CASE REPORT

Primary Large Cell Neuroendocrine Carcinoma of the Breast, a Case Report with an Unusual Clinical Course Maxwell Janosky, MD,* Jessica Bian, MD,† Shubhada Dhage, MD,* Jamie Levine, MD,* Joshua Silverman, MD, PhD,* Kathryn Jors, MD,* Linda Moy, MD,* Joan Cangiarella, MD,* Franco Muggia, MD,* and Sylvia Adams, MD* *New York University Cancer Institute, NYU School of Medicine, New York, New York; †Brown University, Providence, Rhode Island

n Abstract: Large cell neuroendocrine carcinoma of the breast (NECB) is an extremely rare type of breast cancer; little is known about effective chemotherapies, and data on pathologic response to treatment are unavailable. We report the case of a 34-years-old woman with large cell NECB with initial clinical and pathologic evidence of treatment response to anthracycline-containing neo-adjuvant therapy. Histologic reassessment early during anthracycline chemotherapy revealed cell death with necrosis of 50% of the tumor cells seen in the biopsy specimen. After completing neo-adjuvant chemotherapy, the patient underwent breast-conserving surgery. Pathologic evaluation of the surgical specimen showed a partial response but margins were positive for residual carcinoma. Despite repeated neo-adjuvant chemotherapy, radiotherapy, and surgical resection, the tumor grew rapidly between surgeries and recurred systemically. Therefore, we review the literature on large cell NECB and its treatment options. n Key Words: adjuvant, breast cancer, large cell, neuroendocrine, treatment

P

rimary neuroendocrine carcinoma of the breast (NECB) is a rare type of breast cancer. In 2012, the World Health Organization (WHO) updated their classification of neuroendocrine breast tumors into three subtypes: (i) neuroendocrine tumor, well-differentiated; (ii) neuroendocrine carcinoma, poorly differentiated/small cell carcinoma; and (iii) invasive breast carcinoma with neuroendocrine differentiation (1). In a series of 1,368 histologically confirmed breast cancers, 0.5% were reported to be NECB (2). The average age of diagnosis is in the sixth decade, similar to other breast cancer subtypes (3–5). The diagnosis of primary NECB is based on pathologic features of the breast tumor. Neuroendocrine carcinoma is confirmed by the expression of neuroendocrine markers (synaptophysin, chromogranin, or neuron-specific enolase [NSE]) in 50% or more of the malignant cells. Furthermore, a breast primary must

Address correspondence and reprint requests to: Sylvia Adams, MD, Associate Professor of Medicine, NYU Cancer Institute, Clinical Cancer Center, 160 E. 34th Street, New York, NY 10016, USA, or e-mail: [email protected] DOI: 10.1111/tbj.12403 © 2015 Wiley Periodicals, Inc., 1075-122X/15 The Breast Journal, 2015 1–5

be established either by the presence of ductal carcinoma in situ (DCIS) or by the exclusion of another primary source by imaging (6). Neuroendocrine carcinoma of the breast, first endorsed by the WHO as a distinct form of breast cancer in 2003 (6), was formerly categorized into three main histologic subtypes (i) solid-carcinoid-like carcinoma, (ii) large cell-, and (iii) small cell type carcinoma. The solid subtype is the most common; small cell and large cell are much less frequently reported (7). We would like to highlight the following features of our case: (i) the young age of the patient at presentation, (ii) her triple-negative tumor status and rapidity of cancer growth, and (iii) the efficacy of various local and systemic therapies including taxane, platinum, and anthracycline chemotherapy). CASE REPORT A 34-years-old Asian woman with no past medical history presented to our clinic with a palpable right breast mass that had been progressively enlarging over 4 months. She had immigrated to the USA 18 months prior from China and had no obvious risk factors for

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Tim me Frame and d Imaging M Modality

Presentatioon (1)

Priorr to Lumpecctomy (2)

Proogression prior to p maastectomy (3)

After Radiootherapy (4)

nt (5) Curren

Figure 1. Clinical and radiologic tumor assessments. n/a, not applicable. (1Ai-ii) On presentation, the protruding tumor is visible in the upper right breast. (1B) Mammogram upon presentation. (1C) Breast MRI upon presentation. (1D) PET avid primary tumor without regional lymph node uptake. (2Ai-ii) Complete clinical remission after dose-dense adriamycin/cyclophosphamide and paclitaxel (dd AC/T). (2B) Calcifications persist on mammogram, but no discreet mass after dd AC/T. (3Ai-ii) Rapid tumor growth on exam while awaiting mastectomy. (3C) Tumor replaces breast parenchyma on MRI. (3D) Large primary tumor regrowth on PET/CT. (4Aii) Hyperpigmentation and mild skin thickening, but no discreet mass visible after concurrent carboplatin and radiotherapy. (4B) Mammogram done prior to mastectomy reveals no mass.

Phyysical Exam (A)

M Mammogrraphy (B)

n/a

M MRI (C)

n/aa

P PET (D)

n/aa

n/aa

n/a

n/aa

breast cancer besides nulliparity. Her family history was negative for cancer, age of menarche was 16, BMI was less than 20, and she did not consume alcohol or have exposure to exogenous hormones. Physical examination was normal except for the right breast. The patient had very small breasts and a firm, palpable mass in the upper inner quadrant of the right breast was present. The mass measured 4 9 4 cm in size and distorted the breast contour (Fig. 1, 1A). There was no palpable supraclavicular or axillary lymphadenopathy. Mammography revealed high-density breast tissue and an irregularly shaped mass with pleomorphic calcifications measuring 4.3 9 1.2 9 2.6 cm, highly suggestive of malignancy (BIRADS-5, Fig. 1, 1B). Further evaluation with magnetic resonance imaging (MRI) revealed an irregular, heterogeneously enhancing mass consistent with the known lesion without any disease in the other quadrants of her right breast or left breast (Fig. 1, 1C). Positron emission tomography (PET) demonstrated hypermetabolic activity within the tumor (standard uptake value 8.5) and no evidence of other primaries or distant metastasis. An ultrasound-guided core biopsy was performed. Pathologic examination of the core biopsy specimen revealed a poorly differentiated carcinoma composed of sheets of large cells with finely stippled chromatin and high mitotic activity (Fig. 2: 1); Ki-67 index was 100% (Fig. 2: 2). The tumor tested negative by immunohistochemistry (IHC) for estrogen, progesterone, and HER2 receptors (all 0%). Greater

1

4

2

5

3

6

Figure 2. Pathologic assessment of tumor. (1) Poorly differentiated large cell carcinoma (breast core biopsy at diagnosis, Hematoxylin and Eosin (H&E) stain, 409 magnification. (2) Ki-67 staining 100%. 409 magnification. (3) NECB with positive immunoreactivity for Chromogranin A. 409 magnification. (4) NECB with positive immunoreactivity for Synaptophysin. 409 magnification. (5) NECB with positive immunoreactivity for CD56 (Neural Cell Adhesion Molecule) 409 magnification. (6) Treatment-induced necrosis (core biopsy 15 days after starting chemotherapy), H&E stain, 49 magnification.

than 80% of cells stained positive for the neuroendocrine markers synaptophysin, chromogranin, and CD56 (Neural Cell Adhesion Molecule; Fig. 2: 3–5).

Primary Large Cell Neuroendocrine Carcinoma of the Breast • 3

There was associated high nuclear grade DCIS, suggestive of a breast primary. Together these findings were consistent with primary large cell NECB, poorly differentiated subtype (1). The clinical AJCC (8) stage was cIIA (cT2N0M0). Serum levels of chromogranin A and NSE were both within normal ranges and the patient was asymptomatic besides the breast mass. Considering her young age at presentation and triple-negative tumor status, the patient underwent testing for BRCA1 and BRCA2 mutations. No deleterious mutations were detected. In an attempt to downstage the tumor to possibly allow for breast-conserving surgery and after presentation to a multidisciplinary tumor board, the patient underwent neo-adjuvant chemotherapy with dosedense doxorubicin, and cyclophosphamide for four cycles followed by paclitaxel for four cycles (dd AC-T). During her treatment, she was monitored closely for a response and she was noted to have a clinical response. She also underwent a repeat core biopsy early during her treatment course to guide therapy. Tumor cell necrosis was seen in approximately 50% of the specimen (Fig. 2: 6). Therefore, she continued and completed dd AC-T with a complete clinical response (Fig. 1: 2A). The post-chemotherapy, preoperative mammogram demonstrated residual calcifications spanning 1.3 cm (reduced from 4.3 cm) and distortion at the site of known malignancy but disappearance of the high-density mass (Fig. 1: 2B). On physical exam, she had no discernible palpable mass. The patient then underwent breast-conserving surgery with needle localization. The surgical specimen revealed an invasive tumor measuring 0.6 cm and associated DCIS measuring 0.5 cm, treatment response and axillary lymph nodes free of carcinoma,

but had two positive margins with invasive carcinoma, and was therefore scheduled for mastectomy. However, prior to surgery, her breast cancer regrew rapidly with invasion into the pectoralis major muscle and infiltration of the entire right breast parenchyma (Fig. 1: 3A–C). Without the ability to obtain negative margins at surgery, she was treated with concurrent weekly carboplatin (AUC 2) and radiotherapy (60 Gy in 30 fractions to the breast, 50 Gy 25 fractions to the supraclavicular field and a posterior axillary boost, all using intensity-modulated radiation therapy). She had a partial clinical response. On physical examination, the mass measured about 3.5 cm although a slight regrowth was again noted during the preoperative week (Fig. 1: 4A). The preoperative mammogram is shown in Figure 1: 4B and restaging by PET/CT showed no evidence of distant disease nor any hypermetabolic activity in the treated breast (Figure 1: 4D). She underwent a mastectomy with pectoralis major muscle resection. The mastectomy specimen revealed a 4 9 3.5 9 1 cm tumor with skeletal muscle invasion but no lymphovascular invasion and margins were negative by at least 0.5 cm. Autologous reconstruction was required for primary closure (Fig. 1: 5A). She was then treated postoperatively with four cycles of carboplatin/paclitaxel (Carboplatin at AUC of five every 3 weeks and paclitaxel 80 mg/m2 weekly). Four weeks after completion of therapy she had new onset cough, but no evidence of disease on physical exam. A PET/CT was obtained and revealed extensive pulmonary and osseous metastases (Fig. 1: 5D). As she recurred systemically within a very short-time period of receiving systemic chemotherapy with taxane/anthracyclines/ platinums, the likelihood of response to additional

Table 1. Published Case Reports of Large Cell Primary Neuroendocrine Carcinoma of the Breast with Available Information on Chemotherapy Author and reference

Pub year

Pt age

ER

PR

HER2

Psoma (18) Menendez (16)

2012 2012

46 44

n/a Pos

n/a Pos

n/a Neg

Okoshi (17) Ghanem (14) Bourhaleb (13)

2012 2011 2009

63 82 28

Neg Pos Neg

Neg Pos Pos

Neg Neg n/a

Kim (15)

2008

24

n/a

n/a

n/a

Systemic treatment Adjuvant Chemotherapy (Cisplatin, Epirubicin, Etoposide) Adjuvant Chemotherapy (Fluorouracil, Epirubicin and Cyclophosphamide) Adjuvant Chemotherapy (Uracil and Tegafur) Adjuvant Endocrine therapy Neo-adjuvant Chemotherapy (Cisplatin/Etoposide), Adjuvant Endocrine Therapy Adjuvant Chemotherapy (type not specified)

Disease-free follow-up time 6 months 48 months 44 months 37 months 12 months 18 months

All of the above patients were female with no distant metastases. Pub, publication; Pt, patient; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; n/a, information not available; Pos, positive; Neg, negative.

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chemotherapy was low. However, her performance status remained excellent and the patient was highly motivated to receive further therapy. Therefore, she was treated with chemotherapy, with limited clinical benefit. The metastases progressed after 3 months of treatment with cisplatinum and etoposide and 2 months after eribulin mesylate therapy. DISCUSSION The updated 2012 classification system for NECB more closely resembles breast cancer subtypes as a whole. However, in associating small cell NECB with poor differentiation, it further distinguishes the rarity of our patient’s large cell poorly differentiated NECB (1). As such, little data are available to guide therapy. Most of the NECB publications were based on the 2003 WHO classification, some reports of NECB in general indicate outcomes similar to invasive ductal carcinoma, while most have reported inferior outcomes (4,5,9,10). In 2010, a case–control study compared clinical outcomes of patients with invasive ductal carcinoma, not otherwise specified (IDC, NOS) with 74 cases of NECB, and NECB was shown to be more aggressive with a higher rate of local and distant recurrences and poorer overall survival. A more recent comparative study between 475 patients with IDC, NOS and 107 patients with invasive NECB also concluded that patients with NECB had higher rates of local recurrence and lower overall survival (5). Due to the rarity of NECB, there are no standard treatment recommendations and patients typically receive conventional breast cancer therapies, including the 74 patients in the report by Wei et al. (4), which did not detail the pathologic response in the subset of patients who received neo-adjuvant chemotherapy. The only case studies which have demonstrated objective responses in the metastatic or neo-adjuvant setting for NECB are reported for endocrine therapy in hormone receptor positive NEBC (7,11), as well as platinum-based chemotherapy in small cell NECB (12). Large cell NECB is a particularly rare subtype of NECB and little data are available to guide treatment selection. Neither of the two aforementioned large series on NECB reported information specific to the large cell subtype. Greater than 90% of tumors included in Wei et al. were hormone receptor positive and less than 21% were poorly differentiated (4); this suggests that the results may not be applicable to our patient with triple negative, large cell NECB.

To our knowledge, there have been only six published case reports of large cell NECB with information on systemic treatment (Table 1): two from Morocco and one from Spain, Japan, Korea, and Greece (13–18). While the number of cases is few, it appears that the age at diagnosis of large cell NECB tends to be far below the average age for IDC, NOS, as was the case for our patient who was diagnosed at age 34. While systemic chemotherapy was administered to all patients, sensitivity to the cytotoxic or endocrine agents was not documented. We report the case of a woman with stage II large cell poorly differentiated, triple-negative NECB, and initial evidence of clinical and pathologic response to treatment with standard breast cancer chemotherapy; however, rapid regrowth of microscopic residual tumor after surgery as well as shortly after systemic treatments, including taxanes, platinums, and anthracyclines occurred. This indicates large cell, poorly differentiated carcinoma of the breast (1) is a truly aggressive phenotype that does not appear to be sensitive to conventional breast cancer chemotherapies, and novel therapies should be explored. Based on this experience, if at any time, a patient’s large cell neuroendocrine tumor could be resected with negative margins, this should be the highest priority. REFERENCES 1. Lakhani SR, Schnitt SJ, Tan PH, van de Vijver MJ. World Health Organization Classification of Tumours of the Breast. Lyon, France: IARC Press, 2012:62–3. 2. Lopez-Bonet E, Alonso-Ruano M, Barraza G, et al. Solid neuroendocrine breast carcinomas: incidence, clinico-pathological features and immunohistochemical profiling. Oncol Rep 2008;20:1369–74. 3. Modlin IM, Shapiro MD, Kidd M. An analysis of rare carcinoid tumors: clarifying these clinical conundrums. World J Surg 2005;29:92–101. 4. Wei B, Ding T, Xing Y, et al. Invasive neuroendocrine carcinoma of the breast: a distinctive subtype of aggressive mammary carcinoma. Cancer 2010;116:4463–73. 5. Zhang Y, Chen Z, Bao Y, et al. Invasive neuroendocrine carcinoma of the breast: aprognostic research of 107 chinese patients. Neoplasma 2013;60:215–22. 6. Ellis IO, S S, S-G X. Invasive Breast Carcinoma. Lyon, France: IARC Press, 2003:13–59. 7. Alkaied H, Harris K, Azab B, et al. Primary neuroendocrine breast cancer, how much do we know so far? Med Oncol 2012;29:2613–8. 8. Edge SB, Byrd D, Compton CC, et al. Breast. AJCC Cancer Staging Manual, 7th edn. New York: Springer, 2010:347–76. 9. Rovera F, Masciocchi P, Coglitore A, et al. Neuroendocrine carcinomas of the breast. Int J Surg 2008;6(Suppl 1):S113–5. 10. van Krimpen C, Elferink A, Broodman CA, et al. The prognostic influence of neuroendocrine differentiation in breast cancer: results of a long-term follow-up study. Breast 2004;13:329–33.

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11. Buttar A, Mittal K, Khan A, et al. Effective role of hormonal therapy in metastatic primary neuroendocrine breast carcinoma. Clin Breast Cancer 2011;11:342–5. 12. Ochoa R, Sudhindra A, Garcia-Buitrago M, et al. Small-cell cancer of the breast: what is the optimal treatment? A report and review of outcomes. Clin Breast Cancer 2012;12:287–92. 13. Bourhaleb Z, Uri N, Haddad H, et al. Neuroendocrine carcinoma with large cells of the breast: case report and review of the literature. Cancer Radiother 2009;13:775–7. 14. Ghanem SKH, Naciri S, Glaoui M. Primary neuroendocrine carcinoma of the breast: a rare and distinct entity. Journal of Cancer Research and Experimental Oncology 2011;3:50–4.

15. Kim JW, Woo OH, Cho KR, et al. Primary large cell neuroendocrine carcinoma of the breast: radiologic and pathologic findings. J Korean Med Sci 2008;23:1118–20. 16. Menendez P, Garcia E, Rabadan L, et al. Primary neuroendocrine breast carcinoma. Clin Breast Cancer 2012;12:300–3. 17. Okoshi K, Saiga T, Hisamori S, et al. A case of cytokeratin 20-positive large-cell neuroendocrine carcinoma of the breast. Breast Cancer 2012;19:360–4. 18. Psoma E, Nikolaidou O, Stavrogianni T, et al. A rare case report of a primary large-cell neuroendocrine carcinoma of the breast with coexisting Paget disease. Clin Imaging 2012;36: 599–601.