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Case Report

Metastatic Breast Neuroendocrine Cancer in Pregnancy: A Case of an Oncologic Emergency and a Review of Literature

De Luca, Caterina1; Tosto, Valentina1; Badr, Dominique A.2,∗; De Luca, Laura3; Porreca, Roberta4; Di Renzo, Gian Carlo1

Editor(s): Pan, Yang

Author Information
doi: 10.1097/FM9.0000000000000068
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Pregnancy-associated breast cancer is defined as breast cancer diagnosed during pregnancy or within 1 year after delivery.1 The average age of diagnosis of pregnancy-associated breast cancer is 33 years with a median gestational age of 21 weeks. Its incidence is estimated at 15–35/100 000 deliveries.1 Breast neuroendocrine carcinoma (B-NEC) is a rare form of breast cancer.

Pregnancy-induced physiological changes may mimic cancer symptoms resulting in delay of proper diagnosis and management. The average reported delay for diagnosis of breast cancer during pregnancy is 5–15 months from the onset of symptoms.2 Hence, clinicians should have a high index of suspicion for breast cancer during pregnancy in the presence of breast mass. Pregnancy, per se, should not be a barrier for full local and distant malignancy workup. Mammography, breast ultrasound, breast magnetic resonance imaging, and breast biopsy are safe in pregnancy. In general, pregnant women should be treated with curative intent according to the guidelines of non-pregnant women, however, in selected cases, optimal management may depend on the trimester of pregnancy and on the type and the stage of the cancer. A multidisciplinary case discussion is mandatory before management. It should include a surgeon, an oncologist, a pathologist, a maternal-fetal specialist, an obstetrician, a neonatologist, and an anesthesiologist.3

Hereby, we report the case of an unusual breast carcinoma with aspects of neuroendocrine differentiation presenting as diffuse bone metastasis with an undetectable primary focus in a young woman at 28 weeks’ gestation. Written consent for the use of case presentation and figures, and consent for publication in print and electronically has been given by the patient.

Case presentation

A 33 year old gravida 3, para 2, Caucasian woman presented to the Obstetrics and Gynecological First Aid of our Department at 28 weeks’ gestation for severe and diffuse back pain. She has had an uneventful pregnancy until 1 month before presentation, when her pain started. She had been evaluated by a specialist who diagnosed her as having sciatica, and treated her by pain killers. Nevertheless, the pain worsened progressively and it extended to the cervical region. Her past medical and obstetric histories were positive for hepatitis C virus infection and 2 normal vaginal deliveries at term without any complication respectively.

Initial orthopedic and neurologic evaluation were negative, and the obstetrical assessment was reassuring as well. Cardiotocogram showed the absence of uterine contractions and a normal fetal heart rate tracing. The fetal ultrasound showed fetal growth at the 55th percentile, posterior placental implantation, normal amniotic fluid index, and normal fetal and utero-placental Doppler studies. The patient was then admitted for further treatment and investigations. She had a hemoglobin level of 110 g/L, a platelets’ count of 242 × 109/L, a negative C-reactive protein, normal coagulation tests, and normal hepatic and renal functions. The initial diagnosis was severe sciatica, for which she received intravenous pain killers and physiotherapy sessions. Five days later, when the pain seemed to be in regression, she suddenly had 1 episode of syncope and several episodes of projectile vomiting. Neurologic evaluation showed bilateral patellar hyperreflexia, as well as rigidity and tenderness with passive bending of the head. Encephalitis, meningitis, and central nervous system malignancies were added then to the differential diagnosis. A magnetic resonance imaging of the head and spine was performed. It showed numerous bone lesions in most of the vertebrae associated with compaction of C5 and L5 leading to medullary compression (Fig. 1). The bony pelvis contained also several similar lesions. A metastatic malignant tumor was highly suspected. Breast, renal, and thyroid ultrasound were performed in search for the primary focus, and were all negative except for the presence of bilateral reactive lymph nodes in the axillary area. Chest X-ray showed normal lung fields and confirmed the presence of multiple osteolytic diffuse lesions of the bony structures. Tumor markers were also performed and their levels were as follow: carcino-embryonic antigen 52.8 ng/mL (normal <5.0 ng/mL), CA15-3 245.5 U/mL (normal <31 U/mL), CA 19-9 15 U/mL (normal <35 U/mL).

Figure 1
Figure 1:
Magnetic resonance imaging of the spine showing diffuse bone lesions of the entire vertebral column (asterisks). A T2-weighted sagittal view of the cervical spine showing the invasion of the C5 vertebra, the instability of the cervical column, and the mild compression of the medullary canal (white arrow). B and C T1-weighted sagittal view of the vertebral column showing vertebral body collapse of the L5 vertebra (dashed arrow).

After a multidisciplinary case discussion, targeted radiotherapy with a single dose of 8 grays (Gy) to control the cervical lesion followed by fetal lung maturation and cesarean delivery were performed to allow further investigations and treatment. The patient delivered a live boy weighing 1 412 grams at 30 weeks’ gestation. The Apgar score was 8 and 9 at 1 and 5 minutes of life respectively. The baby was transferred to the neonatal intensive care unit for observation. Pathological examination of the placenta was negative for malignancy.

At day 1 post-cesarean delivery, a mammography was done without showing any lesion. A total body scan, a bone scintigraphy, and a bone biopsy were also performed (Fig. 2). The biopsy showed a poorly differentiated breast carcinoma with nuclear grade 2. The tumor cells were positive for cytokeratin CK7, GATA3, Ki-67 (14%), estrogen receptors (90%), and human epidermal growth factor receptor 2 (C-erb-B2, 10% of neoplastic cells, score 2+). The diffuse positivity for synaptophysin and chromogranin, along with the focal positivity for neuron specific enolase confirmed the neuroendocrine differentiation of the tumor. Progesterone receptors, CK20, and CDX2 were negative (Fig. 3). The genetic studies for BRCA1 and BRCA2 genes were negative. At the meantime, the patients received another palliative targeted radiotherapy at the level of lumbo-sacral area (from L1 to S5) with a total dose of 20 Gy fractioned into five sessions. She was also on steroids therapy to decrease spinal cord edema at the level of the compressions. The analgesic therapy was optimized and it included transdermal fentanyl and morphine.

Figure 2
Figure 2:
Imaging studies of the malignancy extent. A and B Bone scintigraphy showing diffuse osteolytic lesions at the level of the ribs, vertebral column, and pelvis. C Breast ultrasound (left side) showing absence of breast lesion. D, E, F, and G Total body computed tomography scan (C5: C5 vertebra).
Figure 3
Figure 3:
Histopathology showing a lesion that is consisting of small nests of cells, some of which show lumens, reminiscent of glandular differentiation. The tumor cells have atypical round to oval hyperchromatic nuclei, and a moderately abundant eosinophilic cytoplasm. Few cells exhibit a signet-ring appearance. A subset of cells displays a plasmacytoid morphology. Mitotic activity is present. A Carcinoma with neuroendocrine features (hematoxylin-eosin, original magnification ×10). B Positive estrogen receptors immunohistochemical stain, (original magnification ×10). C Synaptophysin immunohistochemical stain, diffusely positive in tumor cells (original magnification ×10). D GATA3 immunohistochemical stain, diffusely positive in tumor cells (original magnification ×10).

Hormone therapy with tamoxifen and leuprorelin 3.75 mg every 28 days, as well as zoledronic acid were started following the result of the biopsy. The patient continued to wear a cervical collar and a dorso-lumbar brace. She started to be cautiously mobilized during the physiotherapy rehabilitation. She was discharged in a stable condition with her baby 20 days post presentation. Three months later, her treatment consisted of zoledronic acid, luteinizing hormone-releasing hormone analog, letrozole, and palbociclib. At 10 months’ follow-up, her condition remained stable.


Neuroendocrine carcinomas (NECs) may occur in almost all the human body organs, notably in the lungs and the gastro-intestinal tract.4 Feyrter and Hartmann5 described invasive breast carcinoma with neuroendocrine differentiation for the first time in 1963. B-NEC is a very rare entity, constituting less than 0.5% of breast malignancies.6 In 2003, the World Health Organization defined B-NEC as a tumor in which more than 50% of the cells are stained immunohistochemically by the staining of the neuroendocrine markers, such as chromogranin A, synaptophysin, and neuron-specific enolase.7 Few years later, in 2012, the World Health Organization subdivided B-NEC into three categories: well-differentiated NECs, poorly-differentiated NECs or small cell carcinomas, and invasive breast carcinomas with neuroendocrine differentiation.8 Data concerning the biological behavior and the prognosis of these tumors are scarce and controversial. Some authors demonstrated that B-NEC is more aggressive and has a greater tendency for local and distant recurrence with a lower overall survival compared to primary invasive breast carcinoma,9 while others showed the opposite.10

The clinical presentation of our patient was challenging. More than 60% of pregnant women report back pain during their pregnancy.11 However, progressive worsening of pain despite adequate pain therapy, and emergence of neurologic deficits should raise suspicion for a possible underlying pathology. The invasion of the vertebral column by osteolytic metastases lead to vertebral compaction of C5 and compression of the spinal cord. This condition is considered as an oncologic emergency because it can lead to paraplegia if not adequately treated. Steroids and spinal stability measures play an important role in such cases for pain palliation, and can be a bridge to definitive treatment.12 Furthermore, targeted radiotherapy was crucial in this case to alleviate the spinal cord and the nerve root compression, hence, a rapid delivery was inevitable to decrease the risk of fetal radiation. In fact, pregnancy management in women with breast cancer usually depends on the stage of the disease. The timing of delivery should be decided upon the oncological needs and fetal development taking into account the fact that fetal maturation is completed by 37 weeks’ gestation. A study done on 1 170 pregnant women who had cancers of all types (39% with breast cancer) showed a live birth rate of 88%, and half of them had preterm delivery.13

After completing primary investigations, and due to the absence of a detectable origin of the malignancy, it was deemed necessary to biopsy one of the metastatic lesions. This biopsy showed a poorly differentiated breast carcinoma with aspects of neuroendocrine differentiation and positive ER. To the best of our knowledge, this is the first time that this rare type of malignancy presents with a such severe clinical picture during pregnancy. Two previous articles reported the clinical presentation of similar malignancy during pregnancy (Table 1).14,15 However, none of them was as severe as the presentation of our patient. In both two aforementioned cases, there was a palpable mass that highlighted the primary focus of malignancy in the breast at 8 and 31 weeks’ gestation, respectively. The breast biopsy showed thereafter solid papillary breast carcinoma with focal neuroendocrine aspects. The early symptomatic manifestation, especially in the second case, permitted a prompt diagnosis and treatment which lead to favorable maternal and neonatal outcomes.

Table 1
Table 1:
Clinical details and neonatal outcome of cases diagnosed with poorly differentiated breast carcinoma and aspects of neuroendocrine differentiation during pregnancy.

In summary, B-NEC is a rare entity of breast cancer and its incidence during pregnancy will remain sporadic. However, obstetricians should always keep in mind a wide differential diagnosis, and consider the possibility of malignancy especially in patients presenting with unusual symptoms, such as, intractable back pain or neurologic symptoms during pregnancy.



Conflicts of Interest



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Neoplasm metastasis; Neuroendocrine breast carcinoma; Oncologic emergency; Pregnancy

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