Key Points
Question
What were the national trends from 2000 to 2017 regarding the use of immunohistochemistry (IHC) staining in diagnostic pathology of melanocytic lesions?
Findings
In this retrospective cross-sectional study among 116 117 older adults enrolled in Medicare, IHC was used diagnostically for 11% of melanoma cases in 2000, increasing to more than half of melanoma cases diagnosed in 2017. Additionally, the trends across the 17 SEER cancer registries varied extensively.
Meaning
A comprehensive understanding of the reasons for variations in the use of IHC, and their association with patient outcomes, is essential.
Abstract
Importance
Pathologic assessment to diagnose skin biopsies, especially for cutaneous melanoma, can be challenging, and immunohistochemistry (IHC) staining has the potential to aid decision-making. Currently, the temporal trends regarding the use of IHC for the examination of skin biopsies on a national level have not been described.
Objective
To illustrate trends in the use of IHC for the examination of skin biopsies in melanoma diagnoses.
Design, Setting, and Participants
A retrospective cross-sectional study was conducted to examine incident cases of melanoma diagnosed between January 2000 and December 2017. The analysis used the SEER-Medicare linked database, incorporating data from 17 population-based registries. The study focused on incident cases of in situ or malignant melanoma of the skin diagnosed in patients 65 years or older. Data were analyzed between August 2022 and November 2023.
Main Outcomes and Measures
The main outcomes encompassed the identification of claims for IHC within the month of melanoma diagnoses and extending up to 14 days into the month following diagnosis. The SEER data on patients with melanoma comprised demographic, tumor, and area-level characteristics.
Results
The final sample comprised 132 547 melanoma tumors in 116 117 distinct patients. Of the 132 547 melanoma diagnoses meeting inclusion criteria from 2000 to 2017, 43 396 cases had accompanying IHC claims (33%). Among these cases, 28 298 (65%) were diagnosed in male patients, 19 019 (44%) were diagnosed in patients aged 65 years to 74 years, 16 444 (38%) in patients aged 75 years to 84 years, and 7933 (18%) in patients aged 85 years and older. In 2000, 11% of melanoma cases had claims for IHC at or near the time of diagnosis. This proportion increased yearly, with 51% of melanoma cases having associated IHC claims in 2017. Increasing IHC use is observed for all stages of melanoma, including in situ melanoma. Claims for IHC in melanomas increased in all 17 SEER registries but at different rates. In 2017, the use of IHC for melanoma diagnosis ranged from 39% to 68% across registries.
Conclusions and Relevance
Considering the dramatically rising and variable use of IHC in diagnosing melanoma by pathologists demonstrated in this retrospective cross-sectional study, further investigation is warranted to understand the clinical utility and discern when IHC most improves diagnostic accuracy or helps patients.
This retrospective cross-sectional study illustrates national-level trends in immunohistochemistry staining for the diagnosis of melanoma in older adult patients enrolled in Medicare.
Introduction
Diagnosing melanoma and other skin conditions can be challenging, with extensive interpathologist variability.1 Although melanoma and other skin cancers are diagnosed based on histomorphologic evaluation of hematoxylin-eosin–stained slides, pathologists often depend on ancillary studies such as the examination of immunohistochemistry (IHC) staining to support or refine the microscopic diagnosis.2,3 Different types of IHC can aid the evaluation of a skin lesion, especially melanocytic lesions. In addition to diagnosis, IHC is used to assess margins, metastasis, prognosis, and treatment. Though the use of IHC is standard in some contexts, guidance for its use for diagnosing melanoma is sparse.
The current literature on IHC for melanoma diagnosis is very limited, describing IHC use only at single sites, for short periods, or biopsies associated with Mohs surgery.4,5,6 One study analyzed melanoma cases sent to a tertiary referral center for consultative diagnoses or second opinion over 15 years and found that 5% of cases in 2001 had at least 1 IHC stain, increasing to 25% by 2015.4 Another study reported IHC use for 64% of 356 melanoma cases in a single clinic over 18 months during 2017 to 2018.5
Although prior studies provide a sense of increasing IHC use over time, the national-level trends are unknown. We describe the use of IHC for melanoma diagnosis in the US by reviewing the linked Surveillance, Epidemiology, and End Results (SEER)–Medicare cancer registry database over 17 years. IHC use trends over time and by patient, tumor, and geographic region characteristics are summarized.
Methods
In this retrospective cross-sectional study, we used the SEER-Medicare database to identify melanoma skin cancer diagnosed between January 2000 and December 2017. SEER collects incident data from population-based cancer registries, covering approximately 27% of the US population; further, the linked Medicare files include enrollment and claims data allowing for examination of health service utilization.7 The University of California, Los Angeles, Office of the Human Research Protection Program determined that this study meets the criteria for an exemption from institutional review board approval, thereby waiving the requirement for informed consent due to deidentified data. Data were analyzed between August 2022 and November 2023.
We selected incident cases of in situ or invasive melanoma of the skin diagnosed in patients 65 years or older (SEER site recode per the International Classification of Diseases for Oncology, Third Revision [ICD-O-3] and World Health Organization 2008 definition 25010). We excluded patients with melanoma who underwent Mohs surgery, patients with regional lymph node procedures or where it was unknown whether the patient had a lymph node procedure, and patients with cancers of another site within 6 months before or after the melanoma diagnosis. Individual patients could contribute multiple melanoma tumors during the 17-year study period.
An associated IHC was defined as the presence of a claim for an IHC during the month of melanoma diagnosis through 14 days into the month after diagnosis (eMethods and eTable 1 in Supplement 1 for Current Procedural Terminology and Healthcare Common Procedure Coding System codes). SEER data on patients with melanoma included demographic variables, tumor characteristics, and area-level data (eMethods in Supplement 1).
We examined IHC use for melanoma diagnosis over time and assessed associations between IHC use and demographic, tumor, and area-level characteristics. Race and ethnicity data were collected through the SEER registry to discern and explore potential associations between the societal outcomes of race and patient care within the scope of this study. We used logistic regression to evaluate associations between IHC use and other characteristics, controlling for the year of diagnosis and testing for trends for ordinal variables. Unknown or not applicable responses were excluded, and we used generalized estimating equation methods to account for multiple melanoma diagnoses per patient. All statistical tests were 2-sided, and statistical significance was evaluated at P < .05. Analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc).
Results
The final sample comprised 132 547 melanoma tumors in 116 117 distinct patients. Of the 132 547 melanoma diagnoses meeting inclusion criteria from 2000 to 2017, 43 396 cases (33%) had accompanying IHC claims (Table). Among these cases, 28 298 (65%) were diagnosed in male patients, 19 019 (44%) were diagnosed in patients aged 65 years to 74 years, 16 444 (38%) in patients aged 75 years to 84 years, and 7933 (18%) in patients aged 85 years and older. Overall, IHC use increased from 462 of 4292 cases (11%) in 2000 to 5447 of 10 640 cases (51%) in 2017 (eTable 2 in Supplement 1). IHC use varied by clinical factors and other characteristics, including summary stage at diagnosis (21 578 of 73 292 in situ cases [29%] vs 1949 of 2595 distant cases [75%]). Increasing IHC use over time occurred for all stages of melanoma (Figure 1). Controlling for the year of diagnosis, IHC use was statistically significantly associated with all demographic, tumor, and area-level characteristics examined except for race and ethnicity (eTable 2 in Supplement 1).
Table. Immunohistochemistry Stain Use Co-Occurring With Melanoma Diagnoses Based on Patient, Tumor, and Area-Level Characteristics.
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| 2000-2017 (n = 132 547) | 2017 only (n = 10 640) | |||
| No IHC stains (n = 89 151) | IHC stains (n = 43 396) | No IHC stains (n = 5193) | IHC stains (n = 5447) | |
| Patient characteristics | ||||
| Sex | ||||
| Female | 32 542 (68) | 15 098 (32) | 1960 (51) | 1892 (49) |
| Male | 56 609 (67) | 28 298 (33) | 3233 (48) | 3555 (52) |
| Race and ethnicitya | ||||
| Hispanic (all races) | 1146 (66) | 596 (34) | 65 (42) | 89 (58) |
| Non-Hispanic American Indian/Alaska Nativeb | 94 (72) | 36 (28) | NR | NR |
| Non-Hispanic Asian or Pacific Islander | 224 (63) | 133 (37) | 16 (48) | 17 (52) |
| Non-Hispanic Blackb | 242 (64) | 134 (36) | NR | NR |
| Non-Hispanic White | 83 835 (67) | 40 575 (33) | 4602 (48) | 4949 (52) |
| Unknown | 3610 (65) | 1922 (35) | 498 (57) | 372 (43) |
| Age at diagnosis, y | ||||
| 65-74 | 40 151 (68) | 19 019 (32) | 2471 (49) | 2620 (51) |
| 75-84 | 35 148 (68) | 16 444 (32) | 1845 (49) | 1920 (51) |
| ≥85 | 13 852 (64) | 7933 (36) | 877 (49) | 907 (51) |
| Tumor characteristics | ||||
| Behavior | ||||
| In situ | 51 714 (71) | 21 578 (29) | 3260 (51) | 3132 (49) |
| Malignant | 37 437 (63) | 21 818 (37) | 1933 (46) | 2315 (54) |
| Summary stage at diagnosis | ||||
| In situ | 51 714 (71) | 21 578 (29) | 3260 (51) | 3132 (49) |
| Localized | 33 558 (66) | 17 081 (34) | 1557 (47) | 1749 (53) |
| Regional | 1002 (41) | 1453 (59) | 32 (24) | 102 (76) |
| Distant | 646 (25) | 1949 (75) | 26 (13) | 175 (87) |
| Unknown | 2231 (63) | 1335 (37) | 318 (52) | 289 (48) |
| ICD-O-3 topography code indicating primary site | ||||
| C44.0: Skin of lip, NOSb | 253 (65) | 138 (35) | NR | NR |
| C44.1: Eyelid | 736 (65) | 398 (35) | 25 (35) | 47 (65) |
| C44.2: External ear | 4022 (67) | 1978 (33) | 205 (52) | 187 (48) |
| C44.3: Skin of other and unspecified parts of face | 19 747 (67) | 9592 (33) | 902 (45) | 1098 (55) |
| C44.4: Skin of scalp and neck | 8568 (64) | 4729 (36) | 539 (48) | 592 (52) |
| C44.5: Skin of trunk | 22 771 (68) | 10 640 (32) | 1405 (49) | 1473 (51) |
| C44.6: Skin of upper limb and shoulder | 22 776 (69) | 10 099 (31) | 1475 (52) | 1356 (48) |
| C44.7: Skin of lower limb and hip | 9333 (70) | 4020 (30) | 589 (53) | 527 (47) |
| C44.8: Overlapping lesion of skinb | 96 (72) | 37 (28) | NR | NR |
| C44.9: Skin, NOS | 849 (32) | 1765 (68) | 41 (21) | 152 (79) |
| First melanoma in SEER | ||||
| First melanoma | 73 349 (68) | 33 945 (32) | 3911 (49) | 4010 (51) |
| ≥1 Prior melanoma(s) | 15 802 (63) | 9451 (37) | 1282 (47) | 1437 (53) |
| Area-level characteristics | ||||
| SEER registry | ||||
| New Mexico | 1546 (57) | 1161 (43) | 66 (32) | 142 (68) |
| Louisiana | 2895 (56) | 2271 (44) | 134 (34) | 262 (66) |
| Seattle–Puget Sound, Washington | 6058 (64) | 3380 (36) | 312 (34) | 609 (66) |
| Hawaiib | 696 (63) | 401 (37) | NR | NR |
| Rural Georgiab | 175 (59) | 123 (41) | NR | NR |
| San Jose–Monterey, California | 2136 (56) | 1660 (44) | 166 (42) | 234 (59) |
| Connecticut | 6139 (70) | 2576 (30) | 197 (47) | 221 (53) |
| New Jersey | 13 455 (64) | 7627 (36) | 758 (48) | 818 (52) |
| Greater California | 19 806 (68) | 9155 (32) | 1226 (50) | 1245 (50) |
| Greater Georgia | 6695 (63) | 3851 (37) | 486 (50) | 478 (50) |
| Utah | 2777 (64) | 1584 (36) | 181 (51) | 174 (49) |
| Los Angeles, California | 4960 (76) | 1609 (24) | 244 (52) | 226 (48) |
| Metropolitan Detroit, Michigan | 4298 (78) | 1193 (22) | 152 (52) | 140 (48) |
| Iowa | 4465 (71) | 1812 (29) | 302 (57) | 227 (43) |
| San Francisco–Oakland, California | 4491 (70) | 1881 (30) | 409 (60) | 271 (40) |
| Kentucky | 5533 (77) | 1676 (23) | 292 (61) | 186 (39) |
| Metropolitan Atlanta, Georgia | 3026 (68) | 1436 (32) | 230 (61) | 144 (39) |
| Portion of census tract population below poverty threshold, % | ||||
| 0 to <5 | 30 083 (69) | 13 400 (31) | 1632 (49) | 1673 (51) |
| 5 to <10 | 26 013 (66) | 13 122 (34) | 1533 (47) | 1711 (53) |
| 10 to <20 | 19 574 (65) | 10 561 (35) | 1247 (49) | 1294 (51) |
| 20 to 100 | 7385 (62) | 4442 (38) | 426 (46) | 510 (54) |
| Unknown or not applicable | 6096 (77) | 1871 (23) | 355 (58) | 259 (42) |
| Rural-Urban Continuum Codesc | ||||
| Nonmetropolitan county | 11 996 (67) | 5983 (33) | 664 (46) | 769 (54) |
| Metropolitan county | 77 136 (67) | 37 404 (33) | 4529 (49) | 4678 (51) |
Abbreviations: ICD-O-3, International Classification of Diseases for Oncology, Third Revision; IHC, immunohistochemistry; NOS, not otherwise specified; NR, not reported; SEER, Surveillance, Epidemiology, and End Results.
Race and ethnicity data were collected through the SEER registry to discern and explore potential associations between the societal outcomes of race and patient care within the scope of this study.
Counts are not shown due to the small number of cases in 2017.
A total of 28 cases were missing data for Rural-Urban Continuum Code by county and are not shown in the counts for this variable.
Figure 1. Proportion of Melanomas Diagnosed With Immunohistochemistry (IHC) Staining by Summary Stage.
The percentage of melanomas with IHC stain claims near the time of diagnosis is illustrated by both year and summary stage, encompassing a total of 128 981 cases. Cases with unknown summary stages were excluded from the figure.
Although all 17 SEER registries showed increasing use of IHC, substantial variation was noted across the different registries (Figure 2). Across all study years, use was lowest with 1193 of 5491 cases (22%) in Metropolitan Detroit, Michigan. Use across all study years was highest in Louisiana and San Jose–Monterey, California, with 2271 of 5166 cases (44%) and 1660 of 3796 cases (44%), respectively. In 2017 alone, use was lowest in Kentucky and Metropolitan Atlanta, Georgia, with 186 of 478 cases (39%) and 144 of 374 cases (39%), respectively. Use in 2017 was highest in New Mexico with 142 of 208 cases (68%) (Table). Finally, greater IHC use was associated with increasing poverty; IHC was used in 13 400 of 43 483 cases (31%) of patients in census tract populations with the least poverty and 4442 of of 11 827 cases (38%) of patients in census tracts with the most poverty. Melanoma incidence also increased throughout the study period, whereas melanoma mortality remained relatively stable (Figure 2; eFigure 2 in Supplement 1).
Figure 2. Immunohistochemistry (IHC) Use, Age-Adjusted Incidence of Melanoma, and Mortality Rates .
The figure depicts the analysis of IHC use, age-adjusted incidence of melanoma, and mortality rates among patients 65 years and older across 15 areas. The data were sourced from the linked Surveillance, Epidemiology, and End Results cancer registry and Medicare claims databases, covering the years 2000 to 2017.
Discussion
The results of this retrospective cross-sectional study demonstrated that IHC use for the diagnosis of melanoma increased from 11% to 51% from 2000 to 2017 in the US SEER registries. All registries showed an increase, but there was also substantial variation across registries. Ideally, any increased use of resources for medical care, such as the diagnostic use of IHC, should benefit patient care.
Multiple factors could contribute to the rising use of IHC.8 Improved IHC stains and new antibodies have been introduced, and they may improve diagnostic accuracy. In addition, newly graduated pathologists might be more likely to have been trained to interpret skin biopsies with IHC support.9,10 General pathologists and the growing number of fellowship-trained dermatopathologists may have different practice patterns in terms of clinical approaches and billing patterns.11,12 Given the risk of litigation for a missed melanoma diagnosis, some increased use could reflect defensive medicine.13,14,15
We found notable regional variation in the use of IHC, suggesting uncertainty about the optimal use of IHC in clinical practice. These findings highlight the need for research to identify where IHC provides the most value and to develop guidelines regarding the appropriate use of IHC.
Limitations
The Medicare data cannot indicate whether IHC use helped patients or improved outcomes. Study data were limited to patients 65 years and older with Medicare in the SEER registry regions. Although the SEER registries are selected to be nationally representative, it is unclear what trends might be noted in non-SEER regions.7 Definitively linking an IHC claim to a melanoma specimen was not possible, so some IHC claims may have been unrelated to the melanoma diagnosis and could be related to assessment of margins or another tissue specimen. Additionally, the procedure codes used to bill for IHC did not identify specific IHC markers.
Conclusions
This retrospective cross-sectional study demonstrated rising IHC use in melanoma cases diagnosed between 2000 and 2017. In 2017, half of melanoma cases were accompanied by IHC claims, although there was large geographic variability. Given the extensive use of IHC in clinical practice, studies examining the resulting outcomes of IHC on different domains, such as symptom burden, quality of life, and mortality, are crucial. Detailed examination of IHC stain use in pathology is vital, and research about the diseases and tumors that benefit from IHC is essential to deepening clinicians’ understanding and ability to best care for patients. These future studies may help identify opportunities to improve pathologist education and provide evidence to guide standardized use of ancillary diagnostic procedures.
eMethods
eFigure 1. Sample selection
eFigure 2. IHC utilization, melanoma age-adjusted incidence and mortality rate for patients aged 65 years and older, 2000-2017 for all SEER registries
eTable 1. HCPCS Codes for immunohistochemistry stains from 2000 to 2017
eTable 2. IHC stain utilization for melanoma cases diagnosed from 2000-2017 by patient, tumor, and area-level characteristics, with hypothesis testing
eReference
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods
eFigure 1. Sample selection
eFigure 2. IHC utilization, melanoma age-adjusted incidence and mortality rate for patients aged 65 years and older, 2000-2017 for all SEER registries
eTable 1. HCPCS Codes for immunohistochemistry stains from 2000 to 2017
eTable 2. IHC stain utilization for melanoma cases diagnosed from 2000-2017 by patient, tumor, and area-level characteristics, with hypothesis testing
eReference
Data Sharing Statement
