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Skin Cancer Course
Skin Cancer Course
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Hello, my name is Yadira Hurley, and I am going to be presenting a portion of the Skin Cancer Course for the AAD. My emphasis will be on lymphoproliferative disorders. I would like to start by discussing appropriate use criteria. These are developed taking into account literature, panel raters, and clinical scenarios. In dermatology, the first set of appropriate use criteria, or AUC, were developed for most. In 2018, the American Society of Dermatopathology published AUC for dermatopathology both in the Journal of Cutaneous Pathology and the JAD. The way I will review my cases today is based on general practice patterns and utilization. We will start with ordered by a dermatopathologist. There are four subgroups of tests for appropriate use criteria in dermatopathology. Lymphoproliferative disorders, melanocytic, soft tissue, and other. As I alluded to before, I will be focusing on lymphoproliferative disorders. Early manifestations of LPDs can be diagnostically challenging. This is because both clinically and histopathologically there is overlap with benign conditions. Molecular clonality assays are used as confirmatory tests in LPDs. However, there are inherent limitations both regarding sensitivity and specificity. PCR amplification of TCR beta or gamma in IGH gene rearrangements allows for detection of clonal rearrangements. For T cell disorders, this can be done in a significant background of reactive T cells. B cell clonality has fewer ambiguous results because they are less prone to artifactual rearrangement patterns. Here is a table of T cell clonality beta and gamma appropriate use scores. Green means usually appropriate, red means rarely appropriate, whereas blue is uncertain appropriateness, and white is no consensus. This is a slide of a patient with cesarean syndrome. The diagnosis was psoriasiform dermatitis because, as you can see, some of the classic findings for mycosis fungoides or cesarean syndrome, such as patria marker abscesses, are not present. T cell clonality assays are usually appropriate in two scenarios. One is as a confirmatory test in cases where clinical diagnosis includes mycosis fungoides and the histology and immunophenotype are concerning, suspicious, or suggestive of MF. They are also very helpful for clone comparison. This is an image of T cell clonality by next-generation sequencing, but PCR, although less sensitive, yields similar patterns. So on the left, you have a polyclonal process, whereas on the right, you have a clonal process and you can see that there are two clones, one that is smaller and one that is larger. There is a high rate of false positives with clonality testing, which in the AUC tables are commonly categorized as uncertain appropriateness. An example is clinically reactive entities, such as pitorises like Anoides chronica. This tells us that better methodologies are needed to evaluate T cell clonality, and there is emergent technology to do so, such as high-throughput sequencing and next-generation sequencing. Next we are reviewing B cell receptor IgH gene rearrangements by PCR. An example of the histopathology of a low-grade B cell lymphoma, which can be hard to distinguish from cutaneous lymphoid hyperplasia. B cell clonality is usually appropriate as a confirmatory test in cases where histology and immunophenotype of the infiltrate is concerning, suspicious, or suggestive of either a primary cutaneous marginal zone lymphoma or follicle center lymphoma. This patient has follicle center lymphoma. In cases where the histopathology is difficult to distinguish from cutaneous lymphoid hyperplasia, B cell clonality assays would be appropriate. Kappa and lambda, like chain monotypia, can be performed by immunohistochemistry or in cytohybridization. This is usually appropriate as a confirmatory test for primary cutaneous marginal zone lymphoma or follicle center lymphoma, or in other instances where plasma cells are prominent. The normal ratio of kappa to lambda is 3 to 1. This example shows lambda restriction. A patient with primary cutaneous marginal zone lymphoma will typically show kappa or lambda restriction. The next set of tests I will review are those that are typically suggested by your dermatopathologist and not performed reflexively. Many cases of Muir-Torr syndrome are caused by a defect in mismatched repair genes. The Muir-Torr-associated sebaceous neoplasms include sebaceous carcinoma, sebaceous epithelioma, sebaceous adenoma, and sebaceoma. Universal screening for Lynch syndrome is recommended by major task forces for all new colorectal cancers in patients that are younger than 70 years old. There is no formal screening guidelines for Muir-Torr syndrome-associated skin neoplasms. A sensitivity as high as 81% has been reported in the literature for MMR analysis by immunohistochemistry and sebaceous neoplasms. However, studies where germline mutation analysis is also available point to high false positive rates due to non-heritable molecular events. Two tables from Muir-Torr syndrome appropriateness scores are congruent for patients older and younger than 60 years of age. An exception is in the younger age group where sebaceous neoplasms on non-head and neck sites were also considered usually appropriate. There is weak support for global or reflective use of MMR testing. Recent scientific evidence shows that a tailored approach using clinical parameters is best. Important to note, MMR testing for periocular sebaceous carcinomas in patients that are older than 60 is rarely appropriate. At our lab, rather than performing this test reflexively, we make a note saying that this test can be performed at the request of the clinician, with the hope that clinical parameters will be included. Sebaceous neoplasms in Neuritor syndrome can occur before, concurrently, or after internal malignancy. The average age of presentation is 53 years. Here is an example of MMR protein analysis by immunohistochemistry. Sebaceous neoplasms may be sporadic or associated with Neuritor syndrome. At the request of the clinician, MR testing can be performed. However, it is rarely appropriate to perform reflective testing. Next, we will be discussing tests that are requested by the dermatologist. Human papillomavirus is implicated in many cutaneous diseases. There are many commercial available type-specific probes and cocktails for the detection of HPV. The type-specific probes are for HPV 6, 11, 16, 18, 31, and 33, and they are the most commonly used by dermatopathologists. Review of the literature for HPV testing reveals some interesting results. There are only two studies that utilize currently available IHC antibodies. Most of the literature for detection of HPV is for condylomas or lesions histologically concerning for condylomas in adults by ISH. The most common HPV type in the pediatric population is HPV 2. HPV 2 is not detected by most of the available assays. Testing for the presence of virus can be performed by ISH or IHC. Type-specific probes exist for HPV 6, 11, 16, 18, 31, and 33. There are only two commercially available antibodies at this time, abcam and daco, and the HPVs identified are listed. This is a summary table for the appropriate use criteria of HPV testing. As you can see, there are only two clinical scenarios in green, which are thought to be usually appropriate. The majority of the clinical scenarios are rarely appropriate and should be done only at the request of the clinician. Compatible with literature, ISH is usually appropriate or majority usually appropriate in a pediatric patient pathology suggestive of condyloma, a patient under 25 years of age with pathologic findings consistent with a seborrheic keratosis of genital skid, perineum, lower abdomen, or inner thighs. While considering testing, communication between the pathologist and the clinician is important, especially given the psychosocial implications of the diagnosis. It is clear that research is needed to assess the value of HPV testing in clinical scenarios other than condyloma, in particular, in squamous cell carcinoma. I will finish with a real-world example. Cytogenetics of dermatofibroma sarcoma protuberans show balanced or unbalanced translocation or a supernumerary ring chromosome. There are multiple modalities of fish that can detect the translocation with similar sensitivities. The sensitivities are high at 94% to 95%. Here's an image of a dual-fusion interface fluorescence in cytohybridization or FISH conducted on a DFSP. Here's the table for the appropriate use course in DFSP. FISH assay for DFSP is usually appropriate when the histology of the tumor is not typical for DFSP and the tumor is CD34 positive. Also, when tyrosine kinase therapy is being considered. FISH assay for DFSP is rarely appropriate or there was no consensus in the listed six clinical scenarios. I will draw your attention to the second no-consensus clinical scenario where the histology is typical for DFSP, it is CD34 positive, but the subcutaneous tissue is not visualized. When subcutaneous tissue is not present in the specimen, it limits the cytologic and architectural histologic evaluation. Therefore, it is important to have adequate tissue sampling in an effort to decrease additional testing with FISH to render a diagnosis. Now we are going to apply the appropriate use criteria for the DFSP we have reviewed. The clinical history is that of a 20-year-old female with a brown patch on the chest. The dermatologist wanted to rule out amoebas. The image of this slide shows a spindle dermal cell tumor, but there is no subcutaneous tissue available. Here, the story form pattern can be appreciated. The tumor is CD34 positive and factor 13A negative. My differential diagnosis consisted of these three entities, DFSP, plaque-like CD34 positive dermal fibroma, or a solitary fibrous tumor. Solitary fibrous tumor is a fibroblastic neoplasm with variable clinical behavior. It mimics DFSP and shows CD34 expression in 95% of cases. Importantly, 95% of solitary fibrous tumors show STAT6 nuclear expression. However, this case was STAT6 negative. This is an article with a clinical image of the other entity that was in my differential diagnosis, plaque-like CD34 positive dermal fibroma. Plaque-like CD34 positive dermal fibroma is a CD34 positive dermal neoplasm with overlapping clinical pathologic features with DFSP. Both entities present as slightly pigmented and indurated plaques on neck, trunk, and extremities. Fish analysis is recommended to distinguish these two entities. An excerpt of the AUC for DFSP shows that there is no consensus when the histology is typical for DFSP, the tumor is CD34 positive, but subcutaneous tissue is not visualized. My case showed no translocation with fish. My preference would have been to have additional tissue with subcutaneous fat. However, the dermatologist, understandably, did not want to do a larger biopsy due to the location of the breast. Interestingly, the excision showed classic histology for DFSP and was CD34 positive. Recently, a PDGFD rearrangement has been reported in 4% of DFSPs. These DFSPs have an apparent predilection for the breast, so it's now understood that there is an alternative rearrangement in DFSPs without PDGFD fusions. Physicians need tools to help make decisions about health care, especially appropriateness of care that achieve value, increase quality, and control costs. We want to be efficient and just, and we want to address ambiguous approaches. What have appropriate use criteria done for dermatologists and dermatopathologists? They have provided guidance for the use of certain ancillary tests in specific clinical scenarios, which will provide the foundation for utilization studies. In addition, there was a compilation of available literature regarding the tests examined. Finally, they highlight snapshots of areas in which available evidence is controversial or underdeveloped, providing potential areas for additional research. An example is my case where more recent literature showed that a small percentage of DFSPs can have an alternate translocation. Thank you for your attention.
Video Summary
Yadira Hurley presents a portion of the Skin Cancer Course focusing on lymphoproliferative disorders in dermatopathology. Discussions include appropriate use criteria, manifestations of LPDs, diagnostic challenges, clonality assays, T cell disorders, B cell clonality, Muir-Torr syndrome-associated neoplasms, Lynch syndrome screening, HPV testing, and DFSP cytogenetics. Testing recommendations for HPV and DFSP are detailed, emphasizing the importance of communication between pathologists and clinicians. A case study of a 20-year-old female with a chest tumor illustrates the application of appropriate use criteria in diagnosing DFSP. The presentation underlines the value of appropriate use criteria in guiding ancillary test utilization, addressing controversies in evidence, and identifying areas for further research in dermatopathology.
Asset Subtitle
M. Yadira Hurley MD, FAAD
Keywords
Skin Cancer Course
lymphoproliferative disorders
dermatopathology
clonality assays
DFSP cytogenetics
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