PMC9433574_01
Skin scaly and erythematous plaques at different phases of the disease history of our patient. (A) Erythematous lesions with some ulcerated and bleeding areas at diagnosis. (B) Lesions appearing less erythematous and with initial signs of re-epithelization after 4 months of treatment with carboplatin, paclitaxel plus trastuzumab. (C) Clinical disease progression during trastuzumab maintenance therapy. (D) Reduction in bleeding and partial epithelialization of skin lesions after starting vinorelbine plus trastuzumab. (E) Clinical disease progression during vinorelbine plus trastuzumab. (F) Rapid disease progression during anti-androgen therapy plus trastuzumab.
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Some of these lesions were erythematous, with some ulcerated and bleeding areas, and others appeared as scaly and eczematous plaques, as shown in  Figure 1A . After 4 months, the patient reported a good clinical response, with skin lesions appearing less erythematous and with initial signs of re-epithelization ( Figure 1B ). In August 2018, when the patient was receiving trastuzumab maintenance, clinical disease progression occurred ( Figure 1C ), with worsening of pain and skin lesion bleeding causing anemia, which required blood transfusions. The patient experienced clinical benefit from vinorelbine plus trastuzumab combination, with reduction in pain and bleeding and partial re-epithelialization of skin lesions, as shown in  Figure 1D  (as compared to  Figure 1C ). In January 2019, after hospital discharge, oral metronomic vinorelbine was resumed at a reduced dose (30 mg on Monday, Wednesday, and Friday every week) in combination with trastuzumab; treatment was continued until May 2019, when clinical disease progression occurred ( Figure 1E ). Based on both AR expression and HER2 overexpression, in June 2019, fourth-line treatment with bicalutamide 50 mg p.o. daily, plus leuprorelin 11.25 mg i.m. every 3 months (according to the schedule commonly used in prostate cancer) was started, together with i.v. trastuzumab maintenance; however, the disease rapidly progressed ( Figure 1F ).
(A) Immunoreactivity for cytokeratin 7. (B) Negativity for cytokeratin 20. (C, E) HER2 strong membranous staining (3+) at immunohistochemical stain magnification, x 10, in two different tumor samples of the patient. (D, F) microscopic image in CISH for HER2 staining in two different tumor samples of the patient. (G) Androgen receptor staining at immunohistochemical stain magnification, x 10.
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Immunoreactivity for cytokeratin 7 ( Figure 2A ) and EMA and negativity for cytokeratin 20 ( Figure 2B ) and Melan-A ruled out secondary pagetoid spread from urothelial or colorectal cancer and malignant melanoma. HER2 was highly expressed by immunohistochemistry (IHC) [score of 3+ according to CAP guidelines ] ( Figure 2C ), and in situ hybridization (ISH) analysis revealed ERBB2 gene amplification ( Figure 2D ). Waltham, MA), as assessed by means of targeted next-generation sequencing (NGS) through the Ion Torrent Personal Genome platform "Hot-spot Cancer Panel" (Thermo Fisher Scientific). While confirming the overexpression/amplification of HER2 (IHC/FISH) ( Figures 2E, F ), these evaluations also revealed the expression of AR in 90% of tumor cells ( Figure 2G ).
FDG PET/CT scan at baseline of patient's clinical history.
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A PET/CT scan showed avid fluorine-18-fluorodeoxy-D-glucose (FDG) uptake [maximum standardized uptake value (SUV max), 5] in correspondence with the cutaneous thickening of the suprapubic region, the perineum, and the right thigh, with bilateral inguinal enlarged lymph nodes (SUV max, 3.3), without metastases in visceral organs ( Figure 3 ).
Timeline of systemic treatments administrated during patient's disease history. BSC, best supportive care; CBDCA, carboplatin; ChT, chemotherapy; ECOG PS, Eastern Cooperative Group Perfomance Status; LHRHa, LHRH analogue; OT, hormonal therapy; PD, progression disease; PR, partial disease response.
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Different patient's treatment lines are summarized in  Figure 4 .