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Distant Metastasis after Surgery for Encapsulated Papillary Carcinoma of the Breast: A Case Report

In the absence of clear interstitial invasion, encapsulated papillary carcinoma (EPC) of the breast may be attributed to an extremely good prognosis if handled similarly to ductal carcinoma in situ (DCIS) with suitable local treatment. Here, we report our experience with a case of EPC of the breast that presented with carcinomatous pleuritis and lymphangitis carcinomatosa postoperatively, which rapidly resulted in a poor outcome. A 67-year-old woman was diagnosed with DCIS of the left breast and underwent left partial mastectomy and sentinel lymph node biopsy. EPC was diagnosed because the pathological examination showed no sign of interstitial infiltration. Postoperative radiation therapy was performed. Five years and 9 months postoperatively, the patient began experiencing cough and shortness of breath on exertion. Imaging showed right pleural effusion and consolidation of the lung field, but nothing suggesting local recurrence in the preserved left breast, local lymph nodes, or opposite breast was observed. Postoperative recurrence of breast cancer, carcinomatous pleuritis, and lymphangitis carcinomatosa were diagnosed based on the results of pleural fluid cytology. One month later, multiple brain metastases were found, and the patient died of the primary disease 5 months after recurrence. After surgery for EPC without clear interstitial infiltration, there was a small possibility of a poor outcome from distant metastasis. Therefore, although distant metastasis is uncommon, regular examination and testing should be performed.


Introduction
Encapsulated papillary carcinoma (EPC) of the breast is a new disease concept proposed in the 4th edition of the World Health Organization (WHO) classification in 2012 [1]. In the 5th edition in 2019, it is listed as a papillary neoplasm under epithelial tumors [2]. EPC is a rare breast disease, accounting for approximately 0.5-2% of all breast cancers [3]. It is recommended that EPC cases without clear interstitial invasion be treated similarly to ductal carcinoma in situ (DCIS), and if appropriate local treatment is provided, the prognosis is extremely good [2]. Here, we report our experience with a case of EPC of the breast that presented with carcinomatous pleuritis and lymphangitis carcinomatosa postoperatively, which rapidly resulted in a poor outcome.

Case Report
A 67-year-old woman underwent left partial mastectomy and sentinel lymph node biopsy for DCIS in the upper-medial left breast. She had no pertinent past family and psychosocial medical history, including relevant genetic information. Upon histopathological examination, papillary, cribriform ductal structures inside dilated ducts and solid proliferating tumor tissue were seen, but no signs of infiltrative changes or vascular invasion around the ducts. Immunohistochemical staining for p63 and cytokeratin (CK) 5/6 showed a mixture of areas  where ducts had a two-layer structure and areas where this structure had disappeared ( Fig. 1). Based on these histopathological findings, we diagnosed the lesion as EPC without interstitial invasion. The tumor was 29 × 18 × 60 mm in size, with a nuclear grade of 1, and had neither lymphatic nor venous invasion. The lesion was estrogen receptor (ER) and progesterone receptor (PgR) positive, and the Ki-67 labeling index was 6%. The resection margin was positive on the nipple and lateral sides, and there was no metastasis to the four sentinel lymph nodes. The Tumor-Node-Metastasis (TNM) classification was pTis (DCIS) N0M0. The patient's prognosis appeared favorable based on the histopathological findings, and radiation therapy was performed on the left breast and tumor bed after surgery.
Five years and 9 months postoperatively, the patient began experiencing cough and shortness of breath on exertion. Chest radiography and computed tomography revealed right pleural effusion and diffuse consolidation in the lung field ( Fig. 2). Nothing suggesting local recurrence was observed in the preserved left breast, local lymph nodes, or opposite breast. Imaging showed nothing abnormal in other organs, but adenocarcinoma cells were found in the pleural fluid cytology (Fig. 3A, B). Immunohistochemical staining indicated that the cells were positive for ER, PgR (Fig. 3C, D), and CK7, and negative for CK20, gross cystic disease fluid protein 15, thyroid transcription factor 1, napsin A, SP-A, calretinin, desmin, and p53. Based on these results, we diagnosed recurrence of breast cancer with carcinomatous pleuritis and lymphangitis carcinomatosa. Chemotherapy was proposed for systemic pharmacotherapy, but the patient refused. Hormone therapy with oral letrozole was instead initiated. Multiple brain metastases were found 1 month later after the patient had fallen repeatedly. The treatment plan was switched to best supportive care. Five months after the recurrence and 6 years and 2 months after the operation, the patient died of the primary disease.

Discussion
EPC is a rare breast disease [3], traditionally classified as a noninvasive form of breast cancer and a variant subtype of DCIS. Clinically, it often presents as a round breast mass with clear boundaries in postmenopausal women and may be accompanied by abnormal nipple discharge. EPC exhibits imaging findings similar to those of other papillary tumors, such as intraductal papilloma and DCIS. Thus, it is often difficult to diagnose this disease based on  [2]. In the present case, the lesion was originally diagnosed as DCIS based on a needle biopsy of the tumor. Diagnosing the presence or absence of invasion and the detailed histology proved to be difficult.
Macroscopically, EPC often presents as a round cystic tumor with a clear boundary and expansive growth. Histopathologically, EPC is composed of multiple fibrous vascular pedicles covered with homogeneous epithelial tumor cells with low-to-moderate dyskaryosis, and surrounded by a capsule. Normally, myoepithelial cells are not found in the interstitium of the vascular pedicles and the tumor cells, although immunohistochemistry for myoepithelial markers (p63, calponin, CD10, etc.) sometimes confirms a small number of myoepithelial cells on the tumor margin [2].
In EPC, infiltrative growth of tumor cells beyond the capsule into the surrounding tissue coating is defined as a "frank invasion." This is also often seen in regular invasive ductal carcinoma [2]. However, the present case did not exhibit clear interstitial invasion. The working group for the 4th edition of the WHO classification recommended that, to avoid overtreatment, EPC without clear interstitial invasion be handled similarly to DCIS and evaluated as pTis (DCIS) in the TNM stage classification [1]. EPC without clear interstitial invasion beyond the capsule may have a very good prognosis if appropriate local treatment is provided. However, in rare cases, EPC with no myoepithelial cells in the tumor margin can develop axillary lymph node and distant metastasis [3]. Therefore, in recent years, EPC without clear interstitial invasion has been considered a self-confined indolent invasive carcinoma that has slow local growth and a prognosis similar to that of noninvasive carcinoma [2].
Currently, surgery is the standard treatment for DCIS. Further, it is customary to add axial lymph node dissection to radiation therapy of the breast after partial mastectomy if a sentinel lymph node biopsy is positive or if lymph node metastasis is found during the mastectomy. When a partial mastectomy is performed, internal endocrine therapy is often administered to prevent recurrence in the breast on that side. Endocrine therapy is selected when there is no clear reason for breast irradiation or when there is thought to be a high risk of recurrence due to a positive resection margin or high nuclear grade [4][5][6][7].
The prognosis of DCIS is extremely good, and lymph node and distant metastases are rare. The 10-year breast cancer-specific survival rate is reported to be 98% [8]. Distant metastasis after DCIS surgery is reported to occur in less than 1% of cases [9,10]. Many cases of DCIS that develop postoperative distant metastasis also exhibit recurrence locally or in the opposite breast before or simultaneously to the distant metastasis. The US National Surgical Adjuvant Breast Project B-17 compared patients after partial mastectomy with and without breast irradiation. Out of 814 DCIS cases, only 6 (0.74%) exhibited distant metastasis as the first recurrence [11].
Factors affecting distant metastasis after surgery for DCIS include young age (≤40 years), lymph node metastasis, microinvasion, comedo necrosis, ER negativity, poor differentiation, and previous or simultaneous local recurrence [10,12,13]. In addition, human epidermal growth factor receptor type 2 positivity and a high Ki-67 labeling index (>10%) have been reported to be pathological prognostic markers associated with recurrence and distant metastasis [14,15]. However, due to the small number of cases of distant metastasis after surgery for DCIS, these previously reported factors have not yet been shown to be statistically significant. The present case did not have any of these factors affecting distant metastasis. There was no local recurrence in the present case in the preserved breast, opposite breast, or local lymph nodes. In the present case, the tumor was a large ductal lesion with a diameter of 60 mm and a positive resection margin. However, we cannot rule out the possibility of some invasive carcinoma with tiny infiltrations that we have missed in the resected specimen, images of the preserved breast, or pathological diagnosis. If it is thought cancer cells might remain in the preserved breast and the risk of recurrence is a concern, additional mastectomy and endocrine therapy should be considered.
The prognosis of EPC of the breast without interstitial invasion is generally as good as that of DCIS. However, in rare cases, distant metastasis may occur after surgery, which leads to a poor outcome. Therefore, although distant metastasis is uncommon, regular examination and testing should be performed.