79.} Bottom left, plump spindle cells with v a r i a b l e amounts of pigmented pale cytoplasm and uniformly atypical oval vesicular nuclei. The nucleoli are large and basophilic. (Hematoxylin-eosin stain, x 500.] Bottom right, high-power view of cells at the base of the lesion revealing moderate cytologic atypia. The tumor cells exhibit failure of maturation, as evidenced by their similarity to the cells in the superficial portion of the lesion with respect to size, abundant cytoplasm, and large nuclei. (Hematoxylin-eosin stain, x 788.]
; ~,j
,,:! .
~:=. 801
"t
"
j
HUMAN PATHOLOGY
Volume ~L No. 8 [August '1986)
FIGIJl/I~2. Case ~6. Minimal deviation melanoma, pigmented spindle cell type, Left,polypoid nodule of tumor ceils extending into the deep reticular dermis, level IV. [Hematoxylin--eosin stain, • ~4.] Right,,tumor cells exhibiting marked fosciculation.The pigmentation end spindle cell character of these cells are apparent. Residual type B nevus ceils in the papillary dermis [arrow} ore markedly atypical at higher magnification [inset}.[Hematoxylin-eosin stain. • 3~; inset, • 500.]
shown a stead)' and significant increase in incidence during the last decade. 8 In approximately one third of individuals with malignant melanomas, the co-existence o f benign nevomelanocytics tumor is demonstrated tfistologically. However, despite the common association of these two lesions, there is convincing evidence that the large majority of nevomelanocytic tumors remain benign throughout their natural history and proceed to complete clinical regression in late adulthood. 9 T h e MDM and BM are now more frequently detected by routine diagnostic procedures. 4 This is due in part to the increasing incidence and detection of malignant m e l a n o m a as well as to the increased awareness of tile histologic variants. Although the MDM and BM have clinical and histologic features suggestive of malignant melanoma, such features fail to meet the criteria used for tile diagnosis of the usual type of malignant melanoma and, therefore, preclude an unequivocal diagnosis of malignant melanoma. Histologically, lesions of this type are nevomelanocytic tumors with mild to moderate atypia, 2"3 as o p p o s e d to benign acquired nevomelanocytic tumors on the one hand and fully evolved malignant melanomas on the other. Sober et al. 1~ assessed 13 prognostic factors related to mortality in 428 patients with clinical stage I malignant melanoma who had been followed up for 24 to 60 months after the initial diag/nosis. Eleven per cent of the patients (48 of 428) died during this period. The deaths of two of our patients with MDM (9 per cent) were attributable to metastatic disease. More revealing information can be obtained by comparing factors associated with mortality and metastatic disease in clinical stage I m e l a n o m a versus MDM and BM (table 3). Tile risk factors associated
atypia characterizes a uniform population of either type A, B, and C nevus cells, or spindle and epithelioid cells. BM may recur. MDM may recur and/or metastasize. Although these lesions exhibit variable atypia in the form of nuclear pleonmrphism and increased mitotic indices, the atypia is mild to moderate within a relatively uniform population of ceils that lack the marked cytologic atypia demonstrated in the fiflly evolved malignant melanoma. Two other features of the MDM should be emphasized. First, the diagnosis of MDM excludes level II melanoma, i.e., by definition, in MDM an expansile nodule of nevomelanocytes fills the papillary dermis and progresses from level III to level IV. Second, a diagnosis of MDM also excludes the presence of a fully evolved radial growth component. Although radial growth phase equivalents may be present, usually in the form of a surrounding lentiginous spindle cell component exhibiting mild to moderate atypia, they are often not seen. Thus, at times, a fully evolved radial growth phase may be associated with a vertical growth phase that exhibits the pattern and histologic features o f MDM. In our opinion, such lesions should be diagnosed as malignant melanoma, subtyped according to the radial growth phase characteristics, and assigned an appropriate level of invasion and measured depth. In addition, we append a note indicating that the vertical growth phase has features of MDM. We recommend this descriptive note bcause we do not know, on the basis of a very small number of cases, whether the behavior of such lesions is different from that of lesions with a fiflly evoh'ed vertical growth phase. Benign nevomelanocytic tumors are very common. Most individuals have one or m o r e of them. 7 Malignant melanomas, although rare, have 802
FIGURE 3. Case 6. Minimal deviation melanoma, combined spindle and epithelioid cell lype, exhibiting dual character in the infiltrating nodule. Top, in one area the cells are in tightly cohesive nests and sheets, whereas in other areas clusters of cells are separated by hyalinized stroma and large ectatic vessels. [Hematoxylin-eosin stain, x 31.) Middle, higher magnification of the areas shown in figure 3, top, illustrating that the tumor cells in the deeper portions of the specimen [hyalinized areas, left of field; cohesive cell clusters, right of field] constitute a relatively uniform p o p u l a t i o n of slightly a t y p i c a l spindle and epithelioid cells. (Hem a t o x y l i n - e o s i n stain, x 200.] Bottom, high-power view of the epithelioid cells [left] a n d the spindle cells [right] revealing a fairly uniform cytologic a p p e a r ance with some atypia. The cells have rather prominent nuclei, and the nuclear chromatin, while finely dispersed along the nuclear memb r a n e in g e n e r a l , a p p e a r s clumped in some cells. (Hematoxylin-eosin stain, x788.)
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HUMAN PATHOLOGY
Volume '17,No. 8 [August 1986]
FIGURE 4. Case 10. Minimal deviation m e l a n o m a , Spitz type. Top, the lesion is entirely intradermal and without junctional activity. Telangiectasia is seen In the papillary dermis, and slight epidermal hyperplasia overlies the tumor. [Hematoxylin-eosin stain, x79.) Bottom left, small nests of uniformly atypical tumor ceils predominate in a sclerotic stroma. ( H e m a t o x y l i n - e o s i n stain. x3~3.] Bottom right, higher magnification showing tumor ceils of fairly uniform size with single and multiple nuclei. The nuclei are irregular and ovoid and contain coarse reticulated chromatin granules. Nucleoli are prominent in most cells. The cytoplasm Is wispy, a m p h o philic, and finely vesiculated. ( H e m a t o x y l i n - e o s i n stain. x 788.]
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ram2--13 of 41 patients (32 per cent) died; location of lesion--acral, six of 23 patients (26 per cent) died. The presence of visceral metastases at two years in clinical stage I melanoma was associated with the poorest prognosis for survival (17 of 17 patients died, 100 per cent mortality). Survival in patients with recurrent lesions was not much improved (26 of 35 patients died, 74 per cent mortality). In each case of BM and MDM, these risk factors were assessed and con-
with mortality in clinical stage I malignant melanoma include thickness--l.70 to 3.64 mm, 20 of 102 patients (20 per cent) died; more than 3.65 ram, 19 of 45 patients (42 per cent) died; level of invasion-level IV, 37 of 146 patients (25 per cent) died; level V, four of 15 patients (27 per cent) died; histologic ulceration--more than 3 ram, 22 of 67 patients (33 per cent) died; presence of microscopic satellites-- 18 of 55 patients (33 per cent) died; six or more mitoses/ 804
MINIMAL DEVIATION MELANOMA (Phillips et al.]
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FIGURE 5. Case '15.Borderline melanoma, small epithelioid cell type [malignant dermal nevus variant]. Left,, well-circumscribed expansile mass of focally pigmented tumor cells present within the dermis without epidermal involvement. [Hematoxylin-eosin stain, x 28.} Right, the tumor cells overall are cytologically uniform but exhibit some atypia in that they have rather prominent nuclei and overall hyperchromasia. Pigmentation is variable. Inset, the cytoplasm is rather uniform from cell to cell, except that of some balloon cells. [Hematoxylin-eosin stain. x 500; inset, x 788.)
trasted with the mortality in clinical stage I melanoma. As shown in table 3, two of the seven patients (29 per cent) with lesions more than 3.65 mm thick died. The one patient who died with a lesion in the thickness range of 0.85 to 1.69 mm had a local recurrence but died of a myocardial infarction. The three patients with BM had level I l l lesions. All were alive and well at the time of the last follow-up examination, from 51 to 65 months after the initial diagnosis. By definition, the lesions of MDM are at least level IV; two o f 18 patients (11 per cent) died. No deaths were seen in patients with histologic ulceration measuring more than 3 ram, while one of 18 patients (6 per cent) with microscopic satellites died 74 mon"~hs after the initial diagnosis. T h e lesions from the two patients who died in our series had fewer than six mitoses/ruraL The two patients (9 per cent) in this series who died both had lesions on the back; however, only one of these lesions was clearly known to be in the BANS region of the back. Both of the patients with MDM and metastases died, while one patient with local recurrent lesions died of an apparently unrelated myocardial infarction 53 months after excision. Metastases or recurrent disease did not develop in any of the three patients with BM.
805
Minimal deviation melanoma, while patently related to other malignant melanomas histologically, exhibits a divergent and, perhaps, muted metastatic metamorphosis. This small study sample does not permit statistically significant extrapolation of the risk of morbidity and mortality in this group. However, crucial prognostic elements related to mortality in clinical stage I malignant melanomas generally were absent in these patients. 1~ One factor that seems to differentiate MDM and BM from other melanomas would be the earlier onset (before the age of 40 years). Additionally, it would appear from our small sample that BANS localization of lesions may carry an increased risk for the development of metastases. Unlike clinical stage I malignant melanoma, our investigation would suggest that sex is not a determinant for the development of metastases. However, the time between diagnosis and death was one year or less for males and more than six years for females, which is consistent with observations o f more conventional metastatic melanonms. Histologically, BM and MDM are too atypical to be ordinary nevi, and yet they do not show the degree of cytologic atypia or the celhdar pleomorphism associated with conventional malignant melanomas. Although the number of cases in this retrospective
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Volume 1L No. 8 (August 1986)
stud)' is small, the findings indicate that the clinical behavior o f these lesions differs from that of the usual malignant melanoma at each level of invasion as well as for the other risk factors. The increased awareness and follow-up studies of patients with the various subtypes of these lesions should resuh in better understanding of their clinical behavior, providing stronger evidence for a conservative approach to therapy.
4.
5. 6. 7. 8.
REFERENCES
9.
1. Muldbauer JE, Margolis RJ, Mihm MC Jr, et al: Minimal deviation melanoma: a histologic variant of cutaneous malignant melanoma in its vertical growth phase. J Invest Dermatol 80:063s, 1983 2. Reed RJ, Ichinose H, Clark WIt Jr, et al: Common and uncommon melanocytic nevi and borderline melanomas. Semin Oncol 2:119, 1975 3. Merot Y, Mihm MG Jr: Aspect inhabituel et meconnu du melanome malin cutane: le melanome malin a deviation
10.
11. 12.
minime. Etude retrospective de 45 cas. Ann Dermatot Venereal (Dermatol) 112:325, 1985 Elder DE, Greene MH, Bondi EE, et al: Acquired melanocytic nevi and melanoma. The dysplastic nevus syndrome. In Ackerman AB (ed): Pathology of Malignant Melanoma. New York, Masson, 1981 McGovern VJ, Mihm MCJr, Bailly C, et al: The classification of malignant melanoma and its histologie reporting. Cancer 32:1446, 1973 Clark WH Jr, Mihm MCJr: Lentigo maligna and lentigo maligna melanoma. Am J Pathol 55:39, 1969 Pack GT, Lenson N, Gerber DM: Regional distribution of moles and melanomas. Arch Surg 65:862, 1952 Elwood JM, LeeJAtt: Recent data on the epidemiology of malignant melanoma. Semin Oncol 2:149, 1975 Stegmaier OC: Natural regression of the pigmented nevus. J Invest Dermatol 32:413, 1959 Sober AJ, Day CL, Fitzpatrick TB, et al: Factors associated with death from melanoma from 2 to 5 years following diagnosis in clinical stage I patients. J Invest Dermatol 80:053s, 1983 Day CLJr, Harrist TJ, Gorstein F, et al: Malignant melanoma. Prognostic significance of microscopic satellites in the reticular dermis and subcutaneous fat. Ann Surg 194:108, 1981 Sober AJ, Day CL, Fitzpatrick TB, et al: Earl)' death from clinical stage I melanoma. J Invest Dermatol 80:053s, 1983
ADDENDUM
In tile article entitled "Immtmohistologic Detection of Estrogen Receptors in P a r a f f i n - e m b e d d e d Breast Cancers: Correlation with Cytosol Meastlrements" by Pascal et al. (HuM PATHOL 17:370, 1986), the source o f tile Eolyestradiol p h o s p h a t e used in tile p r o c e d u r e was i n a d v e r t e n t l y omitted. It was kindly s u p p l i e d by Ayerst Laboratories, New York, New York.
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