,

A Case of Umbilical Invasive Extramammary Paget Disease With a High Tumor Mutational Burden Successfully Treated With Pembrolizumab

,

Introduction

Extramammary Paget’s disease (EMPD) is a rare skin cancer that develops commonly in apocrine gland-rich skin; the genital, perianal, and axillary. Lesions in the genital most commonly affect Caucasian females, but lesions in the umbilicus have been reported predominantly in elderly Asian males [1,2]. EMPD tends to be indolent and is often identified as lesions in situ at the time of diagnosis. For advanced EMPD, chemotherapy with taxane-based treatments is used, but there is no established standard treatment [3]. Anti-programmed cell death protein 1 (PD-1) agents are indicated for the treatment of advanced skin cancer with a high tumor mutational burden (TMB) in Japan, but neither drug is necessarily effective for EMPD. As far as we know, the present patient is the first case of advanced EMPD with complete response (CR) to immune checkpoint inhibitor (ICI) monotherapy.

Case Presentation

An 83-year-old male Japanese patient presented with a reddish tumor on his umbilicus. His medical history included hepatocellular carcinoma (HCC), type 2 diabetes, and monoclonal gammopathy of indeterminate significance. Three years before the initial presentation, a physical examination revealed a macerated, reddish, 3-cm tumor on the umbilicus (Figure 1a). The tumor was totally excised with a 1-cm margin as Sister Mary Joseph’s nodule in the gastrointestinal surgery department. HCC was controlled with local therapy alone. Three years later, he was referred to the dermatology department for an enlarged lymph node in the left inguinal region. After computed tomography (CT) found no other anomalies, a lymph node dissection was performed (18th July 2023). The metastasis of adnexal carcinoma was found in two lymph nodes. The pathological examination revealed tumor cells containing mucin in the intracytoplasmic, pagetoid spreading in the overlying epidermis of the primary tumor, and immunoexpression of cytokeratin 7, GATA3, and GCDFP15, and negative for hepatocyte paraffin 1 (HepPar1), α-1-fetoprotein, estrogen receptor, CD117, CDX2, all of which fit the diagnosis of invasive EMPD on the umbilical site rather than the umbilical metastasis of HCC (Figures 1b-1d).

No erythema was found on the genitals or in the axilla. Positron emission tomography-CT revealed metastases to the lung and the transverse processes of the fifth thoracic vertebra (17th August 2023). S-1 plus docetaxel therapy was begun. Two months later, CT demonstrated shrinkage of the metastases (partial response) (11th December 2023); however, five months later, the progression of the lesions was evident (Figures 2a, 2b) (30th May 2024). Genetic panel testing (FoundationOne CDx, Foundation Medicine, Inc.) found several genomic alterations (amplification of ERBB2, PARP1, PIK3C2B and RAD51B c.1037-1G>A, CDKN2A p.E88K and p.D108N) and TMB of 12.07 Muts/Mbp, and microsatellite stability. Treatment with pembrolizumab 200 mg Q3W was begun. After the second administration, Grade 3, CTCAE v5.0 acute kidney injury (AKI) developed as a result of ICI-induced tubular necrosis (9th July 2024). The patient was admitted to the hospital for intravenous fluid therapy following a rise in blood urea nitrogen (60.6 mg/dL) and serum creatinine (5.05 mg/dL). Although renal function began to improve within approximately two weeks, it took five months to fully normalize. CT demonstrated progression in multiple lung metastases (9th July 2024), prompting the discontinuation of pembrolizumab therapy. No treatment was given after two doses of pembrolizumab. However, five months after the start of pembrolizumab administration, CT demonstrated shrinkage in the lesions (Figure 2c) (7th October 2024). By month seven, after the start of pembrolizumab administration, all the metastases had disappeared (nearly complete response) (Figure 2d) (20th December 2024). Thereafter, the patient requested that the treatment be discontinued without follow-up.

Discussion

The present case was marked by findings that were atypical for EMPD. Approximately 92% of lesions occur in areas typically covered by underwear, with involvement of the umbilical region being extremely rare, accounting for less than 1% [4]. In cases where lesions are found in atypical sites such as the umbilicus, it has been reported that multiple lesions, including those in the genital area, may coexist [1]. Clinically, erythema is the most characteristic presentation, and lesions presenting solely as nodules are uncommon [4]. Apocrine carcinoma can present as a nodule in the umbilical region and may be difficult to distinguish from EMPD due to their similar histopathological features [5]. Careful diagnosis is essential, including a thorough examination of the entire tissue architecture to identify pagetoid cells, as well as the use of immunohistochemical staining.

While pembrolizumab is indicated for the treatment of high tissue TMB solid tumors in Japan [6] and 21.5% of EMPD cases have this classification, the drug may not be effective in the latter cases [7]. Moreover, while nivolumab is approved for the treatment of epithelial skin malignancies in Japan, the rate of response of EMPD to the drug was 25%, and there were no cases of CR [7,8]. In addition, a case of advanced EMPD showing a response to pembrolizumab has been reported; however, its effect was temporary [9]. Transient tumor progression after ICI administration has been reported, followed by delayed tumor regression [10]. Therefore, it is important to evaluate the therapeutic effects of ICIs over a longer period. The present report describes a patient with EMPD achieving CR to only two ICI administrations.

Furthermore, the rate of response to ICIs was found to increase when immune-related adverse events (irAEs) occurred [11]. Early incidence of irAEs has been reported to be associated with improved treatment outcomes [12]. Thus, in the present case, the rare irAEs of nephropathy may have been related to the CR following ICI administration. The incidence of AKI due to irAEs related to anti-PD-1 antibody therapy alone is reportedly 2.1% [13]. It has been reported that most cases of ICI-associated AKI occur within the first six months after initiation of ICI, and partial kidney recovery occurred following discontinuation of the ICI [14].

Conclusions

One limitation of the present report is the fact that recurrences after CR were not evaluated owing to the patient's wish to discontinue therapy. Advanced EMPD is very rare, and there, as of yet, no standard treatment. The efficacy of ICIs against EMPD awaits future investigation enrolling a larger patient cohort.

References

  1. Ishiguro A, Iwashita N, Abe M, Ogawa A, Takeo T, Watanabe D: Recurrence of quadruple extramammary Paget's disease after 12 years: a case report and literature review. Case Rep Dermatol. 2024, 16:149-55. 10.1159/000538675

  2. Dai C, Baird BA, Lyon TD, Sokumbi O, Degesys CA: Extramammary Paget disease of the axilla and scrotum in a Caucasian man. JAAD Case Rep. 2022, 23:87-9. 10.1016/j.jdcr.2022.03.004

  3. Yoshino K, Fujisawa Y, Kiyohara Y, et al.: Usefulness of docetaxel as first-line chemotherapy for metastatic extramammary Paget's disease. J Dermatol. 2016, 43:633-7. 10.1111/1346-8138.13200

  4. Kibbi N, Owen JL, Worley B, et al.: Evidence-based clinical practice guidelines for extramammary Paget disease. JAMA Oncol. 2022, 8:618-28. 10.1001/jamaoncol.2021.7148

  5. Seo SH, Shin DH, Sung HW: Apocrine carcinoma of the groin possibly associated with extramammary Paget's disease. Ann Dermatol. 2011, 23:519-22. 10.5021/ad.2011.23.4.519

  6. Marabelle A, Fakih M, Lopez J, et al.: Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020, 21:1353-65. 10.1016/S1470-2045(20)30445-9

  7. Narasaki M, Kato J, Sato S, et al.: Extramammary Paget's disease treated with of anti-programmed cell death protein 1 therapy after docetaxel therapy failure. J Dermatol. 2025, 52:359-62. 10.1111/1346-8138.17500

  8. Matsumura N, Mandai M: PMDA regulatory update on approval and revision of the precautions for use of anticancer drugs: approval of nivolumab for unresectable advanced or recurrent epithelial skin malignancies in Japan. Int J Clin Oncol. 2024, 29:639. 10.1007/s10147-024-02524-0

  9. Horisaki K, Taki T, Mori S, Okumura M, Akiyama M: A case of advanced extramammary Paget's disease with a high tumor mutation burden that showed partial lymph node regression with pembrolizumab. Cureus. 2024, 16:e72592. 10.7759/cureus.72592

  10. Wang Q, Gao J, Wu X: Pseudoprogression and hyperprogression after checkpoint blockade. Int Immunopharmacol. 2018, 58:125-35. 10.1016/j.intimp.2018.03.018

  11. Das S, Johnson DB: Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer. 2019, 7:306. 10.1186/s40425-019-0805-8

  12. Morehouse C, Abdullah SE, Dar M, Ranade K, Higgs B: Early incidence of immune-related adverse events (irAEs) predicts efficacy in patients (pts) with solid tumors treated with immune-checkpoint inhibitors (ICIs). J Clin Oncol. 2019, 37:2653. 10.1200/JCO.2019.37.15_suppl.2563

  13. Manohar S, Kompotiatis P, Thongprayoon C, Cheungpasitporn W, Herrmann J, Herrmann SM: Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis. Nephrol Dial Transplant. 2019, 34:108-17. 10.1093/ndt/gfy105

  14. Perazella MA, Sprangers B: AKI in patients receiving immune checkpoint inhibitors. Clin J Am Soc Nephrol. 2019, 14:1077-9. 10.2215/CJN.02340219

© myEMPD.com • Helping those with extramammary Paget’s disease (EMPD).