Baseline neutrophil‑to‑lymphocyte ratio predicts the prognosis of castration‑resistant prostate cancer treated with abiraterone acetate

  • Authors:
    • Masato Yasui
    • Yoriko Hasegawa
    • Takashi Kawahara
    • Yohei Kumano
    • Yasuhide Miyoshi
    • Nobuaki Matsubara
    • Hiroji Uemura
  • View Affiliations

  • Published online on: February 13, 2018     https://doi.org/10.3892/mco.2018.1573
  • Pages:587-591
Metrics: HTML 0 views | PDF 0 views     Cited By (CrossRef): 0 citations

Abstract

Abiraterone acetate (AA), a CYP17 inhibitor, now has a crucial role in the treatment of castration-resistant prostate cancer (CRPC), and previous studies have reported several prognostic clinical factors for AA treatment. The neutrophil‑to‑lymphocyte ratio (NLR) has also been investigated for a CRPC treatments in a few reports, however it has not been identified to be a prognostic factor for AA treatment in Japanese patients. The present study aimed to assess the association of the baseline NLR with the overall survival (OS) in CPRC patients treated by AA. The present study retrospectively reviewed a total of 90 consecutive patients with CRPC treated with AA from 2011 to 2016 at Yokohama City University Medical Center and National Cancer Center Hospital East. The primary endpoint of the study was the OS, which was defined as the survival from the start of AA administration. The secondary endpoint was the prostate‑specific antigen (PSA) response. PSA response was defined as a reduction in antigen levels of >50%. Complete blood cell counts were performed, and the NLR was calculated using the neutrophil and lymphocyte counts obtained on the same day or a few days prior to the initiation of AA therapy. The NLR cut‑off point was determined to be 3.76 for the OS, and divided into the high NLR group of 34 patients and the low NLR group of 56 patients. A PSA response was obtained in 8 patients (23.5%) in the high NLR group and in 24 (42.9%) in the low NLR group. The difference of PSA response between the two groups was significant (P=0.037). Kaplan‑Meier curves demonstrated that a high NLR [NLR ≥3.76; median OS: 8.4 months; 95% confidence interval (CI): 6.325‑10.475 months] was correlated with a risk of mortality compared with a low NLR (NLR <3.76; median OS not reached). A multivariate analysis demonstrated that the NLR was an independent predictor for the OS (hazard ratio: 2.682; 95% CI: 1.143‑6.293; P=0.023). The findings suggest that the NLR may be a useful novel biomarker for predicting the prognosis of CRPC patients treated with AA.

Introduction

Squamous cell carcinoma (SqCC) is a malignant neoplasm of epidermal keratinocytes that arises most commonly on the skin and organs lined with squamous cells. Squamous cell carcinoma is a rare form of metaplastic carcinoma in breast that accounts <0.1% (1). The precursor of pure squamous carcinoma is a benign squamous metaplasia that occurs in the epithelium of cysts, fibroadenomas ana phyllodes tumors. It can be also associated with ductal and lobular hyperplasia or papillomas. Recent studies confirmed that benign squamous metaplasia of ductal and lobular epithelial cells can be linked with fat necrosis and infracted ademonas. Squamous cell carcinoma should be differentiated between lesions of keratinizing squamous carcinoma and squamous metaplasia associated to mammary carcinoma (2). The characteristic features of metaplastic cell carcinoma include: i) primary carcinoma without other neoplastic components such as ductal or mesenchymal elements, ii) the tumor origin is independent of the overlying skin and nipple and iii) absence of primary epidermoid tumors present in other site (oral cavity, bronchus, esophagus, bladder, cervix ect.) (3). However, squamous metaplastic carcinoma should be also differentiated with pure squamous cell carcinoma of skin in the breast. The extensive infiltrate of squamous cancer cells to the skin can make it difficult to confirm the cutaneous origin of tumor and exclude the presence of malignant metaplastic changes as a primary breast. In the present study, cases of cutaneous squamous cell carcinoma and primary metaplastic squamous cell carcinoma of the breast are described. To our knowledge, such cases are great diagnostic challenge in pathomorphology and should be carefully analyzed in daily practice.

The present study was performed in conformity with the Declaration of Helsinki for Human Experimentation and the protocol was approved by the Bioethics Committee of the Medical University of Bialystok. Written informed consent was obtained from both participants.

Case report

Case 1
History

A 72-year-old female was admitted to the Department of Surgical Oncology in Bialystok (Poland) for planned surgery. There was no family history of malignant neoplasms. Patient had used some medication against hypertension. She complained of abdominal pain with normal peristalsis and had normal stools. She was postmenopausal and had given birth to 3 children. Previously, the histological examination of the biopsy material, obtained during a fine-needle aspiration (FNA), confirmed the presence of the cancer cell infiltrate in the left breast (Fig. 1A). The description of preoperative, physical examination demonstrated a large mass with ulceration localized on the left breast. Tumor took the three quarters of the breast and raised several years. The skin and the nipple-areola complex were involved. The tumor was attached underlying chest wall. No abnormalities were observed in the opposite breast nor axilla. Local lymph nodes were not enlarged on palpation examination. Chest X-ray was performed preoperatively and demonstrated the heterogenic, rounded area of increased density, 1.3 cm diameter in size, located in the right supraclavival field of the left lung. In addition, diaphragm was normal. The preoperative blood parameters showed the low levels of red blood cells, hemoglobin and hematocrit and the increased levels of CA125 and CA15.3. Following normalization of anemia with the concentrate of red blood cells, patient was qualified for scheduled surgery. Due to large size tumor that infiltrated the chest wall, the left radical mastectomy was performed according to the Halsted's method (1). The surgical procedure included the removal of the breast tumor with a greater pectoral muscle and axilla with local lymph nodes. The left breast was reconstructed with the latissimus dorsi musculocutaneous flap. There was no postoperative morbidity. The clinical staging was T4 N0 MX.

Histopathology

Macroscopically, the postoperative formalin-fixed material of the left breast 17.0×16.5 cm in size, showed a huge, ulcerative tumor with cauliflower-like appearance, 16.8×16.2 cm in size, of gray-brown surface with a narrow margin at the periphery of the skin without the presence of nipple. On cross-sections, tumor was solid, gray-brown color with gray-white foci of necrosis, coming near this deep incision line. Fourteen local lymph nodes were dissected with no evidence of metastases. The biggest lymph node was 3.1×1.8 cm in size. Optimal surgical margins were obtained (Fig. 2A).

The microscopic examination of the surgical specimen revealed a moderately differentiated (G2) squamous cell carcinoma according to WHO Classification of the Skin Tumours (4). Cancer cells have abundant eosiphilic cytoplasm with large vesicular nucleus. The prominent intracellular brigdes, central keratinization and pearl formation were observed. SqCC does not infiltrate along nerve sheaths and lymphovascular vessels. Cancer cells proliferated from the stratified squamous epithelium covering the breast into 2.5 cm deeper layers of the organ. No other primary site and metastatic disease to breast were ruled out (Fig. 3A and B). Immunohistochemical analysis confirmed negative nuclear expression of progesterone and estrogen receptors, and HER2. Moreover, we observed a positive membrane reaction of adhesion protein-E-cadherin. The diagnosis of the tumor was established as triple negative SqCC of breast skin with moderate proliferation index (Ki67 positive in 20% cancer cells).

Follow-up

Patient was discharged home in good general condition and received five courses of chemotherapy with Taxotere + Cisplatin (110 mg i.v.). After 1.5 month following the surgery, patient visited the Surgical Outpatient Clinic and was directed to USG of abdomen and retroperitoneal space, and the FNA of right breast. Imaging studies confirmed the presence of a heterogeneous good well-isolated area with dimensions 27.0×22.0 mm, probably metastatic changes. The material obtained from the FNA cytology of right breast showed the presence of poorly differentiated cancer cells, probably originated from squamous cancer. The change was treated as a distant metastases. One month later, imaging studies of PET-CT confirmed an active metabolic process in the left side of nasopharynx. Patient was qualified for surgery under local anesthesia. Macroscopically, it was visualized a smooth mucosa of the nasopharynx without significant changes. The histopathological study of the nasopharynx did not show a presence of cancer cells but only morphological features of chronic inflammation markers. Another CT scan showed numerous secondary changes within both lungs, the largest diameter of 35.0 mm and a single focus in the segment V of the liver diameter of 24.0 mm. We did not detect secondary changes in the skeletal system. Disease progression of cancer was revealed.

Case 2
History

A 59-years-old woman evaluated in our hospital for recent onset of pain and tenderness in the left breast. Physical examination revealed a palpable well circumscribed mass in the left upper lateral quadrant. The right breast appeared normal. There was no evidence of supraclavicular or axillary lympadenopathy. The overlying skin was unremarkable. An ultrasound examination of the left breast revealed a defined 3.0 cm mass with reduced central echogenicity, consistent with a cystic space. Mammography showed a round, high-density mass (without microcalcifications) with almost regular margins, measuring approximately 3.0 cm, which was classified as BIRADS 4. A fine-needle aspiration biopsy was performed and yielded 0.5 ml of white dense fluid material. Cytological preparations revealed markedly atypical squamous cells arranged in sheets, clusters and as a single cell as well as numerous neutrophils. Several cells were keratinized and some showed degenerative changes (Fig. 1B).

Histopathology

The patient had an ultrasound-guided core biopsy of the left breast mass at the local anesthesia. Patient underwent radical mastectomy with axillary lymph nodes dissection. Gross examination revealed a 6.0 cm tumor with central cystic space containing necrotic material (Fig. 2B). Microscopically, large polygonal cells with keratinizing eosinophilic cytoplasm were presented. Individual cells have abundant eosinophilic cytoplasm and hyperchromatic pleomorphic nuclei with abortive squamous pearl formation (Fig. 3C and D). Histopathological analysis revealed metaplastic carcinoma (a pure primary squamous cell carcinoma of the breast) according to WHO Classification of the Breast (2). The breast tumor profile was negative for estrogen receptors, progesterone receptors and HER2/neu expression.

Follow-up

Patient had adjuvant chemotherapy based on cisplatin and 5-fluorouracil. She had no evidence of recurrence 6 months after surgery.

Discussion

Squamous cell carcinoma is one of the most common skin cancer that was developed in association with prolonged exposure to sunlight. However, not all squamous cell cancers are directly related to UV radiation. They can grow in the shores of chronic ulcers, within the scars burn of skin or as a result of damage to the epidermis the chemical or radiation therapy. Also patients with immune suppression have an increased risk of squamous cancer (4). We reported a very unusual location-skin overlying the breast in first case. To our knowledge, first patient described in our paper is the one third of cases of breast or axilla reported in the literature. Miranda et al (5) confirmed the presence of three small changes of SqCC in the axillary skin. Moreover, we noted histological type of metaplastic cancer of the breast, which probably evolved directly from glandular tubes or is developed in the basis of squamous metaplasia in second case (3). This type of breast carcinoma accounts for ~1% of all malignancies in this location and its presence was described in several reports in the literature (611). The incidence of PSqCC falls to 5–6 decade of life compared to SqCC of skin that occurred usually in patients aged above 70 years (12,13).

Squamous cell carcinoma of the skin develops in the form of initially small, hard lumps, often in the middle ulcers, modified necrotic or excessively keratinizing (4). The development of tumor takes years, as observed in our first case. The lesion was large, a diameter of 16,0 cm, and within the ulcerated surface. In evaluated tissue material, it was found a tumor ulcerous and necrotic surface with the presence of inflammatory granulation tissue. Macroscopically, tumor occupied the outer skin surface of the breast and nipple-areola complex. In contrast, metaplastic cancer of the breast formed tumors with rapid growth, involving several months (14,15). These lesions are accompanied by inflamed multicystes or abscesses in 50% of cases (1618). In the second described case, the gross examination revealed the presence of grayish-white, solid tumor located in the middle part of the breast in size 6 cm. Tumor has a central cystic space containing necrotic material. The overlying skin was unremarkable. In both cases, we ruled out the presence of suspected cancer focuses in other locations.

The large size of the tumor and advanced process of necrosis caused a difficulty of confirmation whether macroscopic tumor derived from the squamous epithelium of the skin or are created in the basis of abnormal glandular epithelium metaplasia. First tumor was built with bands of moderately differentiated squamous cancer cells with large vesicular nucleus. We observed prominent intracellular bridges, central keratinization and pearl formation. SqCC does not infiltrate along nerve sheaths and lymphovascular vessels. Cancer cells proliferated from the stratified squamous epithelium covering the breast into deeper layers of the body. Morphological image of metaplastic breast cancer is very similar. They also may have focal anaplastic component or focal clear cell changes (19). Squamous cell carcinomas showed morphological similarity regardless of location. However, the differentiating feature of our case was the way of cancer spread. In the case of skin, we observed a cancer infiltration that was continuous and formed in ‘icicles’ from the skin into the tissue of the breast. Therefore, metaplastic cancer had irregular growth of squamous cell that creates cystic-solid tumor confined to the breast parenchyma.

Moreover, because of the similar changes in both histogenesis, we can not use immmunophenotype methods to differentiated cancer cells. Immunohistochemical analysis also does not allow to determine whether it is a primary lesion or metastatic one. In both of our cases, we recorded a positive expression of pancytokeratin which confirms the presence of cells differentiated towards squamous cell carcinoma. In case 1, the characteristics of immunophenotyping were: Cytokreatyna7 (−), cytokeratin 20 (−) and triple negative receptor status suggests that this lesion will probably not derive from the mammary gland. However, in the majority of metaplastic breast cancers also observed a lack of expression of estrogen, progesterone, and HER2 (17). A positive response to these antigens were reported in few percentage of cases (19,20). Only one of case described in literature was confirmed as a SqCC of breast with HER2-basal phenotype (21).

Treatment of squamous cell carcinoma of the skin and metaplastic breast cancer are depends mainly on the stage of the cancer. Typically, the patients are undergoing surgery in the first stage of therapy then adjuvant treatment such as radio- or chemotherapy was used (2224). In our two cases, the total mastectomy was performed that included removing of breast with local lymph nodes. Chemotherapy was used as a second part of treatment. In SqCC case of skin, we recorded metastases located in the second breast after 1.5 months. In the following months, there was a further progression of the disease manifested by the presence of multiple metastatic lesions in the lungs and a single metastatic focus in the segment V of the liver. In the literature it has been shown that the risk of developing metastatic squamous cell carcinoma of the skin, which is accompanied by changes in sun-damaged (0.5%) is lower than in patients in places not exposed to sunlight (25). Moreover, the ability of squamous cancer cells of the skin metastasize is dependent on the depth of invasion, tumor size, and involvement of vascular and lymphatic vessels (26). In case 2, we did not notice relapse within 6 months after surgery. Time progression-free survival in patients with metaplastic cell carcinoma of the breast is 2–36 months (18,20,24). Overall survival after 2 years was 80%, and after 5 years of 35–67% (19,20,27). It has been shown that tumors with the presence of >10% of spindle cell component have a worse prognosis, however, the focal length of keratinization determines longer overall survival (27). It seems that despite of the similar morphology of cancer cells, the determination of the originality of the tumor may be important in identification of prognostic factors.

In conclusion, cutanous squamous cell carcinoma and metaplastic cell carcinoma of breast are extremely rare lesions that should be differentiated from primary squmanous cell carcinoma in this localization and should be treated with special clinician's and pathomorpgologist's attention. In our opinion, such cases are great diagnostic challenge in pathomorphology and should be more carefully analyzed in daily practice.

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APA
Yasui, M., Hasegawa, Y., Kawahara, T., Kumano, Y., Miyoshi, Y., Matsubara, N., & Uemura, H. (2018). Baseline neutrophil‑to‑lymphocyte ratio predicts the prognosis of castration‑resistant prostate cancer treated with abiraterone acetate. Molecular and Clinical Oncology, 8, 587-591. https://doi.org/10.3892/mco.2018.1573
MLA
Yasui, M., Hasegawa, Y., Kawahara, T., Kumano, Y., Miyoshi, Y., Matsubara, N., Uemura, H."Baseline neutrophil‑to‑lymphocyte ratio predicts the prognosis of castration‑resistant prostate cancer treated with abiraterone acetate". Molecular and Clinical Oncology 8.4 (2018): 587-591.
Chicago
Yasui, M., Hasegawa, Y., Kawahara, T., Kumano, Y., Miyoshi, Y., Matsubara, N., Uemura, H."Baseline neutrophil‑to‑lymphocyte ratio predicts the prognosis of castration‑resistant prostate cancer treated with abiraterone acetate". Molecular and Clinical Oncology 8, no. 4 (2018): 587-591. https://doi.org/10.3892/mco.2018.1573