Criteria that really discriminate Dirk M. Elston, MD Medical Universiity of South Carolina, Charleston 1
Secondary syphilis is protean Syphilis Often not suspected clinically Old men widowed and lonely Old women Sexual abuse Sometimes nursing home patients If you don t consider the diagnosis, you will miss it. Classic presentation Plasma cells @2/3 Elongation of rete Endothelial swelling Scale/crust Lymphs w/ cytoplasm 2
Would you have ordered a T pallidum immunostain on this case? Untreated syphilis: Tabes Paresis Aortic dissection 3
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Incidence doubled since 2001 Incidence 5.3 cases in 100,000 Local outbreaks Majority in men who have sex with men (MSM) regardless of race, ethnicity, or socioeconomic status The great imitator" Often not suspected clinically Atypical clinical and false negative laboratory tests are more common in patients with human immunodeficiency virus (HIV) infection Prozone reactions Histology Wide spectrum, from interface dermatitis to granulomatous disease Detection rates of spirochetes Silver stain 33%-70% IHC 71% Review of 106 cases of syphilis Most common findings Interstitial inflammatory pattern Endothelial swelling Irregular acanthosis Elongated slender rete ridges Is it acceptable to miss 30% of your cases of syphilis? 6
Most common vs Most helpful The most helpful features are those that occur in cases with relatively few diagnostic features As few as 2 features could be present in some slides Review of 106 cases of syphilis No biopsy specimen demonstrated only a single feature... but as few as 2 or as many as 10 features could be present in a given slide Number of diagnostic features Overall Frequency Neutrophils in Stratum Corneum 34 (32.1%) Effacement 21 (19.8%) Total Cases 106 Number of Features Number of Cases (%) 1 0 (0%) 2 2 (1.9%) Irregular Acanthosis 82 (77.4%) Psoriasiform Acanthosis 3 (2.8%) Elongated Rete Ridges 80 (75.5%) Vacuolar Pattern (more holes than lymphs) 15 (14.2%) 3 5 (4.7%) 4 7 (6.6%) 5 15 (14.2%) 6 30 (28.3%) 7 28 (26.4%) 8 14 (13.2%) 9 4 (3.8%) 10 1 (1.0%) Vacuolar Pattern (equal holes and lymphs) 77 (72.6%) Lichenoid Pattern 25 (23.6%) Interstitial Inflammation 97 (91.5%) Plasma Cells 74 (69.8%) Lymphocytes with ample cytoplasm 58 (54.7%) Endothelial Swelling 93 (87.7%) Cases with 5 or fewer features Neutrophils in Stratum Corneum 2 (6.9%) Effacement 13 (44.8%) Irregular Acanthosis 7 (24.1%) Psoriasiform Acanthosis 2 (6.9%) Elongated Rete Ridges 8 (27.6%) Vacuolar Pattern (more holes than lymphs) 2 (6.9%) 4 or fewer features Neutrophils in Stratum Corneum 0 (0%) Effacement 6 (42.9%) Irregular Acanthosis 1 (7.1%) Psoriasiform Acanthosis 2 (14.3%) Elongated Rete Ridges 1 (7.1%) Vacuolar Pattern (more holes than lymphs) 2 (14.3%) Vacuolar Pattern (equal holes and lymphs) 15 (51.7%) Vacuolar Pattern (equal holes and lymphs) 4 (28.9%) Lichenoid Pattern 1 (3.4%) Interstitial Inflammation 22 (75.9%) Plasma Cells 14 (48.3%) Lymphocytes with ample cytoplasm 11 (37.9%) Endothelial Swelling 21 (72.4%) Lichenoid Pattern 1 (7.1%) Interstitial Inflammation 9 (64.3%) Plasma Cells 5 (35.7%) Lymphocytes with ample cytoplasm 4 (28.9%) Endothelial Swelling 8 (57.1%) 7
3 or fewer features Only 2 features Total Cases 7 Neutrophils in Stratum Corneum 0 (0%) Effacement 2 (28.6%) Irregular Acanthosis 1 (14.3%) Psoriasiform Acanthosis 0 (0%) Elongated Rete Ridges 0 (0%) Vacuolar Pattern (more holes than lymphs) 1 (14.3%) Total Cases 2 Neutrophils in Stratum Corneum 0 (0%) Effacement 0 (0%) Irregular Acanthosis 0 (0%) Psoriasiform Acanthosis 0 (0%) Elongated Rete Ridges 0 (0%) Vacuolar Pattern (more holes than lymphs) 0 (0%) Vacuolar Pattern (equal holes and lymphs) 1 (14.3%) Vacuolar Pattern (equal holes and lymphs) 0 (0%) Lichenoid Pattern 0 (0%) Interstitial Inflammation 5 (71.4%) Plasma Cells 3 (42.9%) Lymphocytes with ample cytoplasm 3 (42.9%) Endothelial Swelling 3 (42.9%) Lichenoid Pattern 0 (0%) Interstitial Inflammation 2 (100%) Plasma Cells 0 (0%) Lymphocytes with ample cytoplasm 1 (50%) Endothelial Swelling 1 (50%) Conclusions Few cases demonstrate all diagnostic features Most cases demonstrate between 5 and 7 diagnostic features. 8 14 (13.2%) 9 4 (3.8%) 10 1 (1.0%) Conclusions Interstitial inflammatory pattern, endothelial swelling, irregular acanthosis and elongated slender rete ridges were the most common findings overall Some more likely to be seen in specimens that demonstrated many findings, so their independent value may be overestimated. Conclusions More important is the likelihood that a given finding will be present in a slide with 5 or fewer diagnostic features these are the cases most prone to misdiagnosis. Most common Intersitial inflammatory pattern ( busy dermis ) Endothelial swelling Conclusions Other helpful findings vacuolar interface dermatitis with a lymphocyte in nearly every vacuole lymphocytes with visible cytoplasm Cases with fewer findings were more likely to demonstrate effacement of the rete pattern, making them more prone to misdiagnosis. 8
Take-Home Points Most cases have 5-7 features Many less frequent in cases with 5 features endothelial swelling (87.7% overall vs 72.4% of cases with 5 features) plasma cells (69.8% vs 48.3%) elongated rete ridges (75.5% vs 27.6%) Take-Home Points Specimens with 5 features more likely to be from the trunk (61.1% of cases with 5 features vs 34.4% overall) demonstrate rete ridge effacement (44.8% vs 19.8%) have pityriasis rosea (33.3% vs 17.2%) or drug eruption (33.3% vs 10.9%) in the clinical differential Take-Home Points An interstitial inflammatory pattern was the most common characteristic of specimens with 5 features (present in 75.9%). Cases with only two diagnostic features demonstrated an interstitial pattern with either endothelial swelling or lymphocytes with ample cytoplasm. Next step Determine positive and negative predictive values of each feature when syphilis is compared with other forms of interface dermatitis. Some, like a lymph in every hole pattern will help you suspect syphilis but discriminate poorly from conditions like PLC How Do We Use Diagnostic Criteria? Our diagnoses should be based on reproducible criteria Criteria Our diagnoses should be based on reproducible criteria How rigorously have our criteria been validated? 9
Polyarteritis nodosa American College of Rheumatology Criteria Weight loss >4 kg, livedo reticularis, testicular pain or tenderness, myalgia / myopathy or muscle tenderness, neuropathy, hypertension (diastolic >90), renal impairment, hepatitis B infection, abnormal arteriogram, biopsy of an artery with neutrophilic inflammation 3 criteria give >82% sensitivity, >86% specificity Major and minor criteria Give weight to individual criteria Polyarteritis nodosa American College of Rheumatology Criteria Weight loss >4 kg, livedo reticularis, testicular pain or tenderness, myalgia / myopathy or muscle tenderness, neuropathy, hypertension (diastolic >90), renal impairment, hepatitis B infection, abnormal arteriogram, biopsy of an artery with neutrophilic inflammation 3 criteria give >82% sensitivity, >86% specificity Major and minor criteria Give weight to individual criteria Dermatopathology KA vs SCC Alopecia Areata Melanoma Neoplastic vs reactive squamous atypia Keratoacanthoma Clinicopathologic correlation Rapid growth followed by termination differentiation and involution Histological Diagnosis KA vs SCC Does it matter? History of rapid growth Crateriform Glassy Neutrophilic microabcesses Eosinophilic infiltrate Central hypergranulosis Lack of acantholysis Elastic trapping 10
Scheduled for amputation Eruptive but not crateriform No neutrophilic microabscesses No eosinophils Glassy Lacked acantholysis Elastic trapping Treated with IL MTX Images courtesy of Omar Noor, MD Elastic trapping Does Elastic Trapping Discriminate? Incidence 71% in KA 37% in SCC (p<0.0001) 5.9% in Hypertrophic LE (p<0.0001) Shah K, Kazlouskaya V, Lal K, et al. J Cutan Pathol 2014; 41:108-12 Does Elastic Trapping Discriminate? Alopecia areata Compared entities Sensitivity Specificity LR (+) (95%CI) LR(-) (95%CI) KA vs. SCC 0.71 0.63 1.9 (1.4-2.6) 0.5 (0.3-0.6) Lesions with elastic trapping are twice as likely to behave like KA Good but not perfect Use in concert with other findings Shah K et al. J Cutan Pathol 2014; 41:108-12 11
What Critera Discriminate Dilated infundibulum Lymphocytes in fibrous tracts 94% Catagen follicles 93% Miniaturized follicles 90% Peribulbar lymphocytic infiltrate 84% Melanin in fibrous tracts 84% Eosinophils in fibrous tracts 44% Pigment casts 44% Peckham SJ, et al. J Am Acad Dermatol. 2011; 65:615-20 Histologic features present in cases without a peribulbar infiltrate Peckham SJ, et al. J Am Acad Dermatol. 2011; 65:615-20 HISTOLOGIC FEATURE Catagen/telogen follicles 15/17 (88%) NUMBER OF CASES (PERCENT) Miniaturization of follicles 15/17 (88%) Melanin in fibrous tracts 12/17 (71%) Pigment casts 10/17 (59%) Lymphocytes in fibrous tracts 7/17 (41%) Eosinophils in fibrous tracts or around bulbs 3/17 (18%) Trichotillomania 12
Trichotillomania shares Alopecia Areata HISTOLOGIC FEATURE Catagen/telogen follicles Shared HISTOLOGIC FEATURE NUMBER OF CASES (PERCENT) Miniaturization of follicles Can be difficult to judge when many catagen hairs are present Melanin in fibrous tracts Melanin in fibrous tracts 12/17 (71%) Pigment casts Shared Lymphocytes in fibrous tracts Eosinophils in fibrous tracts or around bulbs Lymphocytes in fibrous tracts 7/17 (41%) Eosinophils in fibrous tracts or around bulbs 3/17 (18%) Melanoma Miniaturized dystrophic hairs: 4% but highly specific Absolute criteria are lacking in many cases Ron Rapini has said he sometimes feels like the weatherman 80% chance of rain today Melanoma Absolute criteria are lacking in many cases Ron Rapini has said he sometimes feels like the weatherman 80% chance of melanoma today Melanoma We can improve our diagnostic criteria by determining which discriminate best alone or in groups Compare with a gold standard Global assessment CGH/FISH Outcome 13
Computer Diagnoses Computer-aided diagnoses Based on diagnostic algorithms and weighted criteria Has been tried in clinical medicine and dermatopathology Computer Diagnoses Computer-aided diagnoses Based on diagnostic algorithms and weighted criteria Has been tried in clinical medicine and dermatopathology Not bad overall, but none of us will have to look for another line of work anytime soon Pagetoid Spitz in a child Pagetoid Intraepidermal Spitz Nevus Pagetoid scatter of epithelioid melanocytes Small Sharply circumscribed End laterally in a nest 14
Sunburned nevus Pagetoid Scatter Melanoma Spitz Pigmented Spindle Cell Nevus Acral Nevus Trauma Sunburn Nevoid Melanoma nasal tip Helpful diagnostic features Lack of maturation and dispersion (especially spitzoid melanomas in children bulbous outline like a blue nevus) Parallel theque pattern (trabecular at base) Lack HMB-45 gradient Deep mitoses Atypical mitoses MIB + cells deep, >10% overall, > 5% deep Displace elastic Nevoid Melanoma: Parallel theque pattern 15
VVG - elastic As reported by Kamino et al Benign nevus MIB-1 / Ki-67 16
Architecture vs Cytology Spitz We focus mostly on architecture at scan But cytology should not be ignored Melanoma: Irregular nuclear contour Clumped chromatin Irregular/stellate nucleoli Multiple/peripheral nucleoli Cytological Criteria for Melanoma Logistic regression multivariate analysis Independent diagnostic value of each feature Features found to be independently useful Pleomorphism with enlarged nuclei Notching of the nuclear envelope Mitotic figures Peppered moth chromatin pattern 1)How We make diagnoses 2) Simple Techniques you may not be using Acral sites: Hyperchromatic, angulated nuclei Irregular dendrites Dirk M. Elston, MD Medical University of South Carolina Research team: Alex Flamm, EunJi Kwon, Qiang Xie, Nathan Cleaver, Khan Thieu, Jeff Shackleton, Filamer Kabigting, Amira Elbendary, Kara Melissa Torres, Manuel Valdebran, 17
Bowen s Squamous Atypia Irregular nuclear contour Nuclear crowding High N/C ratio Enlarged prominent nucleoli Hyerchromasia Squamous Atypia Atypical mitotic figures Rarely seen, but highly specific Malhotra S, Kazlouskaya V, Andres C, et al. J Cutan Pathol. 2013 Apr;40(4):371-8 Not Statistically Significant Multiple nucleoli Clumped chromatin Number of mitotic figures At the End of the Day Dermatopathology will remain an art Malhotra S, Kazlouskaya V, Andres C, et al. J Cutan Pathol. 2013 Apr;40(4):371-8 18
At the End of the Day Dermatopathology will remain an art Weighing histological features in context will remain a complex skill set At the End of the Day Dermatopathology will remain an art Weighing histological features in context will remain a complex skill set Skills can be learned Validated objective criteria can improve our accuracy Challenge Deconstruct each set of diagnostic criteria in dermatopathology and test the positive predictive value of individual criteria alone and in groups Challenge Deconstruct each set of diagnostic criteria in dermatopathology and test the positive predictive value of individual criteria alone and in groups We re really good, but we can always be a bit better better 19