Appropriate Statistical Methods to Assess Cross-study Diagnostic 23-Gene Expression Profile Test Performance for Cutaneous Melanocytic Neoplasms.

ABSTRACT: Comparing studies of molecular ancillary diagnostic tests for difficult-to-diagnose cutaneous melanocytic neoplasms presents a methodological challenge, given the disparate ways accuracy metrics are calculated. A recent report by Boothby-Shoemaker et al investigating the real-world accuracy of the 23-gene expression profile (23-GEP) test highlights this methodological difficulty, reporting lower accuracy than previously observed. However, their calculation method-with indeterminate test results defined as either false positive or false negative-was different than those used in previous studies. We corrected for these differences and recalculated their reported accuracy metrics in the same manner as the previous studies to enable appropriate comparison with previously published reports. This corrected analysis showed a sensitivity of 92.1% (95% confidence interval [CI], 82.1%-100%) and specificity of 94.4% (91.6%-96.9%). We then compared these results directly to previous studies with >25 benign and >25 malignant cases with outcomes and/or concordant histopathological diagnosis by ≥3 dermatopathologists. All studies assessed had enrollment imbalances of benign versus malignant patients (0.8-7.0 ratio), so balanced cohorts were resampled according to the lowest common denominator to calculate point estimates and CIs for accuracy metrics. Overall, we found no statistically significant differences in the ranges of 23-GEP sensitivity, 90.4%-96.3% (95% CI, 80.8%-100%), specificity, 87.3%-96.2% (78.2%-100%), positive predictive value, 88.5%-96.1% (81.5%-100%), or negative predictive value, 91.1%-96.3% (83.6%-100%) between previous studies and the cohort from Boothby-Shoemaker et al with this unified methodological approach. Rigorous standardization of calculation methods is necessary when the goal is direct cross-study comparability.

Diagnostic discordance among histopathological reviewers of melanocytic lesions.

BACKGROUND: Histopathological examination is adequate for the diagnosis of most cutaneous melanocytic neoplasms. However, there is a subset that is either difficult to definitively diagnose or would have diagnostic disagreement upon review by multiple dermatopathologists if a more exhaustive review was performed. METHODS: Melanocytic lesions underwent an independent, blinded diagnostic histopathological review of hematoxylin and eosin-stained sections. Each lesion was reviewed by three to six dermatopathologists and categorized as benign, malignant, or unknown malignant potential (UMP). Diagnoses were grouped as concordant (all the same designation); opposing (received benign and malignant designations); majority (single designation with the highest number of diagnoses, no benign/malignant opposing designations); and non-definitive (equal number of non-opposing designations [i.e., benign/UMP or malignant/UMP]). Lesions with equivocal designations (concordant or majority UMP, opposing, majority, and non-definitive) were utilized in a patient treatment model of projected surgical treatment discrepancies. RESULTS: In total, 3317 cases were reviewed, and 23.8% of lesions received equivocal diagnoses. Of these, 7.3% were majority benign, 4.8% were majority malignant, 2.7% were majority UMP, 0.5% were concordant UMP, 6.9% were opposing, and 1.6% were non-definitive. Patient treatment models of those with equivocal lesions (n = 788) revealed a potential of overall surgical treatment variations ranging from 18% to 72%, with the highest variation amongst lesions with opposing, non-definitive, or majority UMP (40%-72%) diagnoses. CONCLUSION: Histopathologic review in this large cohort demonstrated substantial diagnostic variation, with 23.8% of cases receiving equivocal diagnoses. We identified diagnostic ambiguity even in lesions where a definitive diagnosis was previously rendered by a single real-world dermatopathologist. The combined clinical impact of diagnostic discordance or a final diagnosis of UMP is highlighted by high diagnosis-dependent treatment variation in the patient treatment model, which could be underreported in a real-world setting, where review by more than one to two dermatopathologists is relatively rare.

Primary cutaneous SMARCA4-deficient undifferentiated malignant neoplasm: A rare case report and literature review.

Primary cutaneous SMARCA4-deficient undifferentiated malignant neoplasm (SD-UMN) is a rare and recently described entity characterized by the loss of expression of the SMARCA4 (BRG1) protein, which is involved in chromatin remodeling. SD-UMN presents a diagnostic challenge due to its rarity and unique histopathological and immunohistochemical features. In this report, we present a case of primary cutaneous SD-UMN in a 67-year-old man who presented with a rapidly growing, ulcerated, and bleeding nodule on his right cheek. Histopathological examination revealed a highly cellular dermal tumor consisting of pleomorphic epithelioid cells with prominent mitotic figures and necrosis, lacking any morphological evidence of differentiation. Immunohistochemical analysis showed a complete loss of SMARCA4 and SMARCA2 expression, while INI-1 expression remained intact. p53 was diffusely expressed, and p16 was completely absent. In addition, a range of markers, including high-molecular-weight cytokeratin, p63, SOX10, INSM1, MCPyV, NKX2.2, CD99, CDX2, CD56, ERG, NUT, desmin, androgen receptor, chromogranin, CD34, and CD43 were all negative. To date, only two cases of primary cutaneous SMARCA4-deficient undifferentiated tumors have been reported in the literature. Therefore, this case report adds to the limited body of knowledge on the clinical and histopathological features of this novel entity. The report highlights the importance of considering SD-UMN in the differential diagnosis of undifferentiated cutaneous tumors.

IgA Vasculitis Associated With COVID-19.

IgA vasculitis, also known as Henoch-Schonlein Purpura (HSP), is an inflammatory disorder of small blood vessels that can present with palpable purpura, arthralgias, abdominal pain, and kidney disease. It is most commonly found in pediatric patients after an inciting infection but has been seen across all ages and associated with certain drugs and vaccines. COVID-19 has been associated with various cutaneous manifestations, but HSP is a rarely reported one. We present a case of a 21-year-old female presenting with a petechial rash found to be seronegative IgA vasculitis presenting concurrently with dyspnea secondary to COVID-19. She was initially seen by an outside practitioner, tested negative for COVID, and was prescribed a course of oral prednisone. Shortly thereafter, she visited the ED for worsening shortness of breath and tested positive for COVID-19, for which she received Paxlovid. Biopsy after a visit to a dermatologist confirmed intramural IgA deposition on immunofluorescence, and she was tapered off prednisone and started on azathioprine.

Sarcoidosis Coexisting With Distinct Forms of Alopecia on the Scalp: A Case Series.

ABSTRACT: Sarcoidosis is an idiopathic multisystem inflammatory disease that can affect virtually any part of the body. Often, it can initially present solely in the skin. Histologically, it is characterized by noncaseating, 'naked' granulomas in the dermis and subcutaneous tissue. Clinically, sarcoidosis is often referred to as a 'mimicker' of many other pathologic processes because of its wide array of presentations. Occasionally, sarcoidosis can present in the scalp as both a scarring and nonscarring alopecia. There are countless reports of sarcoidosis mimicking various other alopecias including acne keloidalis nuchae, discoid lupus erythematosus, frontal fibrosing alopecia, lichen planopilaris, and alopecia areata totalis. In this case series, we present 2 novel cases of sarcoidosis not just clinically mimicking other forms of alopecia but occurring in conjunction with a separate and histologically distinct primary alopecia.

Ancillary testing for melanoma: current trends and practical considerations.

The diagnosis of melanocytic lesions is aided by ancillary testing, but clinical inspection with the histomorphological assessment on biopsy remains sufficient in most cases. Immunohistochemistry and molecular studies have proven useful for diminishing the pool of histomorphologically borderline lesions, and sequential testing may further improve overall diagnostic performance, but these assays should be used in a stepwise fashion if at all. Ancillary tests vary based on their technology, performance, and practical considerations, including but not limited to the specific diagnostic question, cost, and turn-around time, which impact test selection. This review examines currently used ancillary tests for the purpose of characterizing melanocytic lesions. Both scientific and practical considerations are discussed.

Superficial GLI1-amplified mesenchymal neoplasms: Expanding the spectrum of an emerging entity which reaches the realm of dermatopathology.

Mesenchymal neoplasms with GLI1 alterations (rearrangements and/or amplification) have been reported recently in several anatomic locations, which include head and neck, soft tissue, and gastrointestinal tract. Herein, to the best of our knowledge, we describe the first three cases of superficial/subcutaneous mesenchymal neoplasm with GLI1 amplification. The neoplasms exhibited low-grade cytologic features with predominant round cell morphology, glomangioma-like areas and a rich background capillary network. There were two to three mitotic figures per 10 HPF and focal necrosis in one case. The tumors exhibited variable expression of CDK4, MDM2, STAT6, D2-40, CD56 and cyclin D1. p16 had strong and diffuse nuclear and cytoplasmic expression in two cases. Numerous other stains were negative. Fluorescence in situ hybridization detected GLI1, DDIT3, and CDK4 coamplification in all cases, while next generation sequencing did not detect a GLI1 gene fusion. The overall features were compatible with a GLI1-amplified mesenchymal neoplasm. In Case 1 a new distant skin lesion appeared 1 month after the surgery exhibiting similar morphology albeit with a higher mitotic index. In Cases 2 and 3, there is no evidence of local recurrence or systemic disease after 8 years and 1 month of follow-up, respectively. These new cases of superficial GLI1-amplified neoplasm expand its clinical spectrum and enter the realm of dermatopathology. The combination of CDK4, cyclin D1, D2-40, and p16 expression with variable MDM2, STAT6, CD56, and S100 immunoreactivity in a low-grade neoplasm with round/ovoid cytomorphology resembling a vascular or adnexal neoplasm may suggest the possibility of GLI1-amplified neoplasm.

Pilomatrical Acanthoma: An Extremely Rare Intraepidermal Variant of Pilomatricoma.

ABSTRACT: Pilomatrical differentiation can be observed in a variety of benign and malignant tumors, with the most common prototype being pilomatricoma. Pilomatricoma often presents in the deep dermis or subcutis, and the sole involvement of epidermis is extremely rare. In our current case series, specimens from 5 patients were included with an average age of 68 years. All lesions presented as solitary verrucous or keratotic papules on the extremities, with 1 lesion having a prominent horn. All lesions have a variable mixture of basaloid matrical cells and shadow cells, and all lesions express ß-catenin (strong nuclear and cytoplasmic), lymphoid enhancer-binding factor 1 within the matrical component, and pleckstrin homology-like domain family A member 1. The histomorphology and immunoprofile of all lesions are of pilomatrical differentiation, confined to the level of the epidermis. Based on these findings and analogous to the terminology used for other benign intraepidermal proliferations (hidroacanthoma simplex and epidermolytic acanthoma), we propose the term "pilomatrical acanthoma" for these rare lesions.

A Short Isoform of Spermatogenic Enzyme GAPDHS Functions as a Metabolic Switch and Limits Metastasis in Melanoma.

Despite being the leading cause of cancer deaths, metastasis remains a poorly understood process. To identify novel regulators of metastasis in melanoma, we performed a large-scale RNA sequencing screen of 48 samples from patient-derived xenograft (PDX) subcutaneous melanomas and their associated metastases. In comparison with primary tumors, expression of glycolytic genes was frequently decreased in metastases, whereas expression of some tricarboxylic acid (TCA) cycle genes was increased in metastases. Consistent with these transcriptional changes, melanoma metastases underwent a metabolic switch characterized by decreased levels of glycolytic metabolites and increased abundance of TCA cycle metabolites. A short isoform of glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) lacking the N-terminal domain suppressed metastasis and regulated this metabolic switch. GAPDHS was downregulated in metastatic nodules from PDX models as well as in human patients. Overexpression of GAPDHS was sufficient to block melanoma metastasis, whereas its inhibition promoted metastasis, decreased glycolysis, and increased levels of certain TCA cycle metabolites and their derivatives including citrate, fumarate, malate, and aspartate. Isotope tracing studies indicated that GAPDHS mediates this shift through changes in pyruvate carboxylase activity and aspartate synthesis, both metabolic pathways critical for cancer survival and metastasis. Together, these data identify a short isoform of GAPDHS that limits melanoma metastasis and regulates central carbon metabolism. SIGNIFICANCE: This study characterizes metabolic changes during cancer metastasis and identifies GAPDHS as a novel regulator of these processes in melanoma cells.

Melanocytic Panfolliculoma: A Case Report of a Rare Benign Follicular Tumor.

ABSTRACT: Panfolliculomas (PF) are rare, benign, follicular tumors that differentiate toward multiple components of the hair follicle, and several variants have been described. We present a case of a rare pigmented PF presenting on actinically damaged skin in an 83-year-old man, which was clinically concerning for malignancy. This tumor arose near an area of atypical squamous proliferation and has evidence of infundibular, outer root sheath, and matrical differentiation and foci of heavy melanin pigmentation and increased melanocytes. We propose the novel designation of "melanocytic PF," akin to melanocytic matricoma but with panfollicular differentiation.

Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee.

BACKGROUND: Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests. METHODS: RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2. RESULTS: For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain." LIMITATIONS: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded. CONCLUSIONS: AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.

Pleomorphic Dermal Sarcoma: A Clinical and Histopathologic Emulator of Atypical Fibroxanthoma, but Different Biologic Behavior.

Description Pleomorphic dermal sarcoma (PDS) can clinically and histopathologically mimic atypical fibroxanthoma (AFX). However, it has a more aggressive clinical course with a higher recurrence rate and metastatic potential. This case presentation aims to report a rapidly-growing, exophytic, 4 cm tumor following a non-diagnostic shave biopsy 2 months prior and to highlight distinctive features between PDS and AFX needed to make the correct diagnosis. Like AFX, PDS occurs on the sun-damaged skin of the elderly, usually on the head and neck. Also, like AFX, PDS histopathologically consists of sheets or fascicles of epithelioid and/or spindle-shaped cells, often with multinucleation, pleomorphism, and numerous mitotic figures. Immunohistochemistry cannot distinguish PDS from AFX but is used to exclude other malignancies. PDS can be distinguished from AFX by size (PDS is usually >2.0 cm) and by the presence of more aggressive histopathologic features, such as subcutaneous involvement, perineural and/or lymphovascular invasion, and necrosis. PDS is a rare entity not well documented in the literature with confusing, misleading, and changing nomenclature. PDS is a diagnosis of exclusion made after complete excision of the tumor with the aid of histopathology and immunohistochemistry.

Acyclovir-Resistant Anogenital Herpes Simplex Virus in an HIV Patient With Pseudoepitheliomatous Hyperplasia Resembling Squamous Cell Carcinoma.

Background: Herpes simplex virus (HSV) is a common infection. However, it may present atypically when patients are immunocompromised, such as with slowly expanding, long-lasting ulcerative or hypertrophic lesions. The histopathologic finding of pseudoepitheliomatous hyperplasia (PEH) can occur in a variety of situations where there is chronic inflammation and can be seen in patients with chronic HSV. Atypical presentations of HSV, particularly hypertrophic lesions with histopathologic findings of PEH, can be misinterpreted as squamous cell carcinoma, create difficulty in diagnosis and hinder appropriate treatment. Case Description: We report a case of a 59-year-old female with a past medical history of human immunodeficiency virus (HIV), who presented at a dermatology clinic with multiple exophytic ulcerations of varying sizes in the perianal region. The patient was diagnosed with HSV and was started on valacyclovir. Over a several-year period, the patient had multiple recurrences of her HSV lesions with persistent vulvodynia despite prophylactic treatment with valacyclovir. Specimens were collected for culture and sensitivities, which revealed acyclovir resistance. The patient's lesions were biopsied due to concern for possible malignancy. Biopsies revealed prominent PEH. The patient had improvement of her HSV with saucerization, topical imiquimod, and increased doses of prophylactic valacyclovir. Conclusion: Atypical, chronic presentations of HSV are common in immunocompromised patients. Hypertrophic HSV is the least common clinical presentation and can be mistaken for squamous cell carcinoma, creating difficulty in diagnosis. Due to concerns for malignancy, our patient's lesions were biopsied, which revealed prominent PEH. While PEH is benign, it can be misdiagnosed as squamous cell carcinoma on histopathology, particularly when there is clinical suspicion for malignancy. In these cases, the clinician needs to alert the pathologist to the immunosuppressed status of the patient. Detailed evaluation for infectious causes, such as HSV, can avoid misinterpretation and potential surgical and oncological overtreatment.

Human Papillomavirus‒Positive and ‒Negative Vulvar Squamous Cell Carcinoma Are Biologically but Not Clinically Distinct.

Vulvar squamous cell carcinoma pathogenesis is traditionally defined by the presence or absence of human papillomavirus (HPV), but the definition of these groups and their molecular characteristics remain ambiguous across studies. In this study, we present a retrospective cohort analysis of 36 patients with invasive vulvar squamous cell carcinoma where HPV status was determined using RNA in situ hybridization and PCR. Clinical annotation, p16 immunohistochemistry, PD-L1 immunohistochemistry, HPV16 circular E7 RNA detection, and RNA sequencing of the cases were performed. A combination of in situ hybridization and PCR identified 20 cases (55.6%) as HPV positive. HPV status did not impact overall survival (hazard ratio: 1.36, 95% confidence interval = 0.307-6.037, P = 0.6857) or progression-free survival (hazard ratio: 1.12, 95% confidence interval = 0.388-3.22, P = 0.8367), and no significant clinical differences were found between the groups. PD-L1 expression did not correlate with HPV status, but increased expression of PD-L1 correlated with worse overall survival. Transcriptomic analyses (n = 23) revealed distinct groups, defined by HPV status, with multiple differentially expressed genes previously implicated in HPV-induced cancers. HPV-positive tumors showed higher global expression of endogenous circular RNAs, including several circular RNAs that have previously been implicated in the pathogenesis of other cancers.

Rare presentation of inflammatory myofibroblastic tumor on a digit.

Inflammatory myofibroblastic tumors (IMTs) are rare soft tissue neoplasms consisting of a mixture of spindle-shaped myofibroblasts or fibroblasts and a variable inflammatory infiltrate composed of eosinophils, plasma cells, and lymphocytes. Associations with trauma and infectious agents have been proposed, but the etiology is unknown. While IMT predominantly develops in the lungs of pediatric patients or young adults, extrapulmonary IMT is well documented and may occur anywhere. Cutaneous IMT is rare and few have been reported on the hand in the English language. The mean age of onset is 10 years, with a slight female predilection. IMT demonstrates intermediate malignant potential, with a tendency to recur locally. Metastases are rare. According to a recent review, anaplastic lymphoma kinase (ALK) positivity on immunohistochemistry is related to local recurrence, but not distant metastases. We report an unusual case of a 36-year-old male, with a lesion on the right second digit, displaying classic histopathologic and immunohistochemical features of IMT, including ALK staining, and confirmatory fluorescence in situ hybridization-proven ALK gene rearrangement.

A standardized approach to classifying melanocytic neoplasms? Comments on the MPATH-Dx system.

The potential benefits and limitations of the MPATH-Dx classification system for melanocytic neoplasms are presented and discussed.

A meissnerian neurofibroma: Case report of a rare neurofibroma variant.

Structures resembling Meissner corpuscles have been described in various nerve sheath tumors, including schwannomas and neurofibromas. When present, they are focal or scattered, and rarely a prominent feature of the lesion. Here, we report a case of a 39-year-old female who presented with an isolated lesion on her abdomen. Histopathologically, the tumor was almost exclusively composed of Meissner corpuscle-like structures (pseudo-meissnerian bodies). At a small edge of the tumor, there were features of a classic neurofibroma, with a mixture of Schwann cells, fibroblast-like cells, and interspersed mast cells. We propose the term "meissnerian neurofibroma" for this extremely rare variant of neurofibroma.

Verrucous pilar cysts infected with beta human papillomavirus.

Epidermoid cysts with histopathologic features of human papillomavirus (HPV) infection have been previously reported and are commonly termed verrucous cysts. We report a series of eight histopathologically distinct verrucous pilar cysts, distinguished from traditional verrucous epidermoid cysts by trichilemmal keratinization, as well as two verrucous hybrid pilar-epidermoid cysts. These lesions contain characteristic stratified epithelial linings with abrupt transitions to compact eosinophilic keratin, as well as areas of papillomatosis, coarse intracytoplasmic keratohyalin granules, and vacuolar structures suggestive of HPV-induced cytopathic change. HPV-24, a ß genus HPV species, was identified by degenerate polymerase chain reaction in DNA extracted from two of the lesions, and the presence of ß-HPV E4 protein was confirmed by immunohistochemistry. HPV-60, the HPV species most commonly reported in verrucous epidermoid cysts, was not detected. Verrucous pilar cysts represent histopathologically and potentially etiologically distinct lesions which may be underrecognized.

Assessment of circularized E7 RNA, GLUT1, and PD-L1 in anal squamous cell carcinoma.

Anal squamous cell carcinoma (ASCC) is a rare, potentially fatal malignancy primarily caused by high-risk human papillomaviruses (HPV). The prognostic implication of programmed death-ligand 1 (PD-L1) expression remains controversial, and glucose transporter 1 (GLUT1) expression has never been examined in ASCC. Covalently closed circular RNAs have recently been shown to be widespread in cancers and are proposed to be biomarkers. We discovered HPV16 expresses a circular E7 RNA (circE7) which has not been assessed as a potential biomarker. A retrospective, translational case series at UT Southwestern was conducted to analyze PD-L1, GLUT1, HPV-ISH, and HPV circE7 in relation to the clinical features and overall survival of patients with ASCC. Twenty-two (22) subjects were included in the study. Improved overall survival was predicted by basaloid histology ( p = 0.013), PD-L1 expression ( p = 0.08), and HPV-ISH positivity ( p & 0.001), but not GLUT1 expression. High levels of circE7 by quantitative RT-PCR predicted improved overall survival in ASCC ( p = 0.023) and analysis of The Cancer Genome Atlas sequencing from HPV-positive head and neck cancer and cervical cancer suggested high circE7 marked improved survival in 875 subjects ( p = 0.074). While our study suggests that circE7 levels correlate with improved survival in ASCC, larger, prospective studies are necessary to confirm the potential role of circE7 as a biomarker.

Muir-Torre syndrome appropriate use criteria: Effect of patient age on appropriate use scores.

BACKGROUND: Muir-Torre syndrome (MTS) is a rare inherited syndrome, with an increased risk of sebaceous and visceral malignancy. Prior reports suggest screening for mismatch repair (MMR) deficiency may be warranted in patients <50 years and when sebaceous neoplasms are located on a non-head and neck location. Previously, appropriate use criteria (AUC) were developed for clinical scenarios in patients >60 years concerning the use of MMR protein immunohistochemistry (MMRP-IHC). This analysis explores the appropriateness of testing in patients ≤60 years. METHODS: Panel raters from the AUC Task Force rated the use of MMRP-IHC testing for MTS for previously rated scenarios with the only difference being age. RESULTS: Results verify the previously developed AUC for the use of MMRP-IHC in neoplasms associated with MTS in patients >60 years. Results also show that in patients ≤60 years with a single sebaceous tumor on a non-head and neck site, MMRP-IHC testing should be considered. Testing can also be considered with a 2-antibody panel on periocular sebaceous carcinoma in younger patients. CONCLUSIONS: Our findings align with known evidence supporting the need to incorporate clinical parameters in identifying patients at risk for MTS, with age being a factor when considering MMRP-IHC testing.