Abstract
Histopathologic evaluation of cutaneous ulcers is indicated when the clinical diagnosis is unclear or when ulcers have not responded to standard of care. Many nonmalignant skin ulcers lack specific histologic findings on biopsy and pose a diagnostic challenge. While the usefulness of skin biopsies to diagnose underlying malignancy in ulcerated lesions has been demonstrated in previous studies, their utility in the diagnosis of ulcers of other etiologies has not been reported. We conducted a retrospective study of 45 nonmalignant ulcer biopsies in a 3-year period to compare the histologic diagnosis with the final diagnosis. Additionally, we assessed the diagnostic concordance among three blinded dermatopathologists when reviewing these cases. The leading histologic diagnosis from each of the three observers agreed with the final clinical diagnosis, on average, for 29.6% of the cases (average pairwise kappa = 0.15). Inflammatory ulcers had the lowest concordance between the observers and final diagnosis with an average of 26.0% of cases (average pairwise kappa = 0.06). The observers agreed with each other for 35.6% of the cases (Fleiss' kappa = 0.32). The highest agreement among observers was in the vascular/vasculopathic category (50%, Fleiss' kappa = 0.44). Our results indicate that skin biopsies alone are useful in the evaluation of nonmalignant ulcers to rule out other conditions (e.g. neoplasm) but frequently not sufficient to establish a definitive diagnosis. Additional clinicopathologic correlation is necessary in the final assessment of nonmalignant ulcers to determine the diagnosis. Future research endeavors should explore alternative approaches to more efficiently diagnose nonmalignant skin ulcers.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 219-223 |
| Number of pages | 5 |
| Journal | Wound Repair and Regeneration |
| Volume | 28 |
| Issue number | 2 |
| DOIs | |
| State | Published - Mar 1 2020 |
ASJC Scopus subject areas
- Surgery
- Dermatology
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In: Wound Repair and Regeneration, Vol. 28, No. 2, 01.03.2020, p. 219-223.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - The utility and challenges of histopathologic evaluation in the diagnosis of nonmalignant skin ulcers
AU - Hammer, Phoebe
AU - Latour, Emile
AU - Bohnett, Mary C.
AU - McKenzie, Fatima
AU - Korcheva, Veselina
AU - Mengden, Stephanie
AU - White, Kevin P.
AU - Ortega-Loayza, Alex G.
N1 - Funding Information: Most “nondiagnostic” ulcers were considered to be atypical. Of the atypical ulcers biopsied, the majority were malignant, supporting biopsy as an appropriate and necessary step in the workup of atypical ulcers, despite the possibility of nondiagnostic results. However, previous empirical, blinded demonstrations of the utility of histopathologic analysis of nonmalignant atypical ulcers have not been demonstrated. This study reflects the difficulty in histopathologic diagnosis of nonmalignant ulcers, a concern commonly encountered in clinical practice, but that previously lacked supporting research. Substantial agreement was not identified in our study, and all concordance values between observers and the final diagnosis fell in the poor to moderate range. A recent study showed similar results in a retrospective study of chronic ulcers; no specific diagnosis could be rendered in almost half of retrospective cases observed histologically. Generally, biopsy of the ulcer edge is advised, as the center of the lesion may be dominated by secondary inflammatory changes, obscuring the primary pathology. This is especially true in older lesions. For suspected infectious ulcers, biopsy of the center of the lesion is recommended. In other cases—such as in suspected pyoderma gangrenosum—multiple biopsies, from both the border and central lesions, might be considered. Generally, a three or four punch biopsy is most appropriate in the workup of ulcers, as shave biopsies may miss pathologic findings in the deep dermis and subcutaneous tissue. Careful handling of the punch biopsy specimen should be undertaken to avoid crush artifact, which could lead to significant errors in histopathologic interpretation. A pathologist's interpretation of an ulcer biopsy is largely affected by biopsy site location, age of ulcer, and type of biopsy selected. The biopsy should include epidermis, dermis, and subcutaneous tissue. Some cases necessitate a second biopsy for immunofluorescence, which requires specialized transport media. Inflammatory ulcers, connective tissue disease‐associated ulcers, and vasculitis may all require immune complex studies. The observers in this study were limited to hematoxylin and eosin stained slides only, and the availability of immunostained sections would likely have increased the concordance among observers and the final diagnosis in some of these cases. In addition to hematoxylin and eosin stained slides, specialized immunohistochemical stains may be required, and can usually be performed on the same biopsy. This is particularly relevant in ulcers with suspected infectious etiology, as fungal, mycobacterial, bacterial, and viral special stains and antibody assays are often available. and clinical appearance can be variable and not always helpful. However, clinical evolution and subsequent response to treatments of the skin ulcer may provide essential clues for the clinician and dermatopathologist. Classification of inflammatory ulcers is then based on the subjective synthesis of clinical and pathologic features, as well as identification of associated comorbidities such as inflammatory bowel disease, rheumatoid arthritis, diabetes, or vasculitis. Ulcers of inflammatory origin posed a particularly challenging histologic diagnosis in our study, with poor agreement among the three dermatopathologists and final diagnosis. The inflammatory ulcers in our study had a broad range of etiologies, including pyoderma gangrenosum, Sweet's syndrome, erythema nodosum, pustular psoriasis, acute generalized exanthematous pustulosis, sarcoidosis, rheumatoid arthritis‐associated ulcer, and inflammatory bowel disease‐associated ulcer. The histopathologic findings for many of these conditions overlap considerably The literature reports misdiagnosis rate as high as 10–20% for patients with pyoderma gangrenosum. Clinical history is the most important diagnostic tool in the workup of pyoderma gangrenosum, as nearly 50 to 70% of cases are associated with systemic inflammatory conditions. For now, pyoderma gangrenosum—as well as many other inflammatory ulcers—exists as a diagnosis of exclusion. The tests required are for the workup of inflammatory ulcers are extensive, including blood work, imaging and venous and arterial studies. However, our high proportion of inflammatory ulcers, particularly pyoderma gangrenosum, is impacted by referral bias, as our institution is a tertiary referral center for inflammatory ulcers. The majority of our inflammatory ulcers had a final diagnosis of pyoderma gangrenosum, an inflammatory skin ulcer that exemplifies these difficulties. Histopathologically, it is an ulcer that changes over time and lacks defining features. The relatively small sample size of cases confined to a single institution limit the generalizability of these results. Future studies would benefit by obtaining more representative samples of nonmalignant skin ulcers, especially in the categories of “infectious” and “other,” which were under‐represented in this study. Expansion to include multiple institutions would also help to reduce the potential bias in single institutional studies. More research is needed to further explore dermatopathologic concordance in the diagnosis of nonmalignant skin ulcers. The low concordance in dermatopathologist agreement of nonmalignant ulcers in the absence of clinical context is compelling and warrants further investigation. A complete clinical history may be essential and should be communicated clearly to the pathologist. Although helpful, biopsies alone are likely not sufficient to establish a definitive diagnosis of nonmalignant atypical ulcers. The consequences of misdiagnosis can be grave. Treatments for ulcers vary greatly based on the etiology, including immunosuppression for pyoderma gangrenosum, antibiotics and debridement for infection, and vascular surgery for venous or arterial ulcers. Source of funding : Medical Research Foundation award Acknowledgements : None Conflict of interest : The authors declare no conflicts of interest. Funding Information: This study reflects the difficulty in histopathologic diagnosis of nonmalignant ulcers, a concern commonly encountered in clinical practice, but that previously lacked supporting research. Substantial agreement was not identified in our study, and all concordance values between observers and the final diagnosis fell in the poor to moderate range. A recent study showed similar results in a retrospective study of chronic ulcers; no specific diagnosis could be rendered in almost half of retrospective cases observed histologically. Most ?nondiagnostic? ulcers were considered to be atypical. Of the atypical ulcers biopsied, the majority were malignant, supporting biopsy as an appropriate and necessary step in the workup of atypical ulcers, despite the possibility of nondiagnostic results. However, previous empirical, blinded demonstrations of the utility of histopathologic analysis of nonmalignant atypical ulcers have not been demonstrated. A pathologist's interpretation of an ulcer biopsy is largely affected by biopsy site location, age of ulcer, and type of biopsy selected. The biopsy should include epidermis, dermis, and subcutaneous tissue. Generally, biopsy of the ulcer edge is advised, as the center of the lesion may be dominated by secondary inflammatory changes, obscuring the primary pathology. This is especially true in older lesions. For suspected infectious ulcers, biopsy of the center of the lesion is recommended. In other cases?such as in suspected pyoderma gangrenosum?multiple biopsies, from both the border and central lesions, might be considered. Generally, a three or four punch biopsy is most appropriate in the workup of ulcers, as shave biopsies may miss pathologic findings in the deep dermis and subcutaneous tissue. Careful handling of the punch biopsy specimen should be undertaken to avoid crush artifact, which could lead to significant errors in histopathologic interpretation. In addition to hematoxylin and eosin stained slides, specialized immunohistochemical stains may be required, and can usually be performed on the same biopsy. This is particularly relevant in ulcers with suspected infectious etiology, as fungal, mycobacterial, bacterial, and viral special stains and antibody assays are often available. Some cases necessitate a second biopsy for immunofluorescence, which requires specialized transport media. Inflammatory ulcers, connective tissue disease-associated ulcers, and vasculitis may all require immune complex studies. The observers in this study were limited to hematoxylin and eosin stained slides only, and the availability of immunostained sections would likely have increased the concordance among observers and the final diagnosis in some of these cases. Ulcers of inflammatory origin posed a particularly challenging histologic diagnosis in our study, with poor agreement among the three dermatopathologists and final diagnosis. The inflammatory ulcers in our study had a broad range of etiologies, including pyoderma gangrenosum, Sweet's syndrome, erythema nodosum, pustular psoriasis, acute generalized exanthematous pustulosis, sarcoidosis, rheumatoid arthritis-associated ulcer, and inflammatory bowel disease-associated ulcer. The histopathologic findings for many of these conditions overlap considerably and clinical appearance can be variable and not always helpful. However, clinical evolution and subsequent response to treatments of the skin ulcer may provide essential clues for the clinician and dermatopathologist. Classification of inflammatory ulcers is then based on the subjective synthesis of clinical and pathologic features, as well as identification of associated comorbidities such as inflammatory bowel disease, rheumatoid arthritis, diabetes, or vasculitis. The majority of our inflammatory ulcers had a final diagnosis of pyoderma gangrenosum, an inflammatory skin ulcer that exemplifies these difficulties. Histopathologically, it is an ulcer that changes over time and lacks defining features. The literature reports misdiagnosis rate as high as 10?20% for patients with pyoderma gangrenosum. Clinical history is the most important diagnostic tool in the workup of pyoderma gangrenosum, as nearly 50 to 70% of cases are associated with systemic inflammatory conditions. For now, pyoderma gangrenosum?as well as many other inflammatory ulcers?exists as a diagnosis of exclusion. The tests required are for the workup of inflammatory ulcers are extensive, including blood work, imaging and venous and arterial studies. However, our high proportion of inflammatory ulcers, particularly pyoderma gangrenosum, is impacted by referral bias, as our institution is a tertiary referral center for inflammatory ulcers. The relatively small sample size of cases confined to a single institution limit the generalizability of these results. Future studies would benefit by obtaining more representative samples of nonmalignant skin ulcers, especially in the categories of ?infectious? and ?other,? which were under-represented in this study. Expansion to include multiple institutions would also help to reduce the potential bias in single institutional studies. More research is needed to further explore dermatopathologic concordance in the diagnosis of nonmalignant skin ulcers. The consequences of misdiagnosis can be grave. Treatments for ulcers vary greatly based on the etiology, including immunosuppression for pyoderma gangrenosum, antibiotics and debridement for infection, and vascular surgery for venous or arterial ulcers. The low concordance in dermatopathologist agreement of nonmalignant ulcers in the absence of clinical context is compelling and warrants further investigation. A complete clinical history may be essential and should be communicated clearly to the pathologist. Although helpful, biopsies alone are likely not sufficient to establish a definitive diagnosis of nonmalignant atypical ulcers. Source of funding: Medical Research Foundation award Acknowledgements: None Conflict of interest: The authors declare no conflicts of interest. Publisher Copyright: © 2019 by the Wound Healing Society
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Histopathologic evaluation of cutaneous ulcers is indicated when the clinical diagnosis is unclear or when ulcers have not responded to standard of care. Many nonmalignant skin ulcers lack specific histologic findings on biopsy and pose a diagnostic challenge. While the usefulness of skin biopsies to diagnose underlying malignancy in ulcerated lesions has been demonstrated in previous studies, their utility in the diagnosis of ulcers of other etiologies has not been reported. We conducted a retrospective study of 45 nonmalignant ulcer biopsies in a 3-year period to compare the histologic diagnosis with the final diagnosis. Additionally, we assessed the diagnostic concordance among three blinded dermatopathologists when reviewing these cases. The leading histologic diagnosis from each of the three observers agreed with the final clinical diagnosis, on average, for 29.6% of the cases (average pairwise kappa = 0.15). Inflammatory ulcers had the lowest concordance between the observers and final diagnosis with an average of 26.0% of cases (average pairwise kappa = 0.06). The observers agreed with each other for 35.6% of the cases (Fleiss' kappa = 0.32). The highest agreement among observers was in the vascular/vasculopathic category (50%, Fleiss' kappa = 0.44). Our results indicate that skin biopsies alone are useful in the evaluation of nonmalignant ulcers to rule out other conditions (e.g. neoplasm) but frequently not sufficient to establish a definitive diagnosis. Additional clinicopathologic correlation is necessary in the final assessment of nonmalignant ulcers to determine the diagnosis. Future research endeavors should explore alternative approaches to more efficiently diagnose nonmalignant skin ulcers.
AB - Histopathologic evaluation of cutaneous ulcers is indicated when the clinical diagnosis is unclear or when ulcers have not responded to standard of care. Many nonmalignant skin ulcers lack specific histologic findings on biopsy and pose a diagnostic challenge. While the usefulness of skin biopsies to diagnose underlying malignancy in ulcerated lesions has been demonstrated in previous studies, their utility in the diagnosis of ulcers of other etiologies has not been reported. We conducted a retrospective study of 45 nonmalignant ulcer biopsies in a 3-year period to compare the histologic diagnosis with the final diagnosis. Additionally, we assessed the diagnostic concordance among three blinded dermatopathologists when reviewing these cases. The leading histologic diagnosis from each of the three observers agreed with the final clinical diagnosis, on average, for 29.6% of the cases (average pairwise kappa = 0.15). Inflammatory ulcers had the lowest concordance between the observers and final diagnosis with an average of 26.0% of cases (average pairwise kappa = 0.06). The observers agreed with each other for 35.6% of the cases (Fleiss' kappa = 0.32). The highest agreement among observers was in the vascular/vasculopathic category (50%, Fleiss' kappa = 0.44). Our results indicate that skin biopsies alone are useful in the evaluation of nonmalignant ulcers to rule out other conditions (e.g. neoplasm) but frequently not sufficient to establish a definitive diagnosis. Additional clinicopathologic correlation is necessary in the final assessment of nonmalignant ulcers to determine the diagnosis. Future research endeavors should explore alternative approaches to more efficiently diagnose nonmalignant skin ulcers.
UR - http://www.scopus.com/inward/record.url?scp=85075389209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075389209&partnerID=8YFLogxK
U2 - 10.1111/wrr.12780
DO - 10.1111/wrr.12780
M3 - Article
C2 - 31705777
AN - SCOPUS:85075389209
SN - 1067-1927
VL - 28
SP - 219
EP - 223
JO - Wound Repair and Regeneration
JF - Wound Repair and Regeneration
IS - 2
ER -