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Skull metastases from extramammary Paget’s disease emerging 8 years after initial treatment with no local progression: illustrative case

BACKGROUND The foci of distant metastasis from extramammary Paget’s disease (EMPD) are the lung, liver, truncal bones, vertebrae, and brain. However, skull metastases have not been reported. OBSERVATIONS The authors treated a patient with calvarial and skull base metastases from EMPD who had undergone wide local resection of EMPD 8 years before, and they report his clinical course. LESSONS Because EMPD with distant metastasis is fatal, it should be recognized that EMPD can metastasize to the skull even when it seemed to be in remission for several years.

Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma (adenocarcinoma in situ) that arises primarily in areas rich in apocrine sweat glands (e.g., vulva, perianal region, and axilla). It can be managed by wide local resection of the primary lesion with a good prognosis. The 5-year survival rate is about 90% in patients with tumor, node, metastasis (TNM) stages I, II, and IIIa tumors. 1 However, about 20% of patients with EMPD have the regional or distant form, and cases involving distant metastasis have poor prognoses. 1,2 The metastatic organs reportedly include the lung, liver, vertebral bones, and brain. [3][4][5][6] Some authors have suggested that the central nervous system is a common metastatic site of EMPD, although skull metastasis has not been reported. We herein describe a patient who developed calvarial metastases 8 years after the removal of EMPD with one sentinel lymph node metastasis.

Illustrative Case
A 77-year-old male with penile and scrotal lesions had been treated by wide local and bilateral sentinel lymph node excision 8 years earlier. He was diagnosed with EMPD with a single lymph node metastasis and was followed up by periodic truncal enhanced computed tomography. The patient felt discomfort and pain in his occipitoparietal region; therefore, he underwent head magnetic resonance imaging (MRI) and was referred to our hospital. The MRI scan showed bilateral occipitoparietal lesions with isointensity on T1-weighted imaging, isointensity on T2-weighted imaging, and mild hyperintensity on diffusion-weighted imaging ( Fig. 1A-C). Contrastenhanced computed tomography indicated that the healthy bone had become filled with cancerous tissue and that the lesions were adjacent to the superior sagittal sinus ( Fig. 1D-F). Gallium scintigraphy showed uptake only in the pelvic bone and skull (Fig. 1G). A skull biopsy revealed adenocarcinoma with fused glands or a trabecular pattern, and the tumor cells were immunohistochemically positive for cytokeratin 7 (CK7), GATA3, androgen receptor (AR), gross cystic disease fluid protein 15 (GCDFP15), BerEP4, and carcinoembryonic antigen (CEA) (focal 10%) ( Fig. 2A-C). In addition, the penoscrotal epidermis exhibited proliferation of large pagetoid cells with pale cytoplasm (primary EMPD) (Fig. 2D). In the sentinel lymph node tissues, similar tumor cells were present in small solid nests or a fused gland pattern and were immunohistochemically positive for CK7, GATA3, AR, GCDFP15, BerEP4, and CEA ( Fig. 2E and F). Therefore, the final diagnosis was distant metastasis from EMPD. We removed the calvarial metastases because of the risk of obstruction of the superior sagittal sinus and pain. We were able to remove the affected bones and replace them with a titanium flap because they were of the intraosseous type and were not adhere to the adjacent skin and dura mater (Fig. 3). The lesions were elastic hard, resembling the consistency of a pencil eraser, and could be damaged by hands. The patient received intensitymodulated radiation therapy (57.5 Gy in 23 fractions) for the tumor bed and skull base lesion as well as chemotherapy (Fig. 4). TS-1  monotherapy was adopted as a second-line therapy after docetaxel monotherapy failure (progression of visceral metastases). The patient was still alive 12 months after the neurosurgical procedure.

Discussion Observations
To the best of our knowledge, this is the first case of calvarial bone metastasis from EMPD. Although patients with progressive disease (such as those with metastases in multiple organs) may exhibit skull metastasis, our patient had no symptoms other than skull metastasis. Local recurrence and metastases were not detected until 8 years after the patient was thought to be in remission. Invasive EMPD metastasizes mainly by the lymphatic route, and Ohara et al. 1 proposed that early lymphatic spread might be controlled by resection based on the difference in the 5-year survival rate between stages IIIa and IIIb. The presence of skull and pelvic bone metastases without lymph node metastasis suggests another metastatic route; this case prompted us to consider the mechanism of skull metastasis. The vertebral venous system, with its rich, valveless ramifications and connections, widely known as Batson's plexus, is an important metastatic route from the pelvis to the vertebral column, resulting in brain, vertebral, and skull metastases. 7 In this system, the venous pressure is relatively low, and the circulation is slow and subject to reversals of the flow direction. The direction depends on various factors, such as posture, gravity, coughing, straining, and the character of the circulation of the allied systemic, portal, and pulmonary systems. 8 The vertebral venous plexus extends directly to the dural sinuses, which also have valveless structures, and their retrograde blood flow may allow cancer cells to reach the parameningeal tissues. 9 Both brain metastases and calvarial metastases could occur by this route.
Distant metastases of EMPD are often fatal. In a study by Yoshino et al., 10 the 1-year overall survival rate was 75.0%, and the median overall survival duration was 16.6 months. Some authors reported brain metastases with progressive EMPD in 2020, and vertebral bone metastasis was found to be a prognostic factor for dissemination in the central nervous system. [4][5][6]11 In comparison, metastatic skull tumors from prostate cancer or breast cancer are widely known to occur, and the median overall survival rates are 23 months and 15 months, respectively. 12,13 Therefore, given the poor prognosis of distant metastases of EMPD and metastatic skull tumors, we should recognize that EMPD can metastasize to the calvarial bone and thus should ensure early diagnosis, treatment, and care.

Lessons
Some cases of EMPD may disseminate to the skull by the vascular route, even when the disease seems to have been in remission for several years.