THE TM HAWAII DERMPATH CONFERENCE
MAUI, HI
25.0 CME AMA PRA Category 1 Credits™ 25.0 SAM Credits (Approved provider) MEETING PROGRAM THURSDAY DERMATOPATHOLOGY
Alopecia
DR BETH RUBEN 1/25/2019
Mighty Women of Dermatopathology Hawaii 2019 Alopecia: Diagnosis via pattern analysis
Beth S. Ruben, MD Professor of Dermatology/Dermatopathology University of California, San Francisco Director of Dermatopathology, Palo Alto Medical Foundation
1
Objectives
Review basic hair anatomy Hair follicle anatomy Sizes of hair and organization Phases of the hair cycle Explore methods used to prepare sections for diagnosis of alopecia Employ pattern analysis in alopecia Discuss common and emerging examples of non-scarring and scarring alopecia
2
Basic hair anatomy
3
1 1/25/2019
Insert Whiting scan
Whiting, 2004
4
Infundibulum SD Isthmus AP Lower follicle
5
6
2 1/25/2019
7
Lower follicle
Hair root
8
Matrix
Hair papilla
9
3 1/25/2019
10
11
Outer root Cortex sheath
Inner Cuticle of Henley inner root root sheath Huxley sheath
Cuticle of hair shaft Fibrous sheath
12
4 1/25/2019
Keratinization of hair shaft (Adamson’s fringe)
Keratinization of inner root sheath (Huxley)
13
14
15
5 1/25/2019
Sizes of hair and organization
16
Vellus hair
Thin, short and hypopigmented hairs
Extend within the upper dermis
The inner root sheath is as thick or thicker than its hair shaft
less than 0.03 mm in diameter
17
Terminal hair
Long, thick hair Extends into the subcutis in the scalp Hair shaft greater than 0.06 mm in diameter Normal T:V ratio: at least 2:1 (some say 4-7:1) Miniaturized hair: smaller hair but associated with a long fibrous tract Indeterminate hair: between vellus and terminal
18
6 1/25/2019
Follicular unit
Contain individual follicles, including 2-5 terminal hairs and 0-2 vellus hairs This organization is apparent in the mid to upper dermis The terminal hairs are more evenly spaced in the subcutis
19
Follicular unit
20
Hair cycle phases
21
7 1/25/2019
Whiting, 2004
22
Anagen phase
The growth phase 85% of hairs in this phase normally, from 2-7 years Multiple concentric layers, depending on the level examined Keratinization occurs differentially to form the hair shaft/inner sheath Zones include inferior, isthmic and infundibular
23
Catagen phase
Brief transitional phase, 1% of hairs normally in this phase, lasts 2-3 weeks
Eosinophilia of epithelium and evidence of apoptosis
24
8 1/25/2019
Telogen phase
Resting phase, 0-15% of hairs in this phase normally, lasts 100 days Involutional, with a convoluted basaloid epithelium
25
Hair phases
Indeterminate phase: in some cases, especially alopecia areata, it may be difficult to determine a precise phase Must examine the hair follicle below the level of the follicular bulge (isthmus or lower) to be able to differentiate between terminal anagen, catagen and telogen hairs
above that the hair shaft is keratinized
26
Preparations of sections for alopecia diagnosis
27
9 1/25/2019
Biopsy requirements
4 mm punch biopsy, at minimum “Bury the punch”, with specimen including subcutis Early active sites, not “empty” areas Match angle of biopsy to angle of exit of hairs, if possible Improved yield with 2 punches? Transverse and routine processing
28
Why do transverse sections?
1-2 follicles/mm of scalp Routine sections through 4 mm punch yields 4-8 follicles 2-4 follicles/mm2 of scalp Transverse sections through 4 mm punch yields 25-50 follicles! The isthmic level of the hair follicle is particularly informative with respect to seeing follicular units, determining the type of hair, and the follicular phase should be present in some sections examined
29
Transverse sections for alopecia diagnosis: biopsy size
4 mm punch 3 mm punch
A=r2
1.5mm 2mm
A=3.14 x 4= 12.56 mm2 A=3.14 x 2.25= 7.06 mm2
30
10 1/25/2019
Methods for processing specimens transversely for alopecia
Headington method Frishberg/Sperling method “Hovert” method Elston/Tyler method
31
Modified from David A. Whiting, MD. The Structure of the Human Hair Follicle, Canfield Publishing, 2004. 32
Embed cut surfaces down in paraffin block
33
11 1/25/2019
34
Headington JT. Transverse microscopic anatomy of the human scalp. A basis for a morphometric approach to disorders of the hair follicle. Arch Dermatol. 1984;120(4):449–456.
35
36
12 1/25/2019
Embed cut surfaces down in paraffin block
37
38
Transverse sections
Dermis Level 6 Level 5 Level 4 Level 3 Level 2 Fat Level 1
Cut Surface Inked Courtesy of John Maize, Jr., MD
39
13 1/25/2019
Frishberg DP, Sperling LC, Guthrie VM. J. Am. Acad. Dermatol. 1996;35(2 Pt 1):220–222. 40
Frishberg-Sperling method
41
42
14 1/25/2019
43
44
45
15 1/25/2019
46
Pattern analysis in alopecia
Fundamental assessment of whether hair loss is present Is it scarring (permanent) or non-scarring? Caveat: many forms of hair loss are biphasic Phases in which the alopecia is not yet permanent, but may become so over time (e.g., androgenetic alopecia) Composition of the infiltrate can be considered important in scarring alopecia mainly Other specific features for final classification
47
Biphasic patterns of alopecia
Modified from A. Solomon, in Sellheyer K, Bergfeld WF. Histopathologic evaluation of alopecias. Am J Dermatopathol. 2006;28(3):236–259.
48
16 1/25/2019
Pattern analysis in alopecia
Analysis depends on the area chosen for biopsy If an area of burnt out alopecia is selected, diagnostic features may not be present If an area with secondary inflammation is chosen, these features may obscure the primary pathology Sampling of an area at the periphery of an alopecic zone without obvious secondary impetiginization or trauma is ideal
49
“CHECKLIST” Adapted from Sperling’s atlas Is the specimen adequate? Is the hair count normal or decreased? Are follicular units evenly spaced, or is there evidence of follicular dropout? could imply a scarring alopecia or extreme miniaturization Do most follicular units contain 2-6 follicles? Are more than 85% of hairs in anagen phase (normal) How many follicles are terminal, how many vellus? Are there sebaceous glands? Is there perifollicular fibrosis? Are there scarred fibrous tracts? Is there solar elastosis (longstanding process)? Is there inflammation, and if so, at what level of the follicle? What is the composition of the infiltrate? Are there follicles or hair shafts with unusual features?
50
Non-scarring versus scarring: common features by pattern
Non-scarring Scarring
Preservation of Perifollicular fibrosis, sebaceous glands at infundibular or
Empty, non-scarred isthmic level follicular tracts Fibrotic follicular tracts
Shifts in follicular Compound follicles phase
51
17 1/25/2019
Non-scarring alopecia
52
Non-scarring alopecia
Androgenetic alopecia Alopecia areata Trichotillomania Traction alopecia
Telogen effluvium Temporal triangular alopecia Alopecia mucinosa
53
Androgenetic alopecia
Clinical features: Progressive thinning at bitemporal hairline, scalp vertex, widening part Thinning > shedding Even though considered a non-scarring alopecia, may become permanent over time (biphasic) Permanent alopecia due to chemotherapy for breast cancer may also display this pattern taxanes, busulfan, cisplatin, etoposide implicated
54
18 1/25/2019
Androgenetic alopecia Clinical features
55
Androgenetic alopecia Histologic features
Progressive miniaturization Hairs of various diameters and lengths Decreased terminal hairs in the subcutis
Reduction in ratio of terminal to vellus hairs (<2:1)
Slight increase in catagen/telogen phase follicles
as hairs miniaturize, spend more time in telogen
Preservation of sebaceous lobules, fibrous tracts
Sparse superficial lymphocytic infiltrate
Late phase: follicular tracts grayish, less vascular the process become irreversible (dec. follicular density/size)
56
57
19 1/25/2019
58
59
60
20 1/25/2019
61
62
63
21 1/25/2019
64
65
66
22 1/25/2019
67
68
69
23 1/25/2019
Permanent alopecia after chemotherapy
All had hair loss during chemotherapy, but then insufficient hair regrowth First attack by chemotherapy with miniaturization/inflammation, then cannot regenerate due to hormonal therapy
Pattern similar to androgenetic alopecia or alopecia areata, but diffuse short hairs common
Increased telogen hairs (anagen 3:1), often in groups may reflect synchronization after anagen effluvium
Terminal:vellus ratio 1:1 (lower than normal scalp and AGA)
Miteva M, Misciali C, Fanti PA, et al. Permanent alopecia after systemic chemotherapy: a clinicopathological study of 10 cases. Am J Dermatopathol. 2011;33(4):345–350. Fonia A, Cota C, Setterfield JF, Goldberg LJ, Fenton DA, Stefanato CM. Permanent alopecia in patients with breast cancer after taxane chemotherapy and adjuvant hormonal therapy: Clinicopathologic findings in a cohort of 10 patients. J Am Acad Dermatol. 2017;76(5):948-957.
70
Courtesy Of Anna Haemel, MD 71
Fonia A, Cota C, Setterfield JF, Goldberg LJ, Fenton DA, Stefanato CM. Permanent alopecia in patients with breast cancer after taxane chemotherapy and adjuvant hormonal therapy: Clinicopathologic findings in a cohort of 10 patients. J Am Acad Dermatol. 2017;76(5):948-957.
72
24 1/25/2019
Androgenetic alopecia
Differential diagnosis: Post-inflammatory phase of alopecia areata (also miniaturized hairs, but marked catagen/telogen shift)
Telogen effluvium (no significant miniaturization in “pure” acute cases)
73
Temporal triangular alopecia
Clinical: localized temporal zone of alopecia may be evident at birth, or occur in the first decade rarely occurs later in life or in other locations persists indefinitely Histologic: normal numbers of hairs all vellus hairs, no terminal no follicular streamers Courtesy of Matt Kanzler, MD no inflammation
74
75
25 1/25/2019
76
77
78
26 1/25/2019
Alopecia areata Clinical features
May affect any hair on the scalp or body, with localized well-marginated alopecic patches
Complete involvement of scalp (totalis) or all body hair (universalis) may occur rarely Exclamation point hairs: they thin and are hypopigmented as they emanate from scalp Affects pigmented hairs preferentially May become irreversible rarely
79
Alopecia areata Clinical features
80
Alopecia areata Histologic features Early to subacute: Normal number of hairs Peribulbar lymphocytic infiltrate of varying intensity, often with eosinophils Dramatic shift to catagen/telogen phase hairs Increased miniaturized hairs Trichomalacia Pigmented hair casts Narrowing of hair shafts Melanin, lymphocytes, eosinophils in fibrous tracts Similar features observed in: Non-scarring alopecia of systemic LE (follicular interface changes); moth eaten alopecia of syphilis (plasma cells); novel drug reactions (e.g., checkpoint inhibitors, CTLA-4, PD-1)
81
27 1/25/2019
82
83
84
28 1/25/2019
Alopecia areata Histologic features
Post-inflammatory phase and chronic longstanding:
Most hairs in catagen/telogen phase
Nanogen hairs (miniaturized rapidly cycling hairs with unusual configurations)
Dilated follicular infundibula (“Swiss cheese” pattern)- corresponds to yellow dots seen dermatoscopically
85
86
87
29 1/25/2019
88
89
90
30 1/25/2019
91
92
93
31 1/25/2019
94
Müller CSL, El Shabrawi-Caelen L. “Follicular Swiss cheese” pattern- -another histopathologic clue to alopecia areata. J. Cutan. Pathol. 2011;38(2):185–189.
95
Adalimumab for Crohn’s disease
Courtesy of Sheila Krishna, MD
96
32 1/25/2019
TNF-inhibitor “psoriasiform” alopecia
97
SLE alopecia slide courtesy of Antoanella Calame, MD, MD
98
99
33 1/25/2019
100
101
Trichotillomania/traction alopecia Clinical features
Due to pulling, twisting of hair in a compulsive manner Irregular patches of alopecia with hairs of uneven lengths
May be accompanied by lichen simplex chronicus or erosions
In traction alopecia, pulling is gentler, more chronic Usually due to tight braiding, other styles which pull on hair Biphasic, scarring over time
102
34 1/25/2019
Trichotillomania/traction alopecia Histologic features
Normal number and size of hairs Dramatic shift to catagen and telogen phase Distorted hair follicles, collapsed inner root sheath Pigment casts (fragmented matrix or cortex at an abnormal level) Trichomalacia (abnormal hair shaft, incomplete cornification) Hemorrhage, no significant inflammation Acute traction alopecia is similar but usually less severe Late traction is scarring decrease in total terminal follicles and follicular units, fibrous tracts, preserved sebaceous lobules, no inflammation
103
104
105
35 1/25/2019
106
107
108
36 1/25/2019
109
110
111
37 1/25/2019
112
Traction
113
EVG
114
38 1/25/2019
Telogen effluvium Clinical features
Occurs when a large number of hairs enter catagen and then telogen phase Results in hair shedding and usually diffuse scalp alopecia, also affects other body hair Causes: physiologic (pregnancy, effluvium of the newborn), medications, metabolic/endocrinologic disturbance, serious illness, infection and/or fever, surgery, psychological stress Hair loss noted 2-3 months after precipitating event, medication use, can be chronic Hair pull test may reveal many club (telogen) hairs
115
Telogen effluvium Histologic features
Increase in terminal telogen phase follicles (greater than 20%) Normal number of hairs in the specimen (in pure cases) Reduced number of terminal hairs in the subcutis (they are shorter when in telogen) Normal terminal to vellus hair ratio (>2:1) in pure cases No significant inflammation Many cases are not pure (element of androgenetic can be confusing)
116
117
39 1/25/2019
118
119
120
40 1/25/2019
Scarring (cicatricial) alopecia
121
Most recent classifications of primary scarring alopecia use the type of inflammatory infiltrate, lymphocytic versus neutrophilic, to stratify it
Olsen EA, Bergfeld WF, Cotsarelis G, et al. J. Am. Acad. Dermatol. 2003;48(1):103–110.
122
Sellheyer K, Bergfeld WF. Histopathologic evaluation of alopecias. Am J Dermatopathol. 2006;28(3):236–259.
123
41 1/25/2019
Lymphocyte-mediated Scarring alopecia
Chronic (discoid) lupus erythematosus (LE) Lichen planopilaris (LPP) Central centrifugal cicatricial alopecia (CCCA) Pseudopelade of Brocq Alopecia mucinosa (rarely scarring) Keratosis follicularis spinulosis decalvans
124
Chronic LE Clinical features
Well-marginated sclerotic atrophic plaques Dyspigmentation and dilated/plugged follicular ostia Early lesions may resemble a non- scarring alopecia
125
Chronic LE Histologic features
Interface reaction, may or may not involve overlying epithelium Lymphocytic infiltrate of varying intensity, superficial and deep and periadnexal (follicles and ductal epithelium) May contain plasma cells (not usually in LPP) Interstitial mucin (not usually in LPP) Epidermal atrophy with hyperkeratosis (also not in LPP usually) Thickened basement membrane zone (not in LPP) DIF may be helpful CD123: large clusters in LE versus LP sometimes
Fening K, Parekh V, McKay K. CD123 immunohistochemistry for plasmacytoid dendritic cells is useful in the diagnosis of scarring alopecia. J Cutan Pathol. 2016 Aug;43(8):643-8. 126
42 1/25/2019
127
128
129
43 1/25/2019
130
131
132
44 1/25/2019
133
134
Lichen planopilaris (LPP) Clinical features
Variants: classic LPP, frontal fibrosing alopecia, and Graham-Little syndrome (involvement of scalp, pubic, axillary hair and keratosis pilaris) Patients with classic LPP may or may not have skin lesions elsewhere The pattern of hair loss varies Perifollicular hyperkeratosis and erythema are constant features Tufted hairs (polytrichia) may be present Frontal fibrosing alopecia affects the frontal hairline and eyebrows (these patients generally do not have other cutaneous lesions of LP)
135
45 1/25/2019
136
Frontal fibrosing alopecia
137
Lichen planopilaris (LPP) Histologic features Early: Perifollicular bandlike infiltrate of lymphocytes, usually not perivascular or peri-eccrine Vacuolar alteration and dyskeratosis Hypergranulosis can occur within affected follicular epithelium Perifollicular fibrosis, often pallid, at infundibular level May contain interfollicular disease, which can be helpful Late: many features not specific to LPP Dropout of follicular units or individual follicles Compound follicles (often in groups of 2 and 3) Cleft between affected follicle and surrounding dermis Naked hair shafts
138
46 1/25/2019
139
140
141
47 1/25/2019
142
143
144
48 1/25/2019
145
146
LPP AB
CD
Abner A and Ruben BS. The distribution of plasmacytoid dendritic cells in alopecia biopsies of discoid lupus erythematosus and lichen planopilaris. Poster, ASDP Annual Meeting, 2015. 147
49 1/25/2019
LE AB
C
DE
148
Central centrifugal cicatricial alopecia (CCCA) Clinical features
Hair loss usually on the vertex/crown Progressive over many years and then tends to abate The area of involvement is usually symmetrical, disease activity occurs at the periphery of the alopecic area Known previously as follicular degeneration syndrome Some consider this to lie on a spectrum with folliculitis decalvans More common in African American patients (most common cause of hair loss in this group) Women more affected than men
149
CCCA
150
50 1/25/2019
Central centrifugal cicatricial alopecia (CCCA) Histologic features
Indistinguishable from LPP, FFA Premature desquamation of the inner root sheath below level of eccrine glands described in some cases as an early finding (usually occurs at mid to upper isthmic level); not specific Results in eccentric follicular atrophy
151
152
153
51 1/25/2019
154
155
156
52 1/25/2019
157
Pseudopelade of Brocq
Controversial! An end-stage alopecia Probably not a distinct clinical condition Porcelain white zones of alopecia Scarring alopecia histologically without inflammation
158
159
53 1/25/2019
160
Studying sections from “burned out” lesions is like scouring a tombstone for the identity of the person buried beneath it.
A. Bernard Ackerman, M.D. 1997
161
Neutrophil-mediated scarring alopecia
Folliculitis decalvans/tufted folliculitis Dissecting cellulitis/folliculitis Bacterial and dermatophytic folliculitis (tinea capitis, kerion) should always be considered in the differential diagnosis
162
54 1/25/2019
Folliculitis decalvans/tufted folliculitis Clinical features
Marginated zone of alopecia with peripheral rim of erythema and pustules Tufted hairs may occur May occur as a reaction to some biologic agents (kinase inhibitors, e.g. erlotinib) for cancer with an overlap with erosive pustular dermatosis
163
Erlotinib reaction Courtesy, Lindy Fox, MD
164
Folliculitis decalvans/tufted folliculitis Histologic features
Suppurative folliculitis Neutrophilic infiltrate, in and around follicles Plasma cells are prominent in later disease Perifollicular and interfollicular fibrosis Compound follicles in larger groups (“six packs” said to be pathognomonic)
165
55 1/25/2019
Courtesy of Timothy McCalmont, MD 166
Pincus LB, Price VH, McCalmont TH. Journal of Cutaneous Pathology. 2011;38(1):1–1.
167
168
56 1/25/2019
169
170
171
57 1/25/2019
172
173
Dissecting cellulitis/folliculitis Clinical features
Often occurs in younger adult African American men Deep nodules, draining sinus tracts and boggy plaques with associated alopecia Vertex and occiput most commonly involved Can be part of follicular occlusion triad (acne conglobata, hidradenitis suppurativa)
174
58 1/25/2019
Dissecting cellulitis/folliculitis Histologic features
Early lesions rarely sampled, may have a dense mostly lymphocytic infiltrate in lower dermis and subcutis, with catagen/telogen shift, and sebaceous glands may be left intact Infiltrate tends to be deep, contains lymphocytes, neutrophils, plasma cells Later lesions contain granulation tissue and extensive fibrosis Sinus tracts (not seen in acne keloidalis)
175
176
177
59 1/25/2019
178
179
Other scarring alopecia
Mixed infiltrate Acne keloidalis nuchae Acne necrotica Erosive pustular dermatosis of the scalp Secondary scarring alopecia Suppurative folliculitides, including tinea capitis; trauma; cicatricial pemphigoid, other bullous diseases; sarcoidosis; radiation; alopecia neoplastica (not really a scarring alopecia but a permanent alopecia due to an infiltrative process)
180
60 1/25/2019
Combined alopecia
Wohltmann WE, Sperling L. Histopathologic diagnosis of multifactorial alopecia. J Cutan Pathol. 2016;43(6):483-491.
181
182
Acknowledgments
Vera Price, MD Timothy H. McCalmont, MD
183
61 1/25/2019
184
References
Headington JT. Transverse microscopic anatomy of the human scalp. A basis for a morphometric approach to disorders of the hair follicle. Arch Dermatol. 1984;120(4):449–456. Frishberg DP, Sperling LC, Guthrie VM. Transverse scalp sections: a proposed method for laboratory processing. J. Am. Acad. Dermatol. 1996;35(2 Pt 1):220–222. Flotte TJ. Transverse sectioning of the scalp (Headington technique) in the 19th century. J. Cutan. Pathol. 2008;35(1):82–85. Nguyen JV, Hudacek K, Whitten JA, Rubin AI, Seykora JT. The HoVert technique: a novel method for the sectioning of alopecia biopsies. J. Cutan. Pathol. 2011;38(5):401–406. Elston D. The “Tyler technique” for alopecia biopsies. J. Cutan. Pathol. 2012;39(2):306. Sperling LC. Scarring alopecia and the dermatopathologist. J. Cutan. Pathol. 2001;28(7):333–342. Sperling LC. An atlas of hair pathology with clinical correlations. Parthenon Publishing, New York, 2003. Whiting DA. The structure of the human hair follicle: light microscopy of vertical and horizontal sections of scalp biopsies. Canfield Publishing, Fairfield, NJ. 2004. Olsen EA, Bergfeld WF, Cotsarelis G, et al. Summary of North American Hair Research Society (NAHRS)- sponsored Workshop on Cicatricial Alopecia, Duke University Medical Center, February 10 and 11, 2001. J. Am. Acad. Dermatol. 2003;48(1):103–110. Sellheyer K, Bergfeld WF. Histopathologic evaluation of alopecias. Am J Dermatopathol. 2006;28(3):236–259. Miteva M, Misciali C, Fanti PA, et al. Permanent alopecia after systemic chemotherapy: a clinicopathological study of 10 cases. Am J Dermatopathol. 2011;33(4):345–350. Peckham SJ, Sloan SB, Elston DM. Histologic features of alopecia areata other than peribulbar lymphocytic infiltrates. J. Am. Acad. Dermatol. 2011;65(3):615–620. Müller CSL, El Shabrawi-Caelen L. “Follicular Swiss cheese” pattern--another histopathologic clue to alopecia areata. J. Cutan. Pathol. 2011;38(2):185–189. Pincus LB, Price VH, McCalmont TH. The Amount Counts: Distinguishing Neutrophil-Mediated and Lymphocyte-Mediated Cicatricial Alopecia By Compound Follicles. Journal of Cutaneous Pathology. 2011;38(1):1–1. Hu JC, Sadeghi P, Pinter-Brown LC, Yashar S, Chiu MW. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol. 2007 Feb;56(2):317-26.
185
References (continued)
Fening K, Parekh V, McKay K. CD123 immunohistochemistry for plasmacytoid dendritic cells is useful in the diagnosis of scarring alopecia. J Cutan Pathol. 2016 Aug;43(8):643-8. doi: 10.1111/cup.12725. Afanasiev OK, Zhang CZ, Ruhoy SM. TNF-inhibitor associated psoriatic alopecia: Diagnostic utility of sebaceous lobule atrophy. J Cutan Pathol. 2017;44(6):563-569. doi:10.1111/cup.12932 Strazzulla LC, Wang EHC, Avila L, et al. Alopecia areata: Disease characteristics, clinical evaluation, and new perspectives on pathogenesis. J Am Acad Dermatol. 2018;78(1):1-12. doi:10.1016/j.jaad.2017.04.1141 Strazzulla LC, Avila L, Li X, Lo Sicco K, Shapiro J. Prognosis, treatment, and disease outcomes in frontal fibrosing alopecia: A retrospective review of 92 cases. J Am Acad Dermatol. 2018;78(1):203-205.
Ma SA, Imadojemu S, Beer K, Seykora JT. Inflammatory features of frontal fibrosing alopecia. J Cutan Pathol. 2017;44(8):672-676. doi:10.1111/cup.12955
Fonia A, Cota C, Setterfield JF, Goldberg LJ, Fenton DA, Stefanato CM. Permanent alopecia in patients with breast cancer after taxane chemotherapy and adjuvant hormonal therapy: Clinicopathologic findings in a cohort of 10 patients. J Am Acad Dermatol. 2017;76(5):948-957. doi:10.1016/j.jaad.2016.12.027 Zarbo A, Belum VR, Sibaud V, et al. Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors. Br J Dermatol. 2017;176(6):1649-1652. doi:10.1111/bjd.15237
Bolduc C, Sperling LC, Shapiro J. Primary cicatricial alopecia: Lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome. J Am Acad Dermatol. 2016;75(6):1081-1099. doi:10.1016/j.jaad.2014.09.058 Bolduc C, Sperling LC, Shapiro J. Primary cicatricial alopecia: Other lymphocytic primary cicatricial alopecias and neutrophilic and mixed primary cicatricial alopecias. J Am Acad Dermatol. 2016;75(6):1101-1117. doi:10.1016/j.jaad.2015.01.056 Kolivras A, Thompson C. Primary scalp alopecia: new histopathological tools, new concepts and a practical guide to diagnosis. J Cutan Pathol. 2017;44(1):53-69. doi:10.1111/cup.12822 LaSenna C, Miteva M. Special Stains and Immunohistochemical Stains in Hair Pathology. Am J Dermatopathol. 2016;38(5):327-337. doi:10.1097/DAD.0000000000000418 Wohltmann WE, Sperling L. Histopathologic diagnosis of multifactorial alopecia. J Cutan Pathol. 2016;43(6):483-491. doi:10.1111/cup.12698
186
62 THURSDAY DERMATOPATHOLOGY
Diagnostic Uses of Molecular Testing in Cutaneous Neoplasia
DR JANE MESSINA 1/25/2019
• I have no conflicts of interest to disclose
• Disclaimers: I am NOT a molecular pathologist; for questions about methodology, please refer to: – https://www.karger.com/Article/FullText/480089 (NGS)
1
Goals
• Review current best practices • Billing and coding considerations • Routinely available tests and indications
2
Clinical grade molecular testing
Fluorescence Genomic profiling of in situ circulating DNA (“liquid hybridization biopsy”, e.g. Guardant360)
Comparative Melanoma‐specific genomic mutation screening hybridization (e.g. MelaCarta)
Gene expression profiling Comprehensive genomic profiling (Decision Dx, myPATH) of tumor (e.g. Illumina MiSeq, Ion Torrent, Foundation Medicine) Gene rearrangement for lymphoid and Specific mutation Carcinoma of soft tissue tumors screening, e.g. BRAF, unknown primary NRAS, c‐KIT panels
3
1 1/25/2019
Molecular testing practices among dermatopathologists
• Survey of ASDP membership, 2017 • 62% order >12 tests/year • More frequent testing associated with training, pathology residency, academic practice, higher volume, onsite laboratory • Barriers cited: coverage, cost, lack of evidence‐based guidelines, availability
Torre K et al. J Cutan Pathol 2018; 45(6): 398‐394 4
Evidence‐based guidelines: appropriate use criteria
• Combine scientific evidence with expert panel rating to assess appropriateness of testing in specific scenarios • 2015, ASDP AUC task force: 12 ancillary tests rated with 89% consensus – Lymphoid: TCR and , IgH rearrangement – Melanocytic: FISH, CGH, qRT‐PCR – Others: HPV, MMR, t(17;22) for DFSP, EWSR1 for clear cell sarcoma
Vidal et al; J Am Acad Dermatol 2019; 80:189‐207.
5
Evidence‐based guidelines: appropriate use criteria
• Combine scientific evidence with expert panel rating to assess appropriateness of testing in specific scenarios • 2015, ASDP AUC task force: 12 ancillary tests rated with 89% consensus – Lymphoid: TCR and , IgH rearrangement – Melanocytic: FISH, CGH, qRT‐PCR – Others: HPV, MMR, t(17;22) for DFSP, EWSR1 for clear cell sarcoma
Vidal et al; J Am Acad Dermatol 2019; 80:189‐207.
6
2 1/25/2019
Practical issues • How much tissue? – Most tests use equivalent of 5‐10 5 recuts, or a 1.5 mm core of FFPE tissue • Is the test covered by insurance? – Ordering physician should be familiar with national and local coverage determinations developed by CMS – Patient may be billed if test not covered – Test must be ordered by physician (for a pathologist, signature on the requisition form)
7
FDA approved companion diagnostic tests for melanoma
• Foundation Medicine cDX • THXID BRAF kit (bioMerieux, Inc) and cobas 4800 BRAF V600 mutation test (Roche Molecular Systems, Inc.)
8
Practical issues: coding and reimbursement (review with Carolyn) Code Test Coverage in Reimbursement Florida? 88381 Microdissection Yes $144.00 81210 BRAF mutation Yes $180.23 81210‐ Other genes (NRAS, KRAS, KIT) Yes* $180‐$725 81479 81445 Targeted gene sequencing 5‐50 Yes, with $602.10 genes provisions* 81450 Targeted gene sequencing >51 genes G0452 Pathologist interpretation of Yes** $19.00 results *must have five actionable genes to bill panel **no more than 6 G codes per panel allowed
9
3 1/25/2019
Coding and reimbursement
Code Test Reimbursement?
88377 or FISH $800‐1100 88374 81228 or Copy number variation testing i.e. CGH Sometimes (Aetna) 81229 81599 Decision Dx pending Under myPATH consideration Under PLA (pigmented lesion assay) consideration 86152/3 Circulating tumor cells Not covered
10
When to test?
Stage I/II Stage III Stage IV Resistance
Molecular testing Consider prognostic Mutation testing or Mutation profile or Reassess tumor profile testing mutation profiling next‐gen sequencing Treatment Surgery Surgery Molecular‐based drug Molecular‐based drug Adjuvant therapy strategy strategy
11
Available molecular tests for melanoma
• Diagnostic aid: FISH, CGH, Myriad myPATH • Prognostic testing: Decision Dx • Direct course of treatment: mutation testing
12
4 1/25/2019
Diagnostic molecular testing
• Frequently used in the evaluation of diagnostically challenging melanocytic proliferations – Atypical Spitzoid proliferations (AST) – Atypical blue nevus‐like proliferations – Nevoid melanoma • NCCN: “consider the use of molecular testing for histologically equivocal lesions” • ASDP: FISH and CGH usually appropriate in MM v all benign nevus variants, inappropriate in definitive cases NCCN guidelines Cutaneous Melanoma 1.2019
13
10 year old with changing scalp lesion
14
15
5 1/25/2019
Fluorescence in situ hybridization
Old assay New assay 6q23 CEP6 6p25, 11q13 8q24 9p21 CEP9 MYB RREB1 CCND1 MYC CDKN2A
Unequivocal Sensitivity: 87% 94% melanoma Specificity: 95% 98% • Availability: – NeoSITE® melanoma, Neogenomics Laboratories (Ft. Myers, FL), $1500 – Inform Diagnostics, Mayo Reference Lab • What about borderline lesions such as this?
16
FISH in histologically ambiguous Spitzoid lesions (AST)
Probe set AST w/o “AST” with poor Typical Spitz recurrence outcome (melanoma)
OLD sensitivity 50‐100% 6,1,4
OLD specificity 57‐91% 4,1 75‐100%5,1
NEW sensitivity 50‐100%3,2
NEW specificity 74‐87%2,3
1 Demarchis EH et al, Pediatr Dermatol. 2014; 31(5) 561‐9 2 Gerami et al, Am J Surg Pathol Feb 2013 3 Tetzlaff et al, Am J Surg Pathol. Dec 2013 4 Massi et al. J Am Acad Dermatol 2011;64:919‐35 5 Dika et al Mel Research 2015; 25(4): 295‐301 6 Vergier et al. Modern Pathology 2011; 24: 613‐623
17
Specific FISH abnormalities associated with outcome in borderline lesions (AST)
• Homozygous deletion of 9p21: predicts local recurrence and only feature predictive of death • Gain of 6p25 and/or 11q13: predicts SLN involvement but not recurrence or death • Heterozygous 9p21 loss: significant sentinel node involvement but no spread beyond the regional nodes • 6q23 (MYB) loss: associated with good long term outcome
Gerami et al, Am J Surg Pathol, Feb 2013 North et al. Am J Surg Pathol 2014;38:824‐31 Raskin et al. Am J Surg Pathol 2011;35:243‐52 18
6 1/25/2019
FISH and lesions with other histology
• Blue nevus‐like melanoma vs epithelioid blue nevus – 90% sensitive, 100% specific in 10 cases – Heavy melanin pigmentation can obscure stain result • Nevoid melanoma – performance comparable to all melanomas – 6p25 in 49%; 8q24 in 27%‐especially amelanotic lesions • Acral melanoma: – performance comparable to all melanomas Yélamos O et al. J Cutan Pathol. 2015 Nov;42(11):796‐806. Pouryazdanparast P et al. Am J Surg Pathol. 2009 Sep;33(9):1396‐400. Su J et al. Pathology. 2017 Dec;49(7):740‐749.
19
FISHing for real melanoma: newer assay
• Tetzlaff et al., 34 ambiguous lesions – “Benign” favored on histology: 3/24 FISH+ – “Malignant” favored on histology: 5/10 FISH+ – Sensitivity 50% , specificity 87% – In setting of a predominantly benign histology, negative FISH is reassuring
Gerami et al, Am J Surg Pathol, Feb 2013 Tetzlaff et al, Am J Surg Pathol, Dec 2013
20
Back to our case…
• IHC: – P16 retained – Ki‐67: 10% proliferation index (4 mitoses noted) • FISH – Could not be performed due to heavy melanin pigmentation • Next step: comparative genomic hybridization
21
7 1/25/2019
Comparative genomic hybridization • Assesses chromosomal copy number changes across tissue, not individual cell abnormalities • 95% of melanomas harbor numerous chromosomal gains and losses • Nevi rarely show aberrations • Exceptions: – 12‐26% of Spitz nevi (esp. recurrent) have 11p or 7q gain – Some AST have abnormal CGH (45%, most common gain of 1p) • Does not predict SLN involvement • Proliferative nodules in congenital nevi may have whole chromosomal gains
Bastian BC et al. J Invest Dermatol. 1999;113:1065–1069. Bastian BC et al. Am J Pathol. 2003;163:1765–1770 Raskin et al. Am J Surg Pathol 2011;35:243–252
22
Comparative genomic hybridization
• Most commonly used to distinguish pediatric atypical Spitz tumor from melanoma • Not widely available, insurance coverage varies • Typical out‐of‐pocket cost $2500
23
Back to our case
• CGH shows gains involving chromosome 4, 6p, interstitial 17q, 20q • Losses involving 6q, 9q • Plan: perform sentinel node biopsy
24
8 1/25/2019
Sentinel node 1
Diagnosis: animal‐type (pigment synthesizing melanoma, 1 of 2 SLN positive
25
19 year old female with cyst‐like lesion on scalp
26
Molecular testing
• FISH – 6p25: 30% nuclei have extra copies (>29% high stringency cutoff) – 8q24(cMYC), CDKN2a, and CCND1 probes WNL • GNAQ/GNA11 testing – mutation in q209P of GNAQ gene • CGH – 4 whole chromosomal gains: 6, 8, 9, and 18
CONCLUSION: Probable melanoma arising in blue nevus
27
9 1/25/2019
Myriad MyPath‐diagnostic aid for equivocal lesions • 23‐gene expression signature that can help differentiate nevi from melanoma‐ utilizes 5 recut slides from paraffin block • Training and validation cohorts of 900+ unequivocal melanoma and nevi: sensitivity 90% specificity 91% • Currently undergoing large‐scale testing of clinical utility with melEvalPRO
Superficial spreading>nodular>lentigo maligna
Compound and dermal nevi
Clarke et al. J Cutan Pathol 2015; 42:244‐252 28
Independent validation of myPath
• 1400 lesions independently reviewed by 3 experts – Triple concordance: 993 lesions (70.9%) – Excluded indeterminate scores: 860 lesions (24% malignant, 76% benign) – Excluded lesions with <10% tumor volume: 763 lesions • Sensitivity 91.5% ‐‐ Specificity 92.5% – False negative risk‐lentigo maligna and desmoplastic melanoma variants – False positive risk‐dysplastic nevi
Clarke et al., Cancer, October 2016 Clarke LE et al. Human Pathol, 2017 Dec; 70: 113‐20
29
29 year old pregnant female with changing lesion on back
Junctional dysplastic nevus with moderate to severe atypia 30
10 1/25/2019
MyPath and FISH for diagnostically challenging lesions (1)
• 39 unequivocal lesions: 62% sensitivity, 95% specificity • 78 challenging lesions with expert consensus (27 favor malignant, 30 favor benign, 21 ambiguous) • myPath score agreed with histology in 64%, agreed with FISH 70% of time – Limited by lack of clinical outcome
SUMMARY: myPath score can increase diagnostic certainty and influence treatment recommendations, BUT performance not proven in ambiguous lesions
Minca et al, Modern Pathology, August 2016, 29:832‐843.
31
MyPath and FISH for diagnostically challenging lesions (2)
• 198 unequivocal and 70 morphologically ambiguous cases • Performance for unambiguous cases similar to original studies • 69% agreement between FISH and myPath • Ambiguous cases using histology as gold standard: – FISH 61% sensitive, 100% specific – MyPath 50% sensitive, 93% specific
Reimann JDR et al. Mod Pathol 2018 Nov; 31(11):1733‐1743
32
PLA assay (pigmented lesion assay) Dermtech
• Gene expression assay from stratum corneum harvested by adhesive – Expression of LINC00518 and PRAME • Performance on unequivocal lesions: – 81% sensitive, 55% specific • Potential utility for selection of lesions for biopsy Gerami P, et al, J Am Acad Dermatol 2017; 76:114‐120 Ferris LK, et al, JAMA Dermatol. 2017 Jul 1;153(7):675‐680 Childs MV: JAMA Dermatology, Dec. 2017 (Published Online) 33
11 1/25/2019
TERT promoter mutations
• Most common non‐coding cancer mutation, found in 60‐80% of melanoma • Presence in early‐stage tumors suggest early role in tumorigenesis • Identified in subsets of atypical Spitz tumors with aggressive behavior (distant metastases, death) • Is part of some large cancer gene panels, but as a single test is only available in research setting currently
Hayward et al. Nature 2017; 545(7653): 175‐180 Lee et al. Sci Rep 2015; 5 (1‐7).
34
Molecular tests for melanoma diagnosis Summary
• FISH and myPath sensitivity and specificity ~90% in unequivocal melanomas and nevi • FISH sensitivity drops to 50‐100% and specificity to 74‐87% in most commonly used scenario: the atypical Spitz tumor • A stepwise approach utilizing FISH, then CGH in equivocal cases may be considered • CGH can aid in atypical cases with negative FISH, but hampered by limited availability and reimbursement
35
Uses for molecular testing in melanoma
• Diagnostic aid • Describe distinct prognostic classes • Direct course of treatment • Predict response to treatment
36
12 1/25/2019
Decision‐Dx prognostic testing (Castle Biosciences)
• 31‐gene expression profile predicts outcome • Training/validation set of 268 Stage I‐IV patients – Multivariate analysis: superior to and independent of Breslow depth, ulceration, MR and AJCC stage in predicting metastatic disease
Training set n=164 Validation set n=107
97% 91% n=104 p<0.0001 31% 25%
Gerami et al. Clin Cancer Res 2015; 21(1): 175‐83.
37
Decision‐Dx + SLNB results may improve prognostic prediction
DFS DMFS OS Class 1/SLN- Class 1/SLN- Class 1/SLN- Class 1/SLN+
Class 2/SLN- Class 1/SLN+ Class 1/SLN+ Class 2/SLN- Class 2/SLN- Class 2/SLN+ Class 2/SLN+ Class 2/SLN+
• Convenience sample of 217 patients from 7 institutions‐ not representative of typical population undergoing SLNB
Gerami et al. J Am Acad Dermatol 2015;72:780‐5. 38
38
Decision Dx‐independent validation in 532 patients
• 40% are Class 2 • 5 year RFS Class 1=88%, Class 2=52% • Test identified 70% of patients who developed metastatic disease‐improved sensitivity over SLNB • Utility of testing unclear – Adjuvant therapy trial? – Enhanced follow up regimens? – Significant number of Class 2 did NOT recur‐anxiety?
Submitted to Annals of Oncology
39
13 1/25/2019
Decision‐Dx practice guidelines
• AAD: lack of surgical or therapeutic trials in context of GEP discourages their use for prognostication or management decisions • NCCN: routine (baseline) prognostic genetic testing of primary cutaneous melanomas not recommended outside of a clinical study (trial)
Swetter et al. J Am Acad Dermatol 2019: 80(1):208‐250 NCCN Guidelines Cutaneous Melanoma 1.2019
40
Uses for molecular testing in melanoma
• Diagnostic aid • Describe distinct prognostic classes • Direct course of treatment • Predict response to treatment
41
Molecular alterations direct targeted therapy
SCF EGF HGF MSH C‐KIT EGFR cMET MC1R • Oncogenes RAS – BRAFv600E: ~50%
PI‐3K BRAF – NRAS: 20‐30% – c‐KIT: 2‐5% PTEN MEK • Tumor suppressors
AKT ERK – PTEN: 10‐50% – CDKN2a/CDK4: 30‐70% mTOR CCND1/C DK4/6
p16
Survival Proliferation
Palmieri et al. Front Oncol 2015;5:183
42
14 1/25/2019
What panel do I use?
• Laboratory‐developed tests: next generation sequencing using pre‐determined panels (e.g. Illumina Trusight, Agena Melacarta)
• Commercially available tests: – Foundation One‐324 genes (cost $5800, no balance billing) – Genoptix‐15 genes – MSK‐IMPACT‐468 genes – Academic reference labs, e.g. Washington University, ARUP, Mayo Medical labs
43
Which gene panel/platform? Ion AmpliSeq
Agena Melacarta • Genoptix Melanoma Molecular Profile: AKT3, BRAF, CCND1, CDK4, ERBB4, GNA11, GNAQ, KIT, MPA2K1, MAP3K0, MITF, NF1, NRAS, PIK3CA, PTEN COMMON GENES: BRAF, NRAS, GNAQ, KIT, PIK3CA, but most can be customized 44
Test for one versus multiple alterations?
• NCCN: Consider broader genomic profiling if the test results might guide future treatment decisions or eligibility for participation in a clinical trial
NCCN guidelines Cutaneous Melanoma 1.2018
45
15 1/25/2019
While you are waiting for your test results… identifying melanoma mutations by immunohistochemistry • VE1 antibody: identifies v600E mutant melanoma by IHC‐ sensitivity 97%, specificity 98% • SP174: NRAS Q61R‐sensitivity and specificity 100% • 26193: NRAS Q61L‐sensitivity 82%, specificity 96% • Initial reports note heterogeneity of staining within patients and individual tumors in up to 18% of cases
Capper et al. Acta Neuropathol 2012 Feb;123(20):223‐33 Long et al. Am J Surg Pathol 2012 (epub ahead of print). Kakavand H et al, Histopathology 2016: 69:680‐686
46
c‐KIT immunohistochemistry
• Immunohistochemical expression does not correlate with sensitivity to inhibitor • IHC stain useful in screening tumor before testing • 181 cases: 85% had >15% cells positive by IHC • no cases with <10% cells positive by IHC were mutation positive
Torres‐Cabala CA et al. Modern Pathol 22:1446‐1456, 2009.
47
Other uses of genomic testing: kinase fusions frequent in Spitzoid lesions
Incidence (%) 28% 34 BAP‐1 loss • Potentially useful if metastatic unknown disease 15% arises NTRK fusion RET fusionRET BRAF 6.1% ROS 9.5% ALK‐ 11% HRAS 1 fusion mutation
Van‐Engen‐van Grunsven et al. Am J Surg Pathol 2010;34:1436‐41 Wiesner et al. Nat Commun 2014;5:3116 48
16 1/25/2019
Other potentially targetable genes
• NF1 mutation (14% of TCGA set): preclinical studies suggest resistance to BRAF inhibition, sensitivity to MEK inhibitors • ALK fusion found in 2.4% primary/metastatic non‐ Spitzoid melanomas: one reported partial response to crizotinib • MET fusions identified in 0.24% of tumors: potential response to cabozantinib
Maertens et al, 2013, Whittaker et al, 2013 Busam et al, Am J Surg Pathol Feb 11 2016 epub of print Yeh et al. Nat Commun 2015 May 27; 6:7174 49
Molecular testing‐negative results?
• Case study: 45 year old male with recurrent soft tissue mass distal arm, originally diagnosed as melanoma • BRAF, NRAS, c‐KIT negative
• EWS/ATF translocation: positive • Diagnosis: clear cell sarcoma
50
Liquid biopsy
• Detects alterations in 73 genes using circulating tumor DNA (~0.4% of total DNA in blood) • Indications: insufficient tumor, follow patients on therapy, or detect rarely tested mutations • Guardant360: in 400 advanced cancer patients, ctDNA and tumor results matched 87% of time; 98% when within 6 months – Uncovered additional mutations not in tumor samples – Little experience in melanoma (n=1)
Zill et al. J Clin Oncol 34, 2016 (suppl; abstr LBA11501)
51
17 1/25/2019
Circulating tumor DNA
• Short nucleic acid fragments (~166 bp) in plasma, released by tumor apoptosis/necrosis • BRAF, cKIT, NRAS, TERT, PIK3CA have all been investigated • Pre‐treatment levels correlate with worse outcome • Sequential levels parallel disease course, may even precede radiologic changes – May distinguish pseudoprogression from true progression
Calpare L et al. Cancer Letters 52
Molecular testing in other cutaneous neoplasia
53
68 year old woman with 6‐month history of forehead mass
54
18 1/25/2019
First and second round of IHC
Ck5/6 p63 CK7
• Panel of organ‐specific markers (NKX3.1, TTF‐1, napsin, GCDFP, mammaglobin, WT‐1, PAX8, ER, CA‐125, mesothelin, CDX2) negative
55
Carcinoma of unknown primary
• Median survival 2‐4 months • Workup expensive, time‐consuming • 56 patients presenting to MCC with CUP: – Primary site found in 7% – 20% survived >1 year (mean 8 months) – Average cost of diagnosis $17,973
Schapira and Garrett Arch Int Med 1995 Oct 23; 155(19): 2050‐4 56
Workup of CUP: NCCN guidelines
• H&P, blood panel, CT chest/abdomen/pelvis, site‐ directed endoscopy, biopsy • Biopsy – Immunohistochemical analysis‐”exhaustive panels have not been shown to increase diagnostic accuracy” • Tier 1: tissue lineage (carcinoma v sarcoma v lymphoma v melanoma) • Tier 2: putative primary site • Tier 3: biomarkers (e.g. RAS, HER2, ALK) – “Gene signature profiling for tissue of origin is not recommended for standard management at this time”
57
19 1/25/2019
Molecular profiles to assess tumor origin
• DNA‐based gene expression profiling (Cancer TYPE ID) and miRNA profile (Rosetta Cancer Origin test) commercially available, accuracy in validation sets ~85% • Accuracy of blinded testing in patients with latent/known primary – GEP: ~75% – IHC: ~65%
Hainsworth JD and Greco FA. Virchows Arch (2014) 464:393‐402
58
GEP v IHC in assessing CUP
• In five series of 117 patients, IHC predicts single site of origin in ~55% of cases – GEP prediction identical in 78% of these • Directing treatment with GEP diagnosis: no evidence of better survival compared to IHC in a single prospective study
Greco et al. 2013 J Natl Cancer Inst. Doi: 10.1093/jnci/djt099 Hainsworth JD and Greco FA. Virchows Arch (2014) 464:393‐402 59
One last test
CD34
60
20 1/25/2019
Dermatofibrosarcoma protuberans
• When to test for t(17:22)? • ASDP: test with CD34+ tumor with atypical histology for DFSP, or considering treatment • Routine testing of unequivocal tumors negative CD34‐negative DFSP with fibrosarcomatous transformation
61
Putting it all together: molecular testing
• Testing for diagnostically controversial lesions common, may augment histologic impression, know pitfalls • Utility of prognostic GEP needs further investigation • Genomic testing of melanoma directs therapy • EWSR1 in patients with dermal tumors with melanoma markers • ctDNA shows great promise • Carcinoma of unknown primary tests do not exceed IHC in accuracy or significantly add to patient care
62
…molecular analysis—allowing more efficient use of healthcare dollars?
63
21 1/25/2019
Thank you Thank you
# 64 64
22 THURSDAY DERMATOPATHOLOGY
Nail Pathology II: Non- melanocytic Neoplasms
DR BETH RUBEN 1/25/2019
Mighty Women of Dermatopathology Hawaii 2019 Nail pathology II: Non-melanocytic Neoplasms
Beth S. Ruben, MD Director, Dermatopathology Palo Alto Medical Foundation, Palo Alto, CA Professor of Dermatology University of California, San Francisco
1
Epithelial and other neoplasms of the nail unit • Some are counterparts to those found elsewhere • Some are entities unique to this site • Unusual features can create diagnostic quandaries • Diagnosis often depends on the adequacy of the specimen and the clinical history
2
Epithelial and other neoplasms
• Benign • Malignant – Onychopapilloma – SCCIS/SCC – Subungual epidermoid – Keratoacanthoma inclusions – Subungual tumors of – Onychomatricoma incontinentia pigmenti – Onychocytic matricoma – Onycholemmal CA – Superficial acral – Onychocytic CA (?) fibromyxoma – Papillary adenoCA
3
1 1/25/2019
Tosti A, Schneider SL, Ramirez-Quizon MN, Zaiac M, Miteva M. Clinical, dermoscopic, and pathologic features of onychopapilloma: A review of 47 cases. Journal of the American Academy of Dermatology. 2016;74(3):521-526.
4
Onychopapilloma
• Clinical findings – Erythronychia – Splinter hemorrhage – Melanonychia – Leukonychia – Distal hyperkeratosis – Distal splitting
Courtesy of Tara Miller, MD
5
Histologic features
• Hyperplasia of distal matrix and nail bed epithelium, papillated distally • Distal subungual hyperkeratosis/parakeratosis • Hemorrhage • Matrical metaplasia (eosinophilic, anucleated cell layer in nail bed) • Large and multinucleate distal nail bed keratinocytes • Sometimes pigmentation (melanocytic activation) • Often need intact lesion to make definitive diagnosis 6
2 1/25/2019
7
8
Courtesy of Leslie Robinson-Bostom, MD 9
3 1/25/2019
Baran R, Perrin C. Longitudinal erythronychia with distal subungual keratosis: onychopapilloma of the nail bed and Bowen’s disease. Br J Dermatol. 2000;143(1):132-135. 10
11
12
4 1/25/2019
Courtesy, of Jon Starr, MD
13
Verruca vulgaris
14
15
5 1/25/2019
16
Subungual epidermoid inclusions
• Small aggregates of keratinocytes or cysts that can be found under the epithelium of the nail bed • An incidental finding, or associated with nail dystrophy, especially a shortened and dystrophic nail plate, or clubbing • A history of trauma is common, and there may be associated underlying bony abnormalities as well • There may be associated hyperkeratosis of the nail bed • Less cystic variants can be mistaken for squamous cell carcinoma or other neoplasms
Lewin K. Br J Dermatol 77:241, 1965 Bukhari IA, Al-Mugharbel R. Saudi Med J Apr;25(4):522-3, 2004 Lewin K. Br J Dermatol 81(671),1969 Telang GH and Jellinek N. J Am Acad Dermatol 56:336-9, 2007 Fanti PA, Tosti A. Dermatologica 178(4):209-12, 1989 Ruben BS, LeBoit PE. J Cutan Pathol. 2008 Jan;35(1):97. 17
Collection of Monica Lawry, M.D.
18
6 1/25/2019
19
20
21
7 1/25/2019
22
23
24
8 1/25/2019
25
26
27
9 1/25/2019
28
29
30
10 1/25/2019
31
Onychomatricoma Baran and Kint
32
Onychomatricoma Clinical presentation
Nodule
Splinter hemorrhages Thickened nail plate Transverse overcurvature
Courtesy of Monica Lawry, MD 33
11 1/25/2019
Hollow area within tumor
Nail bed
34
Specimen for pathology
35
36
12 1/25/2019
Onychomatricoma
Clinical features: • Mean age 50.5 (24‐68), lighter‐skinned patients • Fingers most often affected, esp. thumb and index • Female to male 2.16:1 • Thickened yellowish nail, transverse overcurvature, splinter hemorrhages, sometimes pigmented • Nodular area corresponding to the matrix • Rarely recurs after surgery
Perrin C, Baran R, Balaguer T, et al. Am J Dermatopathol. 2010;32(1):1-8. Di Chiacchio N, Tavares GT, Tosti A, et al. Br J Dermatol. 2015;173(5):1305-1307. Reserva JL, Ruben BS, Venna SS. Skin Appendage Disord. 2017;3(1):32-35.
37
Onychomatricoma Key histologic features: • Multiple fibroepithelial projections • Thick V‐shaped keratogenous zone, mimics normal matrix • Matrical hyperplasia of varying degree • “Glove‐finger” appearance of nail plate and matrix interaction • Altered nail plate thin proximally, thick distally, with multiple cavities (wormwood) • Fibrocellular stroma of varying degree –CD34+; CD99, S100, EMA‐ –More cellular superficially, perpendicular collagen bundles deeply –Myxoid stroma similar to superficial acral fibromyxoma, rare
38
Normal nail
39
13 1/25/2019
Thick, altered nail plate Fibroepithelial component
40
41
Pigmented onychomatricoma
Courtesy of A. Christine Miller, MD
42
14 1/25/2019
43
44
45
15 1/25/2019
46
47
48
16 1/25/2019
Pleomorphic OM
Courtesy of Laura Pincus, MD
49
“Pleomorphic” OM
• Only seven cases now reported: –2 as “unguioblastic fibroma” –2 possibly as pleomorphic fibroma –2 in a large series of 19 cases of OM • Although pleomorphic, no history of adverse biologic behavior
Fernandez-Flores’ A, Barja-Lopez J-M. J. Cutan. Pathol. 2014;41(7):555-560. Petersson F, Tang ALY, Jin ACE, Barr RJ, Lee VK. Am J Dermatopathol 2010;32(4):387-391.
50
Ki-67
51
17 1/25/2019
Nail clipping for diagnosis
52
Miteva M. et al. Arch Dermatol. Tallon B, Strydom F, Emanuel PO. 2011;147(9):1117–1118. J Cutan Pathol. 2013;40(1):2–3.
53
Perrin C, Baran R, Balaguer T, et al. Onychomatricoma: new clinical and histological features. A review of 19 tumors. Am J Dermatopathol. 2010;32(1):1-8. 54
18 1/25/2019
55
56
Onychomatricoma Differential Diagnosis‐ Histologic • Angiofibroma (Koenen’s tumor) • Acquired digital fibrokeratoma • Cellular digital fibroma • Perineurioma CD34+ • Pleomorphic fibroma • Superficial acral fibromyxoma EMA • Verruca vulgaris S100 • SCC in situ (rarely) CD99
57
19 1/25/2019
Superficial acral fibromyxoma
Courtesy of Dr. Morgan Magid
58
59
Superficial acral fibromyxoma
Courtesy of Brad Naylor, DPM 60
20 1/25/2019
61
62
63
21 1/25/2019
64
65
66
22 1/25/2019
67
CD34
68
EMA
69
23 1/25/2019
Fetsch JF, Laskin WB, Miettinen M. Hum Pathol. 2001 Jul;32(7):704-14.
70
Superficial acral fibromyxoma Clinical features • A benign spindle cell proliferation • Predilection for hands and feet, fingers and toes, often with close relationship to nail unit • Broad age range (mean, 43) • Duration 3 mos to 30 years • Size 0.6 cm‐5 cm, may impinge on bone • Behavior: most did not recur after excision
Fetsch JF, Laskin WB, Miettinen M. Hum Pathol. 2001 Jul;32(7):704-14.
71
Superficial acral fibromyxoma Histologic features • Spindled to stellate cells • Random, loose storiform or fascicular patterns • Myxoid to collagenous, prominent mast cells • Occasional multinucleate cells, rare mitoses • CD34+, CD99 variable +, EMA focal/– • Nestin positive, RB1 loss • Probable fibroblastic differentiation Fetsch JF, Laskin WB, Miettinen M. Hum Pathol. 2001 Jul;32(7):704-14. Cullen D, Díaz Recuero JL, Cullen R et all. Am J Dermatopathol. 2017;39(1):14-22. Agaimy A, Michal M, Giedl J et al. Hum Pathol. 2017;60:192-198. 72
24 1/25/2019
Chattopadhyay M, Farrant P, Higgins E, Hay R, Calonje E. Clin Exp Dermatol. 2010 Oct;35(7):807-9 73
Courtesy of Jeff North, MD
74
75
25 1/25/2019
Pleomorphic fibroma
76
Angiofibroma
77
78
26 1/25/2019
Perrin C, Cannata GE, Bossard C, et al. Onychocytic matricoma presenting as pachymelanonychia longitudinal. A new entity (report of five cases). Am J Dermatopathol. 2012;34(1):54–59.
79
Courtesy of Mark Holzberg, MD
80
81
27 1/25/2019
82
83
Melan-A
84
28 1/25/2019
85
86
Perrin C, Cannata GE, Bossard C, et al. Onychocytic matricoma presenting as pachymelanonychia longitudinal. A new entity (report of five cases). Am J Dermatopathol. 2012;34(1):54–59.
87
29 1/25/2019
Acanthotic type 88
Papillomatous Keratogenous
89
Melanocytes and melanin
90
30 1/25/2019
Bon-Mardion M, Poulalhon N, Balme B, Thomas L. Ungual seborrheic keratosis. J Eur Acad Dermatol Venereol. 2010;24(9):1102–1104. 91
92
Wanat KA, Reid E, Rubin AI. Onychocytic matricoma: a new, important nail-unit tumor mistaken for a foreign body. JAMA Dermatol. 2014;150(3):335-337.
93
31 1/25/2019
Stinco G, Errichetti E, Patrone P. Ungual seborrhoeic keratosis: report of a case and its dermoscopic features. J Eur Acad Dermatol Venereol. 2014. doi:10.1111/jdv.12866.
94
Nail dystrophy began 3 years ago, slowly more raised
Courtesy of Drs. Jane Bellet and Ken Ellington
95
distal
proximal
96
32 1/25/2019
97
98
99
33 1/25/2019
SCC of the nail unit
• Most common tumor of nail unit, but still uncommon • Atypical clinical presentations the rule – Dystrophy, onycholysis, ulceration, paronychia, nail loss, and rarely longitudinal melanonychia • Predisposing factors – Immunosuppression – Oncogenic HPV – Radiodermatitis
100
Squamous cell carcinoma In situ Invasive
101
Sneaky SCC
Partial nail plate avulsion reveals nail bed abnormality Courtesy of Monica Lawry, MD 102
34 1/25/2019
103
104
SCCIS of the nail unit
105
35 1/25/2019
106
107
Pigmented SCCIS
108
36 1/25/2019
Subungual keratoacanthoma
109
110
111
37 1/25/2019
112
113
von Kossa
114
38 1/25/2019
Subungual keratoacanthoma
115
Painful subungual tumorsof incontinentia pigmenti
• Well-recognized but rare complication of IP, a late manifestation • Corresponds to the verrucous stage, IP • Fingers > toes • DDX: subungual keratoacanthoma, verruca, epidermoid cysts, subungual fibroma, chronic paronychia • Intense pain and osteolysis may occur • Excision or amputation may be necessary • Retinoids have been used with some promise
Young et al. JAAD 2005
116
117
39 1/25/2019
118
Chaser BE, Renszel KM, Crowson AN, et al. Onycholemmal carcinoma: A morphologic comparison of 6 reported cases. J. Am. Acad. Dermatol. 2013;68(2):290–295.
119
Chaser BE, Renszel KM, Crowson AN, et al. Onycholemmal carcinoma: A morphologic comparison of 6 reported cases. J. Am. Acad. Dermatol. 2013;68(2):290–295.
120
40 1/25/2019
Chaser BE, Renszel KM, Crowson AN, et al. Onycholemmal carcinoma: A morphologic comparison of 6 reported cases. J. Am. Acad. Dermatol. 2013;68(2):290–295.
• Clinical features: – Female to male 1:1 – Middle age to older patients – Finger: thumb: toe: unknown 3:1:1:1 – Symptoms/signs: ulceration, swelling, paronychia-like, onycholysis, periungual erythema, pain – May abut the bone but no bony involvement – Indolent course (no aggressive behavior) – Treatment: Mohs surgery, excision, nail unit excision, radiation, amputation – Conservative treatment advocated
121
Chaser BE, Renszel KM, Crowson AN, et al. Onycholemmal carcinoma: A morphologic comparison of 6 reported cases. J. Am. Acad. Dermatol. 2013;68(2):290–295.
• Histologic features – Cytologically bland – Poorly circumscribed, infiltrative pattern – Lobular and cystic – Abrupt keratinization (reminiscent of proliferating pilar tumor) – Authors consider this an acral SCC – 1 case studied was negative for HPV
122
123
41 1/25/2019
Onycholemmal carcinoma
Courtesy of Michael Morgan, MD
124
125
126
42 1/25/2019
127
128
129
43 1/25/2019
Perrin C, Langbein L, Ambrossetti D, Erfan N, Schweizer J, Michiels J-F. Onychocytic carcinoma: a new entity. Am J Dermatopathol. 2013;35(6):679-684.
130
Perrin C, Langbein L, Ambrossetti D, Erfan N, Schweizer J, Michiels J-F. Onychocytic carcinoma: a new entity. Am J Dermatopathol. 2013;35(6):679-684.
131
Wang L, Gao T, Wang G. Invasive onychocytic carcinoma. J Cutan Pathol. 2015 May;42(5):361-7
• 51 yo woman, ulceration of left ring finger, 4 years • Began with trauma, then formed a longitudinal split • Gradual destruction of whole nail bed • First biopsy inconclusive
132
44 1/25/2019
Wang L, Gao T, Wang G. Invasive onychocytic carcinoma. J Cutan Pathol 2015 May;42(5):361-7.
Invasive
Matrix-like cytology Retiform contour
Keratinization
133
Jih DM, Elenitsas R, Vittorio CC, Berkowitz AR, Seykora JT. Aggressive digital papillary adenocarcinoma: a case report and review of the literature. Am J Dermatopathol. 2001;23(2):154-157.
134
Digital papillary adenocarcinoma History
• First described by Helwig, 1979 (AAD CPC) • Rare low grade malignant adnexal tumor • Formerly, aggressive digital papillary adenoma (ADPA) • Despite somewhat bland histologic appearance, some cases found to behave aggressively • 2000, Duke et al propose ADPA is malignant without a benign counterpart, renaming as PDA to reflect this behavior, suggest aggressive treatment • 2009, Hsu et al suggest that wide excision may be adequate for some more limited cases (use Ki-67 proliferation index as a guide)
135
45 1/25/2019
Digital papillary adenocarcinoma Clinical features • Painful or painless cystic mass, acral skin, volar surfaces of fingers and toes • Male predominance • Unusual presentations include as PG, hemangioma, SCC-like, osteomyelitis, soft tissue infection, and paronychia • Preferred location: between nail unit and DIP
Kao GF, Helwig EB, Graham JH. J Cutan Pathol. 1987 Jun;14(3):129-46. Duke WH, Sherrod TT, Lupton GP. Am J Surg Pathol. 2000 Jun;24(6):775-84.
136
Courtesy of Tara Miller, MD
137
Digital papillary adenocarcinoma Histology Mixed papillary, tubuloalveolar, solid, cystic patterns; variable atypia, mitotic rate, necrosis Squamous metaplasia, clear cells, spindle cells Stains with S100, CEA, p63 Also EMA, ER, PR, CK7, CK77, PHLDA, SMA, AR May contain myoepithelial cells No histologic features predict biologic behavior Ki-67 proliferation rate? Suchak R et al. Am J Surg Path.36:1883-91, 2012 Weingertner N et al. J Am Acad Dermatol. 2017;77(3):549-558.e1. 138
46 1/25/2019
139
140
141
47 1/25/2019
142
143
144
48 1/25/2019
145
146
147
49 1/25/2019
Digital papillary adenocarcinoma Differential diagnosis
• Metastatic carcinoma • Tubular apocrine adenoma • Hidradenoma
148
Digital papillary adenocarcinoma Prognosis and treatment • Local recurrence in 5%, up to 50% if not widely excised • Metastasis 12-14%, often to lung (70%) • In some series, metastatic rate approaches 50% • Treatment: wide local excision, amputation, Mohs surgery, sentinel node sampling??
Morita R et al. Plast Reconstr Surg. 2006 Feb;117(2):710-2. Rismiller K, Knackstedt TJ Dermatol Surg. March 2018.
149
Take home points
• Epithelial and other neoplasms may have distinctive features in the nail unit • Orientation of the tissue may be key to recognition • Determining benign versus malignant can sometimes be tricky • Some diagnoses are unique to this site • Be on the lookout for new entities!
150
50 THURSDAY DERMATOPATHOLOGY
Melanoma Staging AJCC 2018
DR LYN DUNCAN HARVARD MEDICAL SCHOOL
AJCC Melanoma Staging 2018
Lyn McDivitt Duncan, MD Professor of Pathology, Harvard Medical School Chief, MGH Dermatopathology Unit
MASSACHUSETTS GENERAL HOSPITAL DERMATOPATHOLOGY 1
The Numbers
Over 90,000 new cases of melanoma in the U.S. in 2017 Over 9, 000 melanoma deaths in U.S. in 2017
75 75% of all skin cancer deaths are from melanoma
50 1 in 50 Americans will develop melanoma in their lifetime 2 Melanoma is 2nd most common cancer diagnosis 17-29 y age group 1 Every hour someone in the U.S. will die from melanoma
2
Melanoma Staging 2018 – Clinically Relevant Stratification
Tumor (T), Node (N), and Metastasis (M) categories and stage groupings
• informs prognostic assessment • Informs clinical decision making • facilitates centralized cancer registry reporting • facilitates the design, conduct, and analysis of clinical trials
Lymphatic mapping and Sentinel lymph node (SLN) biopsy
Major new classes of effective systemic therapeutic agents • immunotherapies (eg, checkpoint inhibitors against CTLA-4 and/or PD-1) • molecularly targeted antitumor therapies (eg, BRAF inhibitors +/- MEK inhibitors)
3
1 Histopathological factors in Melanoma
Primary melanoma: Sentinel lymph nodes: tumor thickness presence of metastasis mitoses number of positive nodes ulceration size of metastasis microscopic satellites detection technique lymphovascular invasion location of metastasis tumor infiltrating lymphocytes regression neural invasion margins melanoma subtype
4
Histopathological factors in AJCC staging
Primary melanoma: Sentinel lymph nodes: tumor thickness presence of metastasis ulceration number of positive nodes microscopic satellites size of metastasis mitoses detection technique lymphovascular invasion location of metastasis tumor infiltrating lymphocytes regression neural invasion margins melanoma subtype
5
AJCC Melanoma Staging 2018, 8th edition 46, 000 patients, 10 centers world wide
1) tumor thickness recorded to nearest 0.1 mm, not 0.01 mm
2) T1a and T1b revised (T1a, <0.8 mm no ulceration; T1b, 0.8-1.0 mm or <0.8 mm with ulceration) mitotic rate no longer a T category criterion
3) pathological (but not clinical) stage IA is revised to include T1b N0 M0 (formerly pathologic stage IB)
4) N category “microscopic” and “macroscopic” redefined “clinically occult” (SLN+) and “clinically apparent”
5) prognostic stage III groupings increased from 3 to 4 subgroups (stages IIIA-IIID)
6) definitions of N subcategories are revised, microsatellites, satellites, or in-transit metastases now N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes
7) descriptors are added to each M1 subcategory designation for lactate dehydrogenase (LDH) level (LDH elevation no longer upstages to M1c); and
8) new M1d designation for central nervous system metastases
6
2 AJCC Melanoma Staging 2018, 8th edition 46, 000 patients, 10 centers world wide
1) tumor thickness recorded to nearest 0.1 mm, not 0.01 mm
2) T1a and T1b revised (T1a, <0.8 mm no ulceration; T1b, 0.8-1.0 mm or <0.8 mm with ulceration) mitotic rate no longer a T category criterion
3) pathological (but not clinical) stage IA is revised to include T1b N0 M0 (formerly pathologic stage IB)
4) N category “microscopic” and “macroscopic” redefined “clinically occult” (SLN+) and “clinically apparent”
5) prognostic stage III groupings increased from 3 to 4 subgroups (stages IIIA-IIID)
6) definitions of N subcategories are revised, microsatellites, satellites, or in-transit metastases now N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes
7) descriptors are added to each M1 subcategory designation for lactate dehydrogenase (LDH) level (LDH elevation no longer upstages to M1c); and
8) new M1d designation for central nervous system metastases
7
Primary Melanoma Thickness (Breslow 1970)
8
Gershenwald, JE, Scolyer, RA, Hess, KR. et al. Melanoma of the Skin. In Amin, MB, Edge, SB, Greene, FL, et al. (Eds.) AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017
TX: primary tumor thickness cannot be assessed (e.g. diagnosis by curettage) T1: < or = 1.0 mm
T0: no evidence of primary tumor T2: 1.1 – 2.0 mm (e.g. unknown primary or completely regressed melanoma) T3: 2.1 – 4.0 mm
Tis: melanoma in situ T4: > 4.0 mm
Tumor thickness measurements now are recorded to the nearest 0.1mm, not the nearest 0.01 mm. Melanomas in the range of 0.75 to 0.84 mm are reported as 0.8 mm, hence T1b.
9
3 Gershenwald, JE, Scolyer, RA, Hess, KR. et al. Melanoma of the Skin. In Amin, MB, Edge, SB, Greene, FL, et al. (Eds.) AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017
10
Mitotic Activity
Tumor mitotic rate was removed as a staging criterion but remains an overall important prognostic factor that should be recorded for all patients with T1-T4 primary cutaneous melanoma.
mitotic figures / mm2 8 year survival*
0 95%
< 6 79%
>6 38%
11
Mitotic Activity
12
4 AJCC Stage I and II: Survival curves by mitoses per mm2 Gershenwald JE, et al. Cancer J Clin 2017;67:472-92
Data from AJCC 8th edition database 13
Ulceration
14
Lymphovascular Invasion
D240/S100
15
5 Lymphovascular invasion, AJCC stage and time to first metastasis
IA
IB no LVI
IIA no LVI IB + LVI
IIB/C no LVI IIB/C + LVI IIA + LVI
Xu X et al. Clin Cancer Res 2012 16
Anatomic level of invasion: Clark
17
Tumor infiltrating lymphocytes (TILs) Brisk “TILs are present throughout the substance of the vertical growth phase or present infiltrating across the entire base of the vertical growth phase.”
Non-brisk “TILs are present in one or more foci of the vertical growth phase”
18
6 TILs – “absent”
19
Tumor Infiltrating Lymphocytes
Overall survival for patients with localized (Stage I and II) melanoma when segregated by lymphoid infiltrates in the primary tumor
TIL’s 10 ys* 5 ys# brisk 55% 77% non-brisk 43% 53% absent 27% 37%
* Clemente CG, Mihm MC,Jr, Bufalino R, et al. Cancer 1996 # Clark WH, Jr., Elder DE, Guerry DI, et al. JNCI 1989 20
Regression
D240/S100
21
7 AJCC Staging (8th Edition) Summary of Changes (T)
• Thickness measured to nearest 0.1 mm (not 0.01 mm) – 0.75 mm = 0.8 mm • Mitoses*: reported but not used in staging • Clark’s level: reported but not used in staging • Difference between T1a and T1b now based on thickness* – T1a: < 0.8 mm without ulceration – T1b: < 0.8 mm with ulceration 0.8 – 1.0 mm with or without ulceration
*Mitoses represent a significant prognostic factor across all tumor thicknesses
22
Gershenwald, JE, Scolyer, RA, Hess, KR. et al. Melanoma of the Skin. In Amin, MB, Edge, SB, Greene, FL, et al. (Eds.) AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017
23
AJCC Stage I and II Melanoma Survival (SLN+ excluded) Gershenwald JE, et al. Cancer J Clin 2017;67:472-92
24
8 AJCC Stage and 5 year survival
AJCC TNM T stage 5 year survival Stage 0 Tis N0 M0 IA T1a N0 M0 < 0.8 mm, no ulcer 97% T1b < 0.8 with ulcer 0.8-1.0 with or without ulcer IB T2a N0 M0 1-2 mm no ulcer 91% IIA T2b N0 M0 1-2 mm + ulcer T3a 2-4 mm no ulcer 81% IIB T3b N0 M0 2-4 mm + ulcer T4a > 4 mm no ulcer 68% IIC T4b N0 M0 > 4 mm + ulcer 53%
25
Microsatellites
. A microscopic metastasis located adjacent or deep to a primary melanoma . No minimal size threshold or distance from the primary tumor . Separated from the tumor by normal tissue (not inflamed or fibrotic) . Levels may be needed to distinguish from periadnexal tracking . Upstages to Stage III
Gershenwald, JE, Scolyer, RA, Hess, KR. et al. AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017 26
27
9 Non-nodal Locoregional Metastases
Result from intralymphatic or possibly angiotropic spread, similar prognosis for any type of locoregional metastasis
Microsatellite: microscopic metastases found adjacent or deep to primary melanoma on pathologic examination
Satellite: grossly visible cutaneous or subcutaneous metastasis within 2 cm of the primary melanoma
In-transit metastasis: clinically evident metastases > 2 cm from the primary melanoma in the region between the primary and the first echelon of regional lymph nodes.
Gershenwald, JE, Scolyer, RA, Hess, KR. et al. AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017 28
Locoregional metastasis and prognosis in melanoma
Gershenwald JE, et al. Cancer J Clin 2017;67:472-92
“intransit” = in transit or satellite 29
Gershenwald, JE, Scolyer, RA, Hess, KR. et al. Melanoma of the Skin. In Amin, MB, Edge, SB, Greene, FL, et al. (Eds.) AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017
Microsatellite, satellite, intransit – no survival difference, staged by number of lymph nodes involved
When non-nodal locoregional metastases are present:
N1c no regional node disease
N2c one clinically occult (SLN+) or clinically detected lymph node
N3c two or more clinically occult (SLN+) or clinically detected nodes or any number of matted nodes
30
10 Gershenwald, JE, Scolyer, RA, Hess, KR. et al. Melanoma of the Skin. In Amin, MB, Edge, SB, Greene, FL, et al. (Eds.) AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017
“microscopic” and “macroscopic” have been redefined as
Clinically occult : clinical stage I – II with nodal metastasis determined at sentinel node biopsy
Clinically detected: clinical stage III
Sentinel lymph node tumor burden is considered a regional disease prognostic factor that should be collected for all patients with positive sentinel lymph nodes but is not used to determine N category groupings
31
32
AJCC staging 2018
. 80 percent of patients diagnosed with melanoma present with localized disease (AJCC clinical stage I & II)
. Prognosis for this group varies from 53-98%
. SLN is offered to those determined to be at highest risk for microscopic LN metastasis
33
11 Who is offered sentinel lymph node mapping?
NCCN Guidelines V1. 2017 Patients with no clinical evidence of metastatic disease AND Clinical stage 1b or greater (e.g. T1b or greater)… SLNB not recommended for primary melanomas ≤ 0.8 mm thick unless there is significant uncertainty about the adequacy of microstaging
Ulceration, high mitotic rate and lymphovascular invasion (LVI) are rare in melanomas ≤ 0.8 mm thick, when present SLNB may be considered
SLN not recommended in patients with comorbidities that reduce life expectancy, or increase morbidity of SLN biopsy, or the biologically elderly
This is a shifting landscape leading to fewer SLN for melanoma < 0.8 mm
34
Progression free and overall survival in 475 MGH patients with sentinel lymph node biopsy
Negative SLN n = 384 Negative SLN n = 384
Positive SLN n = 91
Positive SLN n = 91 Overall Survival Progression Free Survival
40 80 40 80 Time (in Months) Time (in Months) Luo S et al. JAMA Surgery 2015 35
Detection of one melanoma cell in SLN upstages to AJCC III
Management of Stage III melanoma is shifting, nevertheless the presence of even one melanoma cell indicates metastatic potential of the primary tumor
Technical aspects impact sensitivity of melanoma detection in SLN: Surgical technique • is a sentinel node only one node? hottest vs. not-hottest
Histopathological technique • levels vs. not • immunohistochemical stains
Histopathological interpretation • nevus vs. melanoma
36
12 Intraoperative Lymphatic Mapping
.Isosulfan blue & Tc99m sulfur colloid
.Blue staining of node and lymphatic
.Hand held gamma counter
.Removal of hot nodes (to 10% of #1)
.Wide excision of cutaneous lesion
Elias et al Arch Surg. 2004
37
91 patients with SLN melanoma metastases positive SLN and Survival (n=475) Hottest SLN positive:79%
SLN-
SLN+ (hottest)
SLN+ (not-hottest) Survival
Non-hottest SLN positive: 21% Counts range 26-97% of hottest
Luo et al. JAMA Surg 2015;150:465-72 38
Sentinel Lymph Node Analysis
12% of positive lymph nodes are missed if levels and immunohistochemical stains are not performed
. 94 patients with negative SLN on one H&E (235 LN)
. deeper levels and immunohistochemical stains revealed melanoma in 12% of patients
. capsular melanocytic nevi in 9% of patients
Yu L, et al. Cancer 1999 39
13 Sentinel Lymph Node Analysis
No standard procedure exists
Analytical platform varies between Cancer Centers – Single H&E – H&E plus one or two immunohistochemical stains* – H&E plus immunostains* at multiple deeper levels
* S100, Mart-1, HMB-45, Melan-A, MITF
15% false negative rate without deeper levels
40
SLN workup for melanoma at 18 institutions
Dekker, J et al. Arch Pathol 2013 41
Metastatic Melanoma MART -1
42
14 Metastatic Melanoma MART -1
43
Diagnostic criteria for metastatic melanoma
. individual cells or nests of epithelioid or spindle cells foreign to the lymph node
. cytological atypia defined as large cells with nuclear pleomorphism, prominent nucleoli, or dusty cytoplasmic melanin granules
. positive staining for one or more melanocytic marker (S-100, MART-1)
. identification of the cells on H&E (not required)
44
Metastatic Melanoma S100
45
15 Metastatic Melanoma S100
46
Metastatic Melanoma
47
Metastatic Melanoma S100
48
16 Nodal Nevus MART-1
49
Criteria for melanocytic nevus in LN
. individual cells in a linear array or nests of epithelioid or spindled cells foreign to the lymph node
. no cytological atypia
. positive staining for one or more melanocytic marker (S-100, MART-1, MelanA, MITF)
. identification of the cells on H&E
. cells are usually present in the fibrous capsule or trabeculae
50
Metastatic Melanoma and Nodal Nevus
MITF 51
17 Distribution of melanoma in SLN
Do we need 3 sets of deeper levels?
475 MGH patients, positive SLNs in 91 patients (19%)
Of 61 cases with all protocol slides available: 64% melanoma in every protocol slide (9 slides) 36% tumor only on selected levels 18% without tumor in the first set of levels
Lobo A. et al. Am J Surg Pathol 2012 52
Distribution of melanoma metastases in sentinel nodes
53
Distribution of melanoma metastases in sentinel nodes
Lobo et al AJSP 2012 = 11 cases with no tumor in first set of levels (18%) 54
18 Sentinel Lymph Node Analysis
> 15% false negative rate if protocol does not include levels into the tissue
> 9% false positive rate by PCR (benign nodal melanocytic nevi)
Immunohistochemical stains aid in detecting microscopic foci of melanoma
Size of sentinel node metastasis correlates with risk of progression
55
SLN Analysis Take Home Points
The presence of one metastatic tumor cell upstages patient to stage III Failure to examine deeper levels leads to a 12-15% false negative rate Immunohistochemical stains help to identify microscopic melanoma
The diagnostic pathology report should contain: . Number of positive LN/ total number of LN . Extracapsular extension present or absent . Maximal diameter of the largest metastatic deposit . Immunohistochemical stains performed and results
In ambiguous primary tumors, metastasis is not diagnostic of melanoma (AST)
56
2007: 37 year old woman Atypical Spitz Tumor (AST) upper arm with severe atypia and mitoses
57
19 Atypical Spitz Cases with Mean follow- Cases with +SLN/ total up in months mets beyond Deaths Tumors patients the SLN/ total Smith et al. 1989 6/32 (19%) 72 0/30 0/30 Lohmann et al. 2002 5/10 (50%) 33.7 0/10 0/10 Su et al. 2003 8/18 (44%) 9.8 0/18 0/18 Gamblin et al. 2006 3/10 (33%) 33.7 0/10 0/10 Urso et al. 2006 4/12 (33%) 26.3 0/12 0/12 Murali et al. 2008 6/21 (29%) 25.8 0/21 0/21 Ludgate et al. 2009 27/57 (47%) 43.8** 0/57 0/57 Busam et al. 2009 11 all + SLNB* 61.4 0/11 0/11
Cerroni et al. 2010 25/35 (71%) 83.5 8/35 1/35 Tom et al. 2011 2/4 (50%) 25.3 0/4 0/4 Raskin et al. 2011 8/15 (53%) Not reported 0/15 0/15 Sepehr et al. 2011 1/6 (17%)*** 64.6 0/76 0/76 Barnhill et al. 2011 4/5 * 10.5 0/5 0/5 Hung et al. 2013 6/23 (26%) 55.6 0/23 0/23 Totals 102/245 (42%) 8/327 (<3.0%) 1/327 <0.5% 58
In the cohort of node-positive patients with intermediate-thickness primary melanomas (defined in this study as 1.20 to 3.50 mm), the study showed a significant advantage with respect to melanoma-specific survival for those who underwent sentinel-node biopsy, had a positive result, and underwent early regional lymphadenectomy, as compared with those who underwent wide excision but not sentinel-node biopsy, with regional lymphadenectomy performed only after regional disease developed.
Known, accepted, and confirmed by MSTLI :
Pathological status of the SLN is the most important prognostic factor
SLN removal led to fewer recurrences
59
SLN and CLND a shifting landscape
Intraoperative lymphatic mapping
Sentinel lymph node biopsy - +
Observation Completion Lymphadenectomy
60
20 7th International Melanoma Pathology Workshop, UCSF November 17, 2015
61
62
MSLTI vs. MLSTII
Now known and accepted and confirmed by MSTLI – Pathological status of the SLN is the most important prognostic factor – SLN removal led to fewer recurrences
MSLTII international Evaluate the usefulness of multicenter (63 sites) Completion Dissection randomized in melanoma patients phase 3 trial with positive SLN
63
21 MSLTII NEJM 2017
Per-protocol analysis 1755 patients Breslow 1.2 mm – 3.5 mm Randomized to CLND ( n= 824) or observation with U/S (n = 931)
• Demographic and primary tumor pathological factors (thickness and ulceration) were similar between cohorts
• Mitoses were not evaluated • Sentinel lymph node metastases size (< 0.1, 0.1-1.0, > 1.0mm) • Fewer than 4% in each cohort had 3 or more positive SLN
64
MSLTII NEJM 2017
There was no significant difference in melanoma specific survival between the CLND (86%) and Observation (86%) cohorts with a median follow up time of 43 months
65
MSLTII NEJM 2017
There was a statistically significant increase in Disease Free Survival in the CLND (68%) cohort when compared to the Observation (63%) cohort, p = 0.05
This is attributed to the increased rate of regional lymph node disease control in the CLND (92%) vs. the Observation (77%) cohorts at 3 years
Lymphedema occurred in 24% of CLND vs. 6% of Observed
66
22 MSLTII NEJM 2017: Conclusions
Completion Lymphadenectomy is associated with:
- increased rate of regional disease control
- prognostic information
- increased rate of lymphedema
- No increase in melanoma specific survival
67
MSLTII NEJM 2017: CLND may no longer be recommended in most patients with SLN metastases
Are there patients who may still benefit from completion lymphadenectomy?
• Patients with more than 2 + SLN represent <5% of all patients in MSLTII • the data do not provide insight into the impact of large SLN metastases (largest cutoff is 1 mm) • there is no evaluation of patients with matted lymph nodes or extracapsular extension • primary tumor mitoses are not included in the analysis • the 3 year (43 month) follow up time is relatively short for early stage melanoma.
Number of positive SLN, and extent of tumor burden in the SLN have been associated with increased risk of non-sentinel lymph node metastasis and decreased melanoma-specific survival.
68
In the broader view of the existing literature:
• Completion lymphadenectomy may not offer a survival advantage for most patients with clinically localized primary cutaneous melanoma and positive sentinel lymph nodes, e.g. patients with 2 or fewer positive lymph nodes, with metastases less than 1 mm, and without extracapsular extension or matted lymph nodes
• Completion lymphadenectomy may be considered in patients with any of these characteristics: 3 or more positive sentinel lymph nodes, SLN tumor burden > 1 mm, extracapsular extension or matted lymph nodes
• Completion lymphadenectomy may be considered in patients with poor compliance and who may be non-surveillable,
• Completion lymphadenectomy may be considered for patients desiring to participate in a clinical trial with completion lymphadenectomy as an enrollment criterion
69
23 SLN and CLND in Melanoma: a shifting landscape
SLN (Sentinel Lymph Node) • In years past SLN was offered for even very thin mitogenic or ulcerated primary cutaneous melanoma (0.3-0.7 mm) • Now only rare circumstances lead to SLN for tumors < 0.8 mm
CLND (Completion Lymphadenectomy) • In years past CLND was offered to patients with SLN metastases of any size (including those with only one tumor cell detected) • Now CLND is rarely recommended (exceptions include requirement for clinical trial eligibility, or inability to comply with observation exams and imaging)
70
AJCC Prognostic Stage Groups: Clinical Staging
Gershenwald, JE, Scolyer, RA, Hess, KR. et al. AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017 71
AJCC Prognostic Stage Groups: Pathological Staging
N1a: one clinically occult node (SLN+) N1b: one clinically detected node N1c: no regional node but non-nodal met* N2a: 2 or 3 clinically occult (SLN+) N2b: 2 or 3 at least one clinically detected N2c: 1 occult or clinically detected and * N3a: 4 or more nodes or 2 or more with * or any with matted nodes N3b: 4 or more nodes with at least one clinically detected or matted N3c: 2 or more occult or clinical, or matted and * * microsatellite, satellite or in-transit
Gershenwald, JE, Scolyer, RA, Hess, KR. et al. AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017 72
24 AJCC Prognostic Stage Groups: Pathological Staging
N1a: one clinically occult node (SLN+) N1b: one clinically detected node N1c: no regional node but non-nodal met* N2a: 2 or 3 clinically occult (SLN+) N2b: 2 or 3 at least one clinically detected N2c: 1 occult or clinically detected and * N3a: 4 or more nodes or 2 or more with * or any with matted nodes N3b: 4 or more nodes with at least one clinically detected or matted N3c: 2 or more occult or clinical, or matted and * * microsatellite, satellite or in-transit
Gershenwald, JE, Scolyer, RA, Hess, KR. et al. AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017 73
AJCC Staging 8th edition (N)
Stage Nodes In transit, satellite or microsatellite mets N1a 1 clinically occult node met No N1b 1 clinically detected node met No N1c No regional lymph node disease Yes N2a 2 – 3 clinically occult No N2b 2 – 3, at least one clinically detected No N2c 1 clinically occult or clinically detected Yes N3a > 4 clinically occult No
N3b > 4, at least one clinically detected, or presence of matted nodes No
N3c > 2 clinically occult or clinically detected and/or presence of matted nodes Yes
74
AJCC Prognostic Stage Groups: Pathological Staging
N1a: one clinically occult node (SLN+) N1b: one clinically detected node N1c: no regional node but non-nodal met* N2a: 2 or 3 clinically occult (SLN+) N2b: 2 or 3 at least one clinically detected N2c: 1 occult or clinically detected and * N3a: 4 or more nodes or 2 or more with * or any with matted nodes N3b: 4 or more nodes with at least one clinically detected or matted N3c: 2 or more occult or clinical, or matted and * * microsatellite, satellite or in-transit
Gershenwald, JE, Scolyer, RA, Hess, KR. et al. AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017 75
25 AJCC Prognostic Stage Groups: Pathological Staging
N1a: one clinically occult node (SLN+) N1b: one clinically detected node N1c: no regional node but non-nodal met* N2a: 2 or 3 clinically occult (SLN+) N2b: 2 or 3 at least one clinically detected N2c: 1 occult or clinically detected and * N3a: 4 or more nodes or 2 or more with * or any with matted nodes N3b: 4 or more nodes with at least one clinically detected or matted N3c: 2 or more occult or clinical, or matted and *
* microsatellite, satellite or in-transit
Gershenwald, JE, Scolyer, RA, Hess, KR. et al. AJCC Cancer Staging Manual. 8th Ed. New York: Springer 2017 76
Gershenwald JE, et al. Cancer J Clin 2017;67:472-92
77
Melanoma staging: Evidence-based changes in AJCC 8th ed. Gershenwald JE, et al. Cancer J Clin 2017;67:472-92
SLN + Clinically detected or one locoregional met 4 or more clinically detected, matted or one locoregional met with one clinically detected LN Ulcerated > 4mm primary with 4 or more clinically detected, matted or one locoregional met with one clinically detected LN
78
26 AJCC Stage I and II Melanoma Survival (SLN+ excluded) Gershenwald JE, et al. Cancer J Clin 2017;67:472-92
79
Melanoma Staging 2018 – Clinically Relevant Stratification
Tumor (T), Node (N), and Metastasis (M) categories and stage groupings
• informs prognostic assessment • informs clinical decision making • facilitates centralized cancer registry reporting • facilitates the design, conduct, and analysis of clinical trials
Lymphatic mapping and Sentinel lymph node (SLN) biopsy
Major new classes of effective systemic therapeutic agents • immunotherapies (eg, checkpoint inhibitors against CTLA-4 and/or PD-1) • molecularly targeted antitumor therapies (eg, BRAF inhibitors +/- MEK inhibitors)
80
27 THURSDAY DERMATOPATHOLOGY
Nail Pathology III: Melanocytic Neoplasms
DR BETH RUBEN 1/25/2019
Mighty Women of Dermatopathology Hawaii 2019 Nail pathology III: Pigmented Lesions of the Nail Unit
Beth S. Ruben, MD Director, Dermatopathology Palo Alto Medical Foundation Professor, Dermatology/Dermatopathology, UCSF
1
Melanonychia
2
Barriers to arriving at a diagnosis
The nail plate covers the source of the pigmentation Clinical cues can be misleading There may be a lack of familiarity with nail anatomy and biopsy techniques Suboptimal specimens may result Most pathologists lack familiarity with normal nail unit histology and pathology Histologic findings may be inconclusive
3
1 1/25/2019
Patterns of nail matrix and bed of longitudinal melanonychia by intraoperative dermatoscopy Hirata SH, Yamada S, Enokihara MI, Di Chiacchio N, de Almeida FA, Enokihara MMSS, Michalany NS, Zaiac M, and Tosti A. J Am Acad Dermatol 2011;65:297‐303
Regular brown pattern: regular brown lines. (BENIGN MELANOCYTIC HYPERPLASIA) 4
Keys to diagnosis
The best technique selected to sample the lesion Specimen submitted carefully and processed optimally Specimen analyzed with additional sections and stains as needed Criteria for diagnosis applied Correlation with the clinical findings If melanoma, staging and surgical treatment options discussed
5
Pigmented lesions of the nail unit
Ruben BS. Semin Cutan Med Surg 29:148-158, 2010
6
2 1/25/2019
Key clinical information in evaluating longitudinal pigmented bands
Solitary or multiple bands Width of the band Homogeneity of the band Hutchinson’s sign (periungual pigmentation) Duration, and any change over time Which digit affected Age of the patient Any extenuating clinical history (drugs, pregnancy, baseline pigmentation) Findings on dermatoscopy?
7
Nail apparatus melanoma (NAM)
Most occur in thumb and great toe Higher mortality than conventional melanoma Mean tumor thickness 4.8 mm at dx May arise in matrix or rarely nail bed (amelanotic) Irregular pigmented band, greater than 3 mm Hutchinson’s sign (periungual pigmentation) Exceedingly rare in children
Thai KE, Young R, Sinclair RD. Nail apparatus melanoma. Australas J Dermatol. 2001 May;42(2):71-81; quiz 82-3.
8
ABCDEF rule for nail unit melanoma
A: Age (50-70 peak); also ? race (African Americans, Asians, Native Americans) B: Band (black to brown); Breadth > 3 mm; Blurred borders C: Change (enlarging or darkening; lack of change/response to treatment for nail dystrophy) D: Digit (thumb>hallux>index finger; single versus multiple; dominant hand) E: Extension of pigment onto surrounding tissues F: Family or personal history of melanoma
Levit EK, Kagen MH, Scher RK, Grossman M, Altman E. The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol. 2000 Feb;42(2 Pt 1):269-74.
9
3 1/25/2019
Helpful clinical information
PHOTOGRAPH!! Describe the band –Width – Any irregularities Any periungual pigmentation? Intraoperative findings Where does the biopsy come from? – It can be difficult to understand tissue orientation – Most specimens should include matrix
10
Courtesy of Eckart Haneke, MD
11
Amelanotic MM
12
4 1/25/2019
13
14
Dermatoscopy for melanonychia
Useful for distinguishing hemorrhage from melanin – Caveat: Melanoma may produce hemorrhage Benign: brown background with regular parallel lines of identical color, spacing and thickness – Caveat: Rarely observed! Melanoma: a brown background with longitudinal lines, irregular in color, thickness, spacing, loss of parallelism is most reliable pattern – Caveat: Nevi in children and sometimes in adults can have irregular lines – An individual irregular line is very suspicious – Granular pigmentation is more common in melanoma
Ronger S et al. Arch Dermatol. 2002;138(10):1327-1333. Di Chiacchio ND, et al. An Bras Dermatol. 2013;88(2):309-313. Benati E et al. J Eur Acad Dermatol Venereol. 2017;31(4):732-736.
15
5 1/25/2019
Ronger, S. et al. Arch Dermatol Mun J-H, Kim G-W, Jwa S-W, et al. Br J 2002;138:1327-1333. Dermatol. 2013;168(6):1224-1229.
16
Koga H, Saida T, Uhara H. J Dermatol. 2011 Jan;38(1):45-52.
17
18
6 1/25/2019
19
20
Patterns of nail matrix and bed of longitudinal melanonychia by intraoperative dermatoscopy Hirata SH, Yamada S, Enokihara MI, Di Chiacchio N, de Almeida FA, Enokihara MMSS, Michalany NS, Zaiac M, and Tosti A. J Am Acad Dermatol 2011;65:297-303 Established and validated patterns for intraoperative dermatoscopy of the nail matrix and bed, in 100 consecutive cases Expose matrical area containing the lesion Use DermLite polarized light dermatoscope, no contact needed Biopsy and perform routine microscopy on all cases 4 dermatoscopic patterns were identified:
regular gray pattern (hypermelanosis) regular brown pattern (benign melanocytic hyperplasia/lentigo) regular brown pattern with globules or blotchs (melanocytic nevi)
irregular pattern (melanoma) Courtesy of Nilton DiChiacchio, MD, PhD 21
7 1/25/2019
Patterns of nail matrix and bed of longitudinal melanonychia by intraoperative dermatoscopy Hirata SH, Yamada S, Enokihara MI, Di Chiacchio N, de Almeida FA, Enokihara MMSS, Michalany NS, Zaiac M, and Tosti A. J Am Acad Dermatol 2011;65:297-303
Regular gray pattern: presence of fine, regular, grayish lines. (HYPERMELANOSIS) 22
Patterns of nail matrix and bed of longitudinal melanonychia by intraoperative dermatoscopy Hirata SH, Yamada S, Enokihara MI, Di Chiacchio N, de Almeida FA, Enokihara MMSS, Michalany NS, Zaiac M, and Tosti A. J Am Acad Dermatol 2011;65:297-303
Regular brown pattern: regular brown lines. (BENIGN MELANOCYTIC HYPERPLASIA) 23
Patterns of nail matrix and bed of longitudinal melanonychia by intraoperative dermatoscopy Hirata SH, Yamada S, Enokihara MI, Di Chiacchio N, de Almeida FA, Enokihara MMSS, Michalany NS, Zaiac M, and Tosti A. J Am Acad Dermatol 2011;65:297-303
Regular brown pattern with globules: regular longitudinal brown lines and presence of globules with regular size and distribution. (MELANOCYTIC NEVI) 24
8 1/25/2019
Patterns of nail matrix and bed of longitudinal melanonychia by intraoperative dermatoscopy Hirata SH, Yamada S, Enokihara MI, Di Chiacchio N, de Almeida FA, Enokihara MMSS, Michalany NS, Zaiac M, and Tosti A. J Am Acad Dermatol 2011;65:297-303
Irregular pattern: longitudinal lines of irregular color and thickness, presenting irregular globules and blotches. (MELANOMA) 25
Patterns of nail matrix and bed of longitudinal melanonychia by intraoperative dermatoscopy Hirata SH, Yamada S, Enokihara MI, Di Chiacchio N, de Almeida FA, Enokihara MMSS, Michalany NS, Zaiac M, and Tosti A. J Am Acad Dermatol 2011;65:297-303
High degree of sensitivity and specificity for NMD when compared with NPD upon histopathologic examination
26
27
9 1/25/2019
From: Dermatologists' Accuracy in Early Diagnosis of Melanoma of the Nail Matrix
Arch Dermatol. 2010;146(4):382-387. doi:10.1001/archdermatol.2010.27
Figure Legend: Percentages of Correct Diagnosis for Each Step of the Test in the 3 Groups of Dermatologists
Copyright © 2012 American Medical Date of download: 12/5/2013 Association. All rights reserved. 28
Which procedure?
Nail clipping – Only for screening: blood, melanin, pigmented onychomycosis – Rarely may find melanocytes in it Shave (tangential) biopsy – Great for most, especially large thin lesions – Can visualize lesion – Technique dependent, leaves plate behind Punch – For small lesions, often a “blind biopsy” Longitudinal en bloc excision – Gold standard, retains all architecture Multiple biopsies if entire nail unit affected Jellinek N. J Am Acad Dermatol. 2007;56(5):803-810. Richert B, Theunis A, Norrenberg S, André J. J Am Acad Dermatol. 2013;69(1):96-104. 29
Haneke E, Baran R. Longitudinal melanonychia. Dermatol Surg 2001;27(6):580-584.
30
10 1/25/2019
Courtesy of Dr. Steve Nelson 31
Melanonychia specimens
Specimens inadequate for diagnosis – Taken from incorrect location (e.g., bed versus matrix) – Too superficial or not enough tissue – Specimen crushed or fragmented – Nail avulsion disrupts most of matrix – Only nail plate submitted (screening) – Nail plate not included (may hold clues)
32
Courtesy of Monica Lawry, MD 33
11 1/25/2019
34
Template courtesy of Specimen courtesy of Phoebe Rich, M.D. Monica Lawry, M.D.
35
Courtesy of Nilton DiChiacchio, MD, PhD 36
12 1/25/2019
Criteria for common causes of melanonychia
Melanocytic activation/hypermelanosis – Clinical: narrow band, tan to gray when solitary – Increased melanin without increased melanocytes – Normal density of melanocytes in matrix, 4-9/mm (mean 7.7) Lentigo – Clinical: generally narrow band, tan to brown to black – Increased single melanocytes, 10-31/mm (mean 15.3) Amin B et al. Am J Surg Pathol. 2008 Jun;32(6):835-43. Nevus – Clinical: same as lentigo – Nests and single melanocytes Melanoma in situ – Clinical: broader band, streaky, irregular edges, may display periungual pigmentation – 39-136/mm (mean 58.9), irregular, confluence, atypical melanocytes, suprabasal scatter, irregular dendrites, periungual extension
37
Melanocytic activation
38
Fontana SOX10
39
13 1/25/2019
Lentigo
Courtesy of Dr. Siegrid Yu 40
41
42
14 1/25/2019
Melan-A
43
SOX-10
44
Melanocytic nevus
Courtesy of Dr. T. Kimura
45
15 1/25/2019
46
47
48
16 1/25/2019
49
50
Melan-A
51
17 1/25/2019
Melanonychia in children
Does not play by the rules! Nevus and lentigo are most common; MIS is rare Nevi may be broad and involve periungual skin, may have blurred borders Nevi may be unstable: – Darkening, fading, enlargement of the band and appearance of nail plate abnormalities Dermatoscopy may display abnormal findings Histology may also be disturbing
Goettmann-Bonvallot S, André J, Belaich S. J Am Acad Dermatol. 1999; 41:17-22. Cooper C et al. J Am Acad Dermatol. 2015;72(5):773-779. 52
Nevi in children-may not play by the rules histologically!
53
Lee JH, Lim Y, Park J-H, et al. Clinicopathologic features of 28 cases of nail matrix nevi (NMNs) in Asians: Comparison between children and adults. J Am Acad Dermatol. 2018;78(3):479-489. 54
18 1/25/2019
Lee JH, Lim Y, Park J-H, et al. Clinicopathologic features of 28 cases of nail matrix nevi (NMNs) in Asians: Comparison between children and adults. J Am Acad Dermatol. 2018;78(3):479-489. 55
Lee JH, Lim Y, Park J-H, et al. Clinicopathologic features of 28 cases of nail matrix nevi (NMNs) in Asians: Comparison between children and adults. J Am Acad Dermatol. 2018;78(3):479-489. 56
Pseudoclubbing
Blue nevus Clinical photos courtesy of Nathaniel Jellinek, MD
57
19 1/25/2019
58
59
60
20 1/25/2019
61
62
63
21 1/25/2019
64
65
66
22 1/25/2019
67
68
Subungual epidermoid inclusions
69
23 1/25/2019
Melanoma in situ
Courtesy of Dr. Jeffrey Sugarman 70
Weighting histologic factors in nail unit MM
Poor circumscription Density of single melanocytes Irregular distribution, inc. confluence of nests Suprabasal scatter Cytologic atypia Anisodendrocytosis (dendrite variation)
Park S-W et al. Scattered atypical melanocytes with hyperchromatic nuclei in the nail matrix: diagnostic clue for early subungual melanoma in situ. J Cutan Pathol. 2016;43(1):41-52. Amin B et al. Histologic distinction between subungual lentigo and melanoma. Am J Surg Pathol. 2008 Jun;32(6):835-43. Massi G, LeBoit PE, eds. Histologic Diagnosis of Nevi and Melanoma. Springer. 2004. pp 565-80. High WA et al. Presentation, histopathologic findings, and clinical outcomes in 7 cases of melanoma in situ of the nail unit. Arch Dermatol. 2004 Sep;140(9):1102-6. Thai KE et al. Nail apparatus melanoma. Australas J Dermatol. 2001 May;42(2):71-81; quiz 82-3.
71
Hutchinson’s sign correlate
72
24 1/25/2019
73
Early melanoma in situ
74
75
25 1/25/2019
Courtesy of Mark Ruben, MD 76
77
78
26 1/25/2019
79
80
81
27 1/25/2019
82
MiTF
83
84
28 1/25/2019
85
MAKE FRIENDS WITH THE NAIL PLATE!
86
87
29 1/25/2019
88
Melan-A
89
90
30 1/25/2019
Helpful stains and pitfalls
Melanocytic markers – Helpful as always in identifying the lesion – Helpful in quantifying melanocytes Best stains to use in epithelium: Melan-A, SOX-10, MiTF S100 protein: unreliable in nail unit epithelium MiTF: stains superficial matrix keratinocyte nuclei (pitfall) Nail plate melanocytes: variable staining, may need to try a few Amin B et al. Am J Surg Pathol. 2008;32(6):835-843. Theunis A et al. Am J Dermatopathol. 2011;33(1):27-34. Ruben BS. Semin Cutan Med Surg. 2015;34(2):101-108.
91
MELAN-A
92
SOX-10
93
31 1/25/2019
Nail matrix nevus PITFALL: MiTF stains superficial matrical keratinocytic nuclei
Courtesy, Molly Hinshaw, MD
Ruben BS. Pigmented lesions of the nail unit. Semin Cutan Med Surg. 2015;34(2):101-108.
94
Courtesy of Mark Holzberg, MD
95
96
32 1/25/2019
MiTF
97
MiTF pitfall in MIS
98
Invasive melanoma
Courtesy of Siegrid Yu, MD
99
33 1/25/2019
100
101
102
34 1/25/2019
103
104
105
35 1/25/2019
106
107
108
36 1/25/2019
109
Proximal nail fold
Superficial matrix epithelium
110
111
37 1/25/2019
112
113
114
38 1/25/2019
115
116
Invasive Melanoma
117
39 1/25/2019
Staging of Nail Unit Melanoma
Independent prognostic factors for this site do not exist Use AJCC guidelines Measurement of thickness can be tricky if nail avulsed, ulceration Partial biopsies may limit full assessment and treatment planning
118
Thick melanoma
Courtesy of Dr. Nina Botto 119
ulceration thickness
mitotic rate perineural lymphovascular invasion invasion
D2-40 120
40 1/25/2019
Conservative surgery for nail unit MM
Appropriate for some MIS and thin MM Complete removal of nail unit/grafting Attention to removal of all matrical epithelium, possibly superficial bone Long term follow up for recurrence
Moehrle M et al. Dermatol Surg. 2003;29(4):366-374. Sureda N et al. Br J Dermatol. 2011;165(4):852-858. Neczyporenko F et al. J Eur Acad Dermatol Venereol. 2014; 28 (5)-550-7. Chow WTH et al. J Plast Reconstr Aesthet Surg. 2013;66(2):274-276. Nguyen JT et al. Ann Plast Surg. 2013;71(4):346-354. Oh BH et al. Ann Dermatol. 2015;27(4):417-422. 121
Neczyporenko F, André J, Torosian K, Theunis A, Richert B. Management of in situ melanoma of the nail apparatus with functional surgery: report of 11 cases and review of the literature. J Eur Acad Dermatol Venereol. 2014; 28 (5)-550-7.
122
Distance from proximal matrix to bone: 0.8 mm
123
41 1/25/2019
Acknowledgments
Monica Lawry, MD Phoebe Rich, MD Nilton Di Chiacchio, MD, PhD Council for Nail Disorders European Nail Society UCSF Dermatology and Dermatopathology PAMF Dermatology
124
Thank you!
125
42 THURSDAY DERMATOPATHOLOGY
Melanocytic Mayhem
DR TAMMIE FERRINGER 1/25/2019
Making Sense of the Mayhem
Tammie Ferringer, MD Geisinger Medical Center, Danville, PA [email protected]
1
2
38 year old female
History of melanoma and dysplastic nevi First presented to our clinic in 2006 with a several year history of a pruritic rash involving the arms, legs, chest, back and neck Flared several times a year without full resolution Clinical suspicion of lichenoid dermatitis
3
1 1/25/2019
BX# 2 in 2006
4
5
BX# 6 in 2008
Clinical: Lichenoid-like eruption, not improving, not confirmed by biopsy DDX: Lichenoid process.
| 6 6
2 1/25/2019
| 7
Patient #1
| 8 8
BX# 6 Skin, left arm: Impetiginized crust with areas of superficial epidermal acantholysis and sparse dyskeratosis. (See comment) Comment: The histologic differential diagnosis includes bullous impetigo or impetiginized Grover’s disease. The presence of sparse dyskeratotic cells militates against an acantholytic process such as pemphigus. There is no evidence of a lichenoid infiltrate. | 9 9
3 1/25/2019
10
BX# 9 in 2013
Clinic Note: Hyperpigmented macules with erythema scattered on trunk. Lichenoid dermatitis ? CARP?
11
BX# 9 in 2013
12
4 1/25/2019
13
Clinical Conference 2015
Skin, left arm: Impetiginized crust with areas of superficial epidermal acantholysis and sparse dyskeratosis. No family history and normal nails but… Darier’s???? Declined oral retinoid but willing to try tazarotene
14
2015
15
5 1/25/2019
16
BX# 11
17
18
6 1/25/2019
2007 Melanoma Series
19
20
21
7 1/25/2019
22
Lets Review
23
Diagnosis?
24
8 1/25/2019
BX# 11
25
Galli-Galli Disease
Galli-Galli disease is an acantholytic variant of Dowling-Degos disease: Additional genetic evidence in a German family Astrid Schmieder, et al. JAAD , Vol. 66, Issue 6, e250–e251. June 2012
26
Dowling-Degos Disease
27
9 1/25/2019
Galli-Galli Disease
Galli-Galli disease is an acantholytic variant of Dowling-Degos disease: Additional genetic evidence in a German family. Astrid S, et al. JAAD, 66(6), e250–e251. June 2012
28
Her 29 year old son may have similar eruption
29
Reticulate Hyperpigmentary Disorders Reticulate acropigmentation of Kitamura Dowling-Degos disease Galli-Galli disease Dyschromatosis universalis hereditaria Dyschromatosis symmetrica hereditaria
30
10 1/25/2019
K5
Wu YH, Lin YC. Generalized Dowling–Degos disease. J Am Acad Dermatol 2007;57:327-34.
31
32
Take Home
Flash back Galli-Galli Disease Darier’s like eruption and hyperpigmented macules Adenoid proliferation of the rete with basal hyperpigmentation and acantholysis
Müller CS, Pföhler C, Tilgen W. J Cutan Pathol. 2009 Jan;36(1):44-8. 33
11 1/25/2019
Take Home
Clinical Images Survey of ASDP members Clinical photo is beneficial in Inflammatory skin disease 92% Pigmented lesions 73% Non-melanocytic tumors and growths 56% 91% able to provide more specific diagnosis
Mohr MR, et al. Arch Dermatol Nov 2010;146(11): 1307-8. 34
Take Home
Clinical Images 100 inflammatory cases Shorter differential
JAAD 2010;63:647-52.
35
31 year old G2P1 female at 8 weeks gestation
36
12 1/25/2019
37
38
CD3+. CD56-, CD4-, ISH for EBV-
CD8 Mib-1
39
13 1/25/2019
Subcutaneous Panniculitis- like T-cell Lymphoma Β-F1 (αβ) positive GM1 (γδ) negative
40
Am J Surg Pathol 2016;40:745–754
41
Mib-1
CD8
42
14 1/25/2019
S/p high dose prednisone Healthy baby girl All was well, until……
43
After delivery developed rapid progression of new lesions despite treatment with increased prednisone, methotrexate and romidepsin Fever Leukopenia, anemia, hyperferritinemia, and increased LFTs Ultrasound suggested cholecystitis Admitted Fatal HPS due to SPLTCL
44
Hemophagocytic Syndrome
Life-threatening syndrome of excessive immune activation Histiocytes activated and secrete excess cytokines Cytotoxic T lymphocytes and NK cells are unable to eliminate activated macrophages
45
15 1/25/2019
Familial Hemophagocytic Lymphohistiocytosis
Mutations in genes involved in perforin- dependent cytotoxicity PRF1, UNC13D, STX11, STXBP2 Most frequently presents in first year of life
Jordan MB, et al. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011 Oct 13;118(15):4041-52.
46
Reactive Hemophagocytic Syndrome Viral illness Autoimmune disease (Macrophage activation syndrome) Lymphoma Immunodeficiency
47
Jordan MB, et al. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011 Oct 13;118(15):4041-52.
48
16 1/25/2019
Hemophagocytosis
Presence of fragments or intact RBC, platelets, or WBCs within the cytoplasm of macrophages
49
Kerl K, et al. Hemophagocytosis in Cutaneous Autoimmune Disease. Am J Dermatopathol. 2014 Jul 24.
50
Courtesy Travis Vandergriff
51
17 1/25/2019
52
HPS at Geisinger Age Underlying Disease Cutaneous Findings Dermatology Outcome Consult 33 SPLTCL SPLTCL + DOD 70 Adult Onset Still Disease AOSD + DOD 49 ? 1st visit: none +DOD 2nd consult: HSV 25 Paramyxovirus Generalized - Alive erythematous papules 7 Juvenile idiopathic “rash” - Alive arthritis 26 EBV/JRA None - Alive 56 HIV/DLBCL/Aspergillus None - DOD pneumonia 53
70 yo male with intermittent fevers, joint pain, and persistent plaques
54
18 1/25/2019
Adult Onset Stills Disease
Eventually developed acute mental status changes and massive GI bleed resulting in his death
55
Adult Onset Stills Disease
Spiking fever >=39 C Arthralgia/arthritis Evanescent rash (77-100%)-asymptomatic salmon pink macules/papules with fever on trunk, extremities and areas of pressure Persistent papules and plaques Increased WBC with 80% neutrophils 12-15% RHS 56
Take Home
Histologic features of SPTCL and lupus panniculitis show marked overlap and may require prolonged follow-up Atypical CD8+/Ki-67+ lymphocytes rimming adipocytes suggest SPTCL
57
19 1/25/2019
Take Home
Non-specific morbilliform, purpuric or trigger- specific eruptions with fever, hepatosplenomegaly, neurologic symptoms, cytopenias, increased ferritin levels, liver function impairment or coagulation problems— think about Hemophagocytic Syndrome Persistent plaques of AOSD have apoptotic keratinocytes
58
71 yo with history of NMSCs and sebopsoriasis
First visit in 2005 2008 tattoo laser removal
59
Mid 2010: pancytopenia with normal BM, spleen ultrasound, and flow Sept 2010: red slightly tender patches for 2 months Otherwise feeling well
60
20 1/25/2019
61
62
63
21 1/25/2019
CD4
64
Negative CD56 CD1a, CD3, CD5, CD20, CD21, CD30, CD99, CD68, myeloperoxidase, lysosome
65
CD123
66
22 1/25/2019
67
Blastic Plasmacytoid Dendritic Cell Neoplasm AKA: Blastic NK-cell leukemia/lymphoma CD4+/CD56+ hematodermic neoplasm First introduced in the 2008 WHO classification
68
Blastic Plasmacytoid Dendritic Cell Neoplasm
Males with average age of 58-60 Most present with skin lesions followed by a leukemic phase Nodules, plaques, or bruise-like areas Median overall survival 9-20 months
69
23 1/25/2019
70
TAKE HOME
BPDCN Often presents in the skin before leukemic phase Nodules, plaques, or bruise-like areas Panel of IHC: CD4 CD56 CD123 TCL1 LYS/MPO (positive in myeloid sarcoma, not BPDCN)
71
72
24 1/25/2019
Otherwise healthy 9 month old Congenital lesion on the chest
73
Case 1
74
75
25 1/25/2019
76
Dermatology 2012; 224:24-30.
77
Dermatology 2012; 224:24-30.
Ped Dermatol 2013; 30(4):e54-56
78
26 1/25/2019
Papular Epidermal Nevus with “Skyline” Basal Cell Layer 2011
Congenital or shortly after birth Trunk and limbs Most reported are sporadic
79
Patient’s brother
80
More than just a cool path finding…
81
27 1/25/2019
Our Patient
Subsequently diagnosed with strabismus at 27 months Developmental language disorder and hearing problems at 34 months
82
Take Home
Waxy flesh-colored congenital patches with palisading basal cell layer May suggest neurocutaneous syndrome
83
13 yo febrile male with syncope and progressive weakness Painful purpuric lesions of palms and soles Facial rash for 1 month prior
84
28 1/25/2019
Denied sexual activity and drug use No N/V/abdominal pain, joint pain or headache 85
86
87
29 1/25/2019
Master Sankar Raj V. Case Rep Pediatr. 2013
88
https://library.med.utah.edu/WebPath/CVHTML/CV122.html 89
Work-up
Anemia Normal anti- Transaminitis myeloperoxidase and anti-proteinase Proteinuria antibodies Increased ESR Hypocomplementemia Normal platelets
90
30 1/25/2019
91
Work-up
Positive Antibodies DsDNA SSA Sm RNP Cardiolipin
92
Libman-Sacks Endocarditis
Manifestation of SLE Verrucous, non-bacterial thrombotic endocarditis Usually silent but can result in embolic phenomena Associated with antiphospholipid antibody
93
31 1/25/2019
Take Home
Acral purpuric lesions due to pauci- inflammatory fibrin thrombi Coagulopathy Embolic (infectious endocarditis, cholesterol, atrial myxoma, aseptic endocarditis …)
94
11 yo presented with draining lesions on the Sept 30 left lower leg Sept 10
95
96
32 1/25/2019
special stains for organisms were negative
97
Tissue cultures were negative No bowel symptoms and endoscopy/colonoscopy negative Developed firm subcutaneous nodule on the left chest
98
99
33 1/25/2019
special stains for organisms were negative
100
Dec 9
Admitted for IV solumedrol
101
Dec 18
102
34 1/25/2019
Work-up for autoimmune and systemic granulomatous disease Proteinuria
103
Dec 22
Anti- proteinase 3 ab 148.7 C-ANCA pattern
104
Granulomatosis with Polyangitis Aka Wegener’s granulomatous Most in men in their 4th decade Upper and lower airway Renal involvement Skin involvement in up to 45% May be the first manifestation 15%
105
35 1/25/2019
106
107
108
36 1/25/2019
109
June 22 9 months later Wound care, mycophenolate and prednisone
110
Take Home
Granulomatosis with polyangitis Not just granulomatous vasculitis Can present with pyoderma grangrenosum Suppurative/acneiform PNGD Churg-Strauss necrotizing extravascular granuloma (Winkelmann)
111
37 1/25/2019
21 yo scalp cyst
112
113
BAPomas/Weisner’s nevus (MBAITs)
Flesh colored dome shaped papules Epithelioid cells Dermal May have common nevus component and frequent TILs IHC loss of BAP1 nuclear expression Wiesner T. Nat Genet, 2012. 114
38 1/25/2019
BAP1
115
Weisner Nevus/BAPoma
116
117
39 1/25/2019
118
BAP1 Tumor Syndrome
31%
13%
22%
67%
Soura E, et al. Hereditary melanoma: Update on syndromes and management. J Am Acad Dermatol 2016;74:412-416.
119
120
40 1/25/2019
Paternal grandfather with mesothelioma at age 60
121
Is This Rare?
122
Take Home
Flesh colored dome shaped papule comes back as epitheloid Spitz consider BAPoma Add this to the list of melanoma predisposing syndromes like CDKN2A that can alter how you follow patients
123
41 1/25/2019
32yo female with Crohn’s on remicade with erythematous scalp with hair loss, fungal culture negative, Scarring alopecia?
124
125
126
42 1/25/2019
127
128
TNF-Inhibitor Induced Alopecia
Am J Dermatopathology 2011;33:161.
129
43 1/25/2019
TNF-Inhibitor Induced Alopecia
Psoriasis + Alopecia Areata + Mixed Infiltrate
Doyle LA, et al. Am J Dermatopathology 2011;33:161.
130
TNF-Inhibitor Induced Alopecia
Am J Dermatopathology 2011;33:161. 131
132
44 1/25/2019
45 yo Crohns patient on adalimumab for 6 mos
133
45 yo Crohns patient on adalimumab for 6 mos
134
TNF-Inhibitor Induced Psoriasiform Eruptions
Most in RA, Crohns, or ankylosing spondylitis patients May not be recognized in patients being treated for psoriasis Most have no personal or family history of psoriasis Can occur many months after starting therapy Disruption of cytokine balance by TNF blockage allowing unopposed IFN-alpha production by PDC
135
45 1/25/2019
TNF-Inhibitor Induced Psoriasiform Eruptions Patterns Plaque psoriasis (48-57%) Palmoplantar pustulosis (29-45%) Guttate, scalp, pustular, erythrodermic, inverse
McKee’s Pathology of the Skin 4th ed) 136
TNF-Inhibitor Induced Psoriasiform Eruptions Can show Lichenoid Spongiotic Apoptotic keratinocytes Eosinophils Plasma cells May lack Tortuous blood vessels Suprapapillary plate thinning 137
Take Home TNF Inhibitor delayed reactions Psoriasiform dermatitis Often with interface, spongiosis and mixed infiltrate Alopecia AA histology with psoriasis, mixed infiltrate and atrophic sebaceous glands
138
46 1/25/2019
139
47