The patient was a 56-year-old female with no remarkable medical history. She visited our hospital with a chief complaint of a right breast mass in April 2011. The mass in the upper medial portion of her right breast was a 3-cm-diameter tumor with an unclear border on mammography, ultrasonography (US), and magnetic resonance imaging (MRI) (Fig. 1a), and the lymph nodes in the axilla and subclavian were swollen (Fig. 1b). The results of a histological examination for a core needle biopsy specimen were a breast cancer (invasive ductal carcinoma) with an immunohistochemical status of ER (+), progesterone receptor (PgR) (+), HER2 (3+), and Ki67 40 %. She received four cycles of epirubicin and cyclophosphamide therapy followed by four cycles of docetaxel and trastuzumab as preoperative chemotherapy, and total mastectomy with axillary dissection was performed in December 2011 (Fig. 1c). A postoperative pathological investigation revealed that almost all of the tumor cells on the resected breast and lymph nodes had disappeared. Thereafter, she received postmastectomy radiation therapy for the chest wall and supraclavicular region, adjuvant trastuzumab for 1 year, and adjuvant hormone therapy with letrozole.
One year and 8 months after the operation, she developed right hydronephrosis and swollen para-aortic lymph nodes (Fig. 1d) and her hormone therapy was changed to fulvestrant therapy. However, she additionally developed left hydronephrosis and multiple bone metastases in the skull, right acetabulum, and right iliac crest 5 months after the therapy was changed (Fig. 1e). Pertuzumab, trastuzumab, and docetaxel therapy was started after left nephrostomy, and after six cycles of the therapy, the bone metastases had shrunk (Fig. 1f) and her bilateral hydronephrosis was relieved. Her disease seemed to be well-controlled. Therefore, maintenance therapy with pertuzumab and trastuzumab (without docetaxel) was introduced and the nephrostomy tube was removed.
Seven months after the start of maintenance therapy, she developed new vertebral metastasis (Fig. 2a) and visited the emergency ward at our hospital complaining of right lower abdominal pain. Computed tomography showed a swollen appendix with fecal stones (Fig. 2b), and a blood test revealed elevated white blood cells (16,270/μl) and CRP (7.07 mg/dl), suggesting acute appendicitis (Fig. 2b). Laparoscopic appendectomy was performed (Fig. 2c). The pathological findings showed infiltration of neutrophils within the submucosa and subserosa, which were consistent with gangrenous appendicitis. Further investigation of the specimen revealed some clusters of atypical cells in the subserosa and muscle layer (Fig. 2d).
An immunohistochemical analysis of the breast tumor showed ER (+), PgR (+), HER2 (3+), and E-cadherin (−) (Fig. 3a), while that of the appendiceal tumor showed ER (+), PgR (−), HER2 (3+), and E-cadherin (−) (Fig. 3b). Although the expression of PgR differed between the breast tumor and appendiceal tumor, both tumors had similar morphologic features, overexpression of HER2, and loss of E-cadherin, and we therefore concluded that the appendiceal tumor was a metastasis from invasive lobular carcinoma (ILC) of the breast.
Thereafter, she received trastuzumab-DM1 therapy, since the appendiceal tumor still had overexpression of HER2, after which the metastatic tumors detected on PET/CT almost disappeared again (Fig. 2e).
Discussion
We experienced having a patient with appendicitis caused by a metastasis of ILC. Thanks to the immunohistochemical analysis of the resected appendiceal tumor, we succeeded in continuing effective anti-HER2 therapy.
ILC of the breast accounts for 14 % of all breast cancer cases [2] and presents with a loss of E-cadherin expression [3]. It can metastasize to the abdominal cavity as peritoneal dissemination, para-aortic lymph node swelling, and small bowel metastasis. Arpino et al. reported that ILC and invasive ductal carcinoma (IDC) develop such metastases in 6.7 and 1.8 % of cases, respectively [4]. In our case, we failed to obtain the histological diagnosis of ILC at the initial therapy session. However, the metastatic pattern of her disease, such as para-aortic lymph node swelling and hydronephrosis, made us suspect ILC, and we succeeded in detecting carcinoma cells that were E-cadherin (−) in the resected appendix.
Connor et al. reported that incidental appendiceal tumor detected after appendectomy accounts for only 0.9 % of cases (74/7990), and among them, metastatic tumor was only found in 11 cases [5]. Yoon et al. previously reported 139 cases with metastatic appendiceal tumors, with primary sites mainly consisting of ovary (56 cases), colon (35 cases), and stomach (7 cases). No cases of appendiceal metastasis from breast cancer were described in their study [6], indicating that appendicitis caused by the metastasis of breast cancer is very rare.
HER2 expression can sometimes differ between the primary and metastatic tumors. Amir et al. reported that an HER2-positive primary tumor and HER2-negative metastatic tumor account for 12.5 % of cases, while an HER2-negative primary tumor and HER2-positive metastatic tumor account for 4.6 % of cases [1]. We must therefore perform biopsy of the metastatic tumor if anti-HER2 therapy for metastatic breast cancer is less effective than expected. In the present case, her metastatic tumor seemed to show resistance to pertuzumab and trastuzumab therapy, and we could not have selected an appropriate subsequent therapy without an immunohistochemical analysis of the resected appendix.
Basic research investigating the efficacy of trastuzumab-DM1 for HER2-positive breast cancer cell lines has found that trastuzumab-resistant cells retain sensitivity to trastuzumab-DM1 [7]. Furthermore, the efficacy of trastuzumab-DM1 was found to be related to the strength of HER2 expression, and trastuzumab-DM1 was not effective against HER2-negative cells [8]. These results suggest that trastuzumab-DM1 is worth trying even in cases with trastuzumab-resistant tumors, and biopsy for metastatic tumors is useful for confirming the strength of HER2 expression.
