Important Decisions in Dermatopathology: The Clinico- Pathologic Correlation Uma Sundram, MD, PhD Departments of Pathology and Dermatology Stanford University May 29, 2008 Dermatopathology Specialists Needed Skin and Allergy News Sep 2007: Interview of Dr. Clay Cockerell Changing trends in dermatopathology Increasing numbers of primary care physicians evaluate skin disorders on a routine basis Many of these biopsies are routed to general pathologists Changing Trends Cockerell: Only 35% of skin biopsies come from dermatologists Economic pressures may also force PCP s to keep and work up their difficult dermatology cases, rather than refer Dermatopathologists not being trained in numbers to meet demand 1
Diagnostic Errors Due to lack of understanding of the dermatologic clinical scenario, overinterpretation or under-interpretation of biopsies take place Purpose of this talk: To stress the importance of clinico-pathologic correlation and assessing the clinical scenario in conjunction with slide interpretation Case I 45 year old female with persistent red patch on the left arm. 2
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What is your diagnosis? 1. Mycosis fungoides 2. Drug eruption 3. Lichen planus 4. Lichenoid keratosis 0% 0% 0% 0% Mycosis fungoides Drug eruption Lichen planus Lichenoid keratosis What is your next step? 1. Call the clinician 2. Initiate immunohistochemical studies 3. Initiate PCR analysis for TCR gene rearrangements Call the clinician 0% 0% 0% Initiate immuno-hist... Initiate PCR analysis f.. If you called the clinician, what would you ask about? 1. Size and number of lesions 2. Appearance of lesions (patches/plaques or papules) 3. Distribution of lesions (sun spared or sun exposed sites) 4. Duration of lesions 5. Drug history 6. All of the above Size and number of l... Appearance of lesion... 0% 0% 0% 0% 0% 0% Distribution of lesions... Duration of lesions Drug history All of the above 4
If ordering immunohistochemical studies, what would you order? 1. CD20 and CD3 2. CD3, CD4, and CD8 3. CD4 and CD8 only 4. CD20, CD3, and CD30 5. None CD20 and CD3 0% 0% 0% 0% 0% CD3, CD4, and CD8 CD4 and CD8 only CD20, CD3, and CD30 None Would you order PCR analysis? 1. Yes 2. No 0% 0% Yes No Clinical Clues Mycosis fungoides: Tend to be patches/plaques in sun protected sites, persistent, no temporal connection to drugs Lichenoid keratosis: Solitary small lesions 5
Clinical Clues Lichen planus: Purple polygonal papules, sometimes related to drugs Drug eruption: Have a temporal relationship to drug exposure We called the clinician and The lesion is solitary, limited to the arm, persistent patch, with no significant drug history Our approach Given the solitary nature of the lesion and lack of clinical concern for mycosis fungoides, our final diagnosis was benign (so called lymphomatoid ) lichenoid keratosis. The solitary nature of the lesion made the diagnoses of mycosis fungoides, lichen planus, and drug eruption less likely 6
Our approach We elected not to perform any further ancillary studies, knowing that reactive conditions can be CD4 predominant 1 and can be clonal 2 1. Harvell JD et al. An immunohistochemical study of CD4, CD8, TIA-1 and CD56 subsets in inflammatory skin disease. J Cutan Pathol 2003 Feb; 30(2):108-13. 2. Plaza JA et al. Assessment of TCR-beta clonality in a diverse group of cutaneous T cell infiltrates. J Cutan Pathol 2008 Apr; 35(4):358-65. Lichenoid Keratosis Common cutaneous entity, also known as lichen planus-like keratosis Clinically, these are solitary small lesions The clinical differential diagnosis usually includes basal cell carcinoma, squamous cell carcinoma, verruca, actinic keratosis, and atypical nevi Lichenoid Keratosis On histology, typically characterized by a dense, relatively superficial lymphocytic infiltrate, numerous necrotic keratinocytes at the dermal-epidermal junction, and epidermal hyperplasia If the lesion is captured in its entirety, it is not unusual to see flanking areas of typical solar lentigo or seborrheic keratosis 7
Other Histologic Variants These include 3,4 : Lupus erythematosus-like Bullous-type Early/interface type Late regressed/atrophic type Mycosis fungoides-like (so called lymphomatoid lichenoid keratosis) 3. Morgan MB et al. Benign lichenoid keratosis. A clinical and pathologic reappraisal of 1040 cases. Am J Dermatopathol 2005 Oct; 27 (5):387-392. 4. Al-Hoqail IA et al. Benign lichenoid keratosis with histologic features of mycosis fungoides: clinicopathologic description of a clinically significant histologic pattern. J Cutan Pathol 2002 29:291-294. Lichenoid Keratosis and Mycosis Fungoides In a study of 15 cases of LK, these features, typical of MF, were found 3 : Pautrier s microabscesses (93%) Epidermotropism (80%) Lymphocytes populating the lower half of the epidermis (93%) Cytologic atypia (47%) 3. Morgan MB et al. Benign lichenoid keratosis. A clinical and pathologic reappraisal of 1040 cases. Am J Dermatopathol 2005 Oct; 27 (5):387-392. Unilesional Mycosis Fungoides Separate from localized pagetoid reticulosis Rare and controversial 5 Some documented association with drug exposure Truncal location, similar to lichenoid keratosis Ultimate separation from lymphomatoid lichenoid keratosis requires clinical correlation 5. Cerroni L et al. Solitary skin lesions with histopathologic features of early mycosis fungoides. Am J Dermatopathol 1999; 21:518. 8
What favors lichenoid keratosis? Histologic features that favor benign lichenoid keratosis, in the context of a small (<2 cm), solitary lesion: Necrotic keratinocytes Flanking findings of solar lentigo or seborrheic keratosis Pointed rather than rounded rete pegs in areas of inflammation Ancillary Studies: Are they needed? Specific comparative ancillary studies have not been done Positive clonality studies have been documented in benign lichenoid keratosis 5 5. Arai E et al. Lymphomatoid keratosis: an epidermotropic type of cutaneous lymphoid hyperplasia-clinicopathologic, immunohistochemical, and molecular biological study of 6 cases. Arch Dermatol 2007; 143:53-59. Case II 35 year old female with a few scattered itchy and tender papules that have developed a hemorrhagic crust. 9
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What is your diagnosis? 1. Malignant lymphoma 2. Pityriasis lichenoides et varioliformis acuta (PLEVA) 3. Arthropod bite reaction 4. Herpetic dermatitis 5. Lupus erythematosus 6. Lymphomatoid papulosis Malignant lymphoma Pityriasis lichenoides... 0% 0% 0% 0% 0% 0% Arthropod bite reaction Herpetic dermatitis Lupus erythematosus Lymphomatoid papu... What would be your next step? 1. Call the clinician 2. Order immunohistochemical studies 3. Perform PCR analysis 0% 0% 0% Call the clinician Order immunohist... Perform PCR analysis 11
If you contact the clinician, what would you ask? 1. Distribution of lesions 2. Duration of lesions 3. Clinical course of the lesions (do they wax/wane or are they persistent) 4. Relationship to the sun 5. Systemic symptoms 6. All of the above Distribution of lesions Duration of lesions 0% 0% 0% 0% 0% 0% Clinical course of the... Relationship to the sun Systemic symptoms All of the above If you ordered immunohistochemical stains, what would they be? 1. None 2. CD20 and CD3 3. CD30 4. CD3, CD4, and CD8 5. CD56 0% 0% 0% 0% 0% None CD20 and CD3 CD30 CD3, CD4, and CD8 CD56 Would you order PCR? 1. Yes, for IgH 2. Yes, for TCR 3. Yes, for both IgH and TCR 4. No 0% 0% 0% 0% Yes, for IgH Yes, for TCR Yes, for both IgH an... No 12
CD30 CD30 Clinical Clues If the lesions are grouped, the differential diagnosis would include arthropod bites and herpes If the lesions are in a sun-related distribution (i.e., face), lupus would enter into the differential 13
Clinical Clues If the lesions wax and wane, and resolve with scarring, the differential would include lymphomatoid papulosis If the lesions are persistent, and the patient has systemic symptoms, lymphoma is a consideration We spoke to the clinician and... The lesions are on the back, somewhat grouped, and not in a sun-related distribution The patient does not have systemic symptoms The lesions are persistent and do not heal with scarring; there is no wax/wane course 1. Yes 2. No Could this be malignant lymphoma? 0% 0% Yes No 14
Our approach Given the nature of the clinical lesions and the clinician s lack of concern for a lymphoma, we favored a reactive process The papillary dermal edema, wedge shaped infiltrate and numerous deeply placed eosinophils suggested an arthropod bite reaction Clinical follow-up supported this diagnosis over lymphomatoid papulosis (the leading entity in the differential) CD30+ Cells in Lymphocytic Infiltrates CD30 is a member of the TNF/NGFR superfamily Recognized by the monoclonal antibody Ki-1 raised on Hodgkin cells Known to be present on activated, but not resting, B and T cells CD30+ Cells in Lymphomas CD30 is expressed in the following entities: Reed Sternberg cells of Hodgkin lymphoma Lymphomatoid papulosis Anaplastic large cell lymphoma Transformed mycosis fungoides Pagetoid reticulosis 15
Inflammatory Diseases Can Also Have CD30+ Cells Herpetic dermatitis 6 Arthropod bite reaction (scabies 7, spider bites 8, tick bites 9, other insect bites) 6. Leinweber B et al. Histopathologic features of cutaneous herpes virus infections (herpes simplex, herpes varicella/zoster): A broad spectrum of presentations with common pseudolymphomatous aspects). Am J Surg Pathol 2006; 30:50-58. 7. Gallardo F et al. CD30 antigen expression in cutaneous inflammatory infiltrates of scabies: a dynamic immunophenotypic pattern that should be distinguished from lymphomatoid papulosis. J Cutan Pathol 2002; 29:368-373. 8. Cepeda LT et al. CD30 positive atypical lymphoid cells in common non neoplastic cutaneous infiltrates rich in neutrophils and eosinophils. Am J Surg Pathol 2003; 27(7): 912-918. 9. Hwong H et al. Persistent atypical lymphocytic hyperplasia following tick bite in a child: report of a case and review of the literature. Ped Dermatol 2001; 18 (6):481-484. Inflammatory Diseases Can Also Have CD30+ Cells Tuberculosis 10 Atopic dermatitis 7 Drug eruption (carbamazepine, cefuroxime) 7 10. Massi D et al. Atypical CD30+ cutaneous lymphoid proliferation in a patient with tuberculosis infection. Am J Dermatopathol 2004; 26(3): 234-236. CD30 Expression in Scabies Gallardo et al. described 11 skin biopsies of patients with known active lesions or persistent nodules post treatment 7 All had dense lymphocytic/eosinophilic infiltrates with varying degrees of CD30 expression Some active lesions had Sarcoptes scabiei mites All lesions were CD4 predominant Lesions of less than 2 month duration were less likely to have CD30+ cells 7. Gallardo F et al. CD30 antigen expression in cutaneous inflammatory infiltrates of scabies: a dynamic immunophenotypic pattern that should be distinguished from lymphomatoid papulosis. J Cutan Pathol 2002; 29:368-373. 16
CD30 Expression in Other Arthropod Bite Reactions Cepeda et al. documented CD30 expression in 7 cases of arthropod bites, including 2 spider bite cases 8 CD30 expression was common in neutrophil-rich and eosinophil-rich inflammatory conditions Gene rearrangement studies were negative for a T cell clone, but some showed B cell oligoclonality 8. Cepeda LT et al. CD30 positive atypical lymphoid cells in common non neoplastic cutaneous infiltrates rich in neutrophils and eosinophils. Am J Surg Pathol 2003; 27(7): 912-918. CD30 Expression in Herpes Leinweber et al examined biopsies from 65 patients with known diagnoses of HSV1/2 and VZV 6 Nearly all demonstrated viropathic changes on histology, some subtle Atypical lymphocytes were present in a majority of cases (67%) CD30 expression also present in a majority (80%) 6. Leinweber B et al. Histopathologic features of cutaneous herpes virus infections (herpes simplex, herpes varicella/zoster): A broad spectrum of presentations with common pseudolymphomatous aspects). Am J Surg Pathol 2006; 30:50-58. CD30 Expression in Herpes About 5 cases had dense lymphocytic infiltrates and numerous atypical cells with CD30 expression Two of these had clusters of atypical CD30+ cells; these were also positive for a T cell clone BUT: classic histologic findings of herpes were present and PCR confirmed presence of herpetic DNA 17
Dr. Cockerell s Cases 65 year old woman sees a primary care physician with a solitary lesion Clinical diagnosis: basal cell carcinoma The pathologist notes epidermotropism of atypical lymphocytes and renders diagnosis of probable mycosis fungoides The patient seeks a second opinion from Dr. Cockerell His diagnosis: benign lichenoid keratosis Dr. Cockerell s Cases 36 year old woman who visits her PCP with complaints of a chronic rash The pathologist notes numerous atypical cells, and renders a diagnosis of T cell lymphoma The patient gets two cycles of chemotherapy which resolve the lesions but they reappear after the therapy has concluded Dr. Cockerell s Cases The oncologist asks for a second opinion Dr. Cockerell s diagnosis: lymphomatoid papulosis, which does not require conventional chemotherapy for treatment 18
Summary Benign dermatologic entities can mimic malignant ones on histopathology ( clinically benign, histologically malignant ) Conversation with the clinician is very important in arriving at an appropriate diagnosis Proper clinicopathologic correlation can avoid inaccurate diagnosis, avoid delay in correct diagnosis, and save money 19