Background

One of the first reports on 3 cases of Occult breast cancer (OBC) with axillary lymph node metastasis as the initial presentation was recorded by Halsted in 1907. Subsequently, occult breast cancer was gradually recognized by everyone. The incidence of occult breast cancer in China is only 0.3%-0.8% (Lin, 2006).Occult breast cancer generally refers to a special type of breast cancer that axillary lymph node metastasis or other parts of distant metastasis as the first manifestation, clinical physical examination failed to find mass, but imaging examination may find a primary breast. OBC is characterized by slow growth of primary breast cancers and rapid progression of metastatic tumors such as lymph nodes or other organs outside the breast. As a rare disease, it is often difficult to find the primary cause of the disease. The definition, diagnosis and treatment of the disease remain controversial. This article mainly reviews the clinical manifestations, diagnosis, differential diagnosis, biopsy, immunohistochemical classification, treatment and prognosis of occult breast cancer.

1 Clinical Manifestations

1.1 Painless lump in axillary region

Most of the occult breast cancer patients with axillary painless lymph node enlargement as the first symptom, the ipsilateral breast volume is too large, can not detect breast lumps in routine examination. Most of the patients were 45~55 years old, and the diameter of axillary lymph nodes was about 3 cm. The axillary lymph nodes was characterized by solitary or multiple, adhesion to each other, fixed, hard texture. It is found that the interval between detecting the metastatic lesions and the primary breast lesions is shorter for a few days, and the elderly can be more than 2 years.

1.2 Distant metastasis

Occult breast cancer mostly metastasis to the abdominal visceral organs, a few occult breast cancer metastasis to supraclavicular lymph nodes.

1.3 Paraneoplastic neurological syndrome

Individual reports of occult breast cancer associated with paraneoplastic neurological syndrome, manifested the clinical progression of peripheral neuropathy with the symptom as distant limbs discomfort, tingling, pain, proximal development, myasthenia (Shao, 2013).

2 Accessory Examination and Biopsy

2.1 Imaging examination

2.1.1 Molybdenum target

X-ray mammography is the golden standard for imaging diagnosis of breast related diseases. X-ray mammography can detect tiny nodules of 2-3 mm, and can show abnormal calcification. The main X-ray features were clusters of small calcifications, small nodules, irregular boundaries, structural disorders of the breast, enlarged axillary lymph nodes and abundant blood flow. Spicule sign is also an important sign of occult breast cancer. In addition, sediment like, needle like, clubbing calcification in X-ray examination also suggest breast cancer. Generally, 15 calcifications per square centimeter can be the standard, and more than 15 can be suspected as breast cancer.

2.1.2 Ultrasound

Ultrasound make up for gaps and omission of mammography, which can detect the edge of breast dysplasia, small breast or chest wall tumor and other blind spots. Ultrasound and mammography is complementary, which improve the sensitivity of detecting breast cancer lesions. Ultrasound has stronger ability to identify soft tissue, and it is better than mammography in distinguishing low echo mass and understanding lymph node metastasis. It can effectively observe the enlargement of axillary lymph nodes. Doppler showed that the axillary lymph nodes of OBC were very rich in blood flow, and the structures of the cortex and medulla were separated, and the lymph node hilus were not clear.

2.1.3 MRI

The sensitivity of breast MRI to breast cancer was 85%-100%, and the specificity was 37%-97%. MRI plays an important role in the search for primary lesions. The advantages of MRI include non-ionizing-radiation, noninvasive, high sensibility, high accuracy, and high localization. MRI is good for soft tissue, especially for deep breast lesions. The number, range and size of lesions can also be evaluated by MRI.

2.1.4 PET-CT

PET can detect tumor growth from molecular level, and help to find metastases from other parts of body. It is reported that PET can detect the abnormal metabolism of mammary gland without abnormal anatomical structure (Ramírez et al., 2014), the sensitivity is 62%-100%, the specificity is 96%-100% (Cenzano et al., 2012). But the price is too expensive, and PET technology successful detecting OBC cases was rarely, bringing about detection space is still limited.

2.1.5 Breast-specific gamma imaging (BSGI)

BSGI as a high resolution imaging type, can detect sub centimeter level occult breast cancer, whose sensitivity and specificity is better than MRI. BSGI can detect tiny cancer foci in dense breast (Brem et al., 2016).

2.2 Needle biopsy

2.2.1 Fine needle aspiration cytology (FNAC)

The technique is suitable for the puncture of enlarged axillary lymph nodes, and the suction cells are examined by liquid based cytology, which can detect whether there are tumor cells.

2.2.2 Core needle biopsy (CNB)

This examination is a pathological biopsy of histology, and it is a common method to detect the primary breast cancer before operation. Axillary lymph node puncture should be performed under ultrasound guidance so as not to damage axillary vein.

2.2.3 Breast MRI localization biopsy

MRI found occult breast cancer suspicious malignant lesions, which need further MRI positioning biopsy, MRI showed OBC lesions characterized by mass like irregular ring enhancement, or non mass like irregular heterogeneous enhancement (Tandon et al., 2016). MRI is more accurate and safe for location of tiny lesions (Gao et al., 2016).

2.2.4 Radioisotope occult lesion localization (location ROLL)

Compared with other localization techniques, the positive rate and pathological positive rate of margin cancer cells in OBC after local excision were greatly reduced. Therefore, radionuclide localization also reduces the possibility of the second operations, better to consider the patient's appearance, and more humanized (Zand and Assarian, 2016).

2.2.5 Digital breast tomosynthesis (DBT)

It has already become a accurate and reliable method to detect those highly suspected breast cancer but mammography and ultrasound localization can not directly see the changes in the structure, the positive predictive value of DBT guided biopsy was up to 47% (Freer et al., 2015).

3 Histology and Immunohistochemical Examination

3.1 Pathology

There is no difference between the occult breast cancer and the normal breast cancer, but the clinical pathology is mainly consist of ductal carcinoma with low differentiation, and the malignant degree of the tumor cells is high, showing diffuse infiltration of lymph nodes. Metastatic lesions were solid tumor cancer characteristics, may come from the breast, showed low differentiation may come from malignant melanoma, serous or mucinous papillary carcinoma may be from primary ovarian cancer, and high columnar cells secreting mucus gland cancer may come from stomach, colon and lung (Shao, 2013).

3.2 Immunohistochemical detection

3.2.1 Estrogen Receptor (ER)

It was said that 50% ER in patients with occult breast cancer is positive, but ER negative and can not exclude OBC. The sensitivity of ER expression in the diagnosis of breast cancer was 0.63 and the specificity was 0.95. The positive rate of ER in occult breast cancer was lower than that in non occult breast cancer (Sun et al., 2014).

3.2.2 Progesterone Receptor (PR)

The positive rate of PR in occult breast cancer is lower than that in ER, and the expression of PR is less. The survival rate of patients with PR (+) is higher than that of patients with PR (-), and the recurrence rate is lower (Wang et al., 2013).

3.2.3 Gross Cystic Disease Fluid Protein-15 (GCDFP-15)

As a marker of plasma secretion, GCDFP-15 has a sensitivity and specificity of 0.98 and 0.62, respectively. GCDFP-15 suggests that the risk of axillary lymph nodes is high in the breast, but about 5% of non breast cancers can also be detected in GCDFP-15.

3.2.4 Breast globin

Axillary lymph node metastasis detected breast globin, the tumor is likely to come from the breast, its sensitivity and specificity are 0.84 and 0.85, respectively.

4 Differential Diagnosis

Axillary lymph node metastasis should be differentiated from gastric cancer, colorectal cancer, pancreatic cancer, lung cancer, lymphoma, accessory breast cancer, thyroid cancer, ovarian cancer, renal cell carcinoma, malignant melanoma and soft tissue sarcoma.

5 Diagnosis

Generally, patients of occult breast cancer can not touch breast lumps, but they can touch axillary lymph nodes with or without other parts of the lymph nodes, with a hard texture, no obvious tenderness, and adhesion with surrounding tissues. The pathological and immunohistochemical examination of the axillary lymph nodes is helpful for the diagnosis of OBC and exclude other diseases that metastasis to the axillary lymph nodes of the axillary lymph nodes.

6 Treatment

6.1 Local treatment

6.1.1 Mastectomy+Axillary lymph node dissection (ALND)

Axillary lymph node metastasis of breast cancer advocate the use of traditional modified radical mastectomy for breast cancer (Auchincloss surgery) and postoperative adjuvant chemotherapy, endocrine therapy and corresponding targeted therapy. Modified radical mastectomy should be performed for patients with higher TNM stage and / or high risk.

6.1.2 Axillary lymph node dissection combined with postoperative radiotherapy (ALND+X-ray Technique, XRT)

The 5 year survival rate was 72% and the 10 year survival rate was 66% of OBC after radiotherapy, respectively. The study showed that patients with radiotherapy had lower ipsilateral breast tumor recurrence rates, local recurrence rates, and higher total survival rate (Barton et al., 2011; Masinghe et al., 2011) when compared with those untreated by radiotherapy patients. In the Francisco B review article, Meta analysis showed that there was no significant difference between ALND+mastectomy and ALND+XRT in the local recurrence rate, distant metastasis and mortality, which manifested that mastectomy can be replaced by radiotherapy in OBC patients after undergoing ALND (Inatome et al., 2016). However, the mortality and local recurrence of ALND+XRT are better than those of ALND alone. Therefore, it suggests that ALND combined with XRT may be the best choice for surgical treatment of occult breast cancer (Macedo et al., 2016).

6.1.3 Axillary lymph node dissection alone (ALND)

It is feasible to combine the operation of breast conserving with ALND alone in patients who no primary foci of the breast .One is the only axillary lymph node dissection (breast conserving 1 type); another is breast quadrant resection, resection of suspected cancer and the surrounding areas of at least 1 cm to expand the scope of resection or quadrant resection (breast conserving 2 type).Walker reviewed the prognosis of the above operation was evaluated. There was no significant difference in the 10 year survival rate between the modified radical mastectomy group and the breast conserving 1 group, but breast conserving 2 group was significantly lower than those two groups. Breast conserving surgery should be used cautiously (Walker et al., 2010) for patients with diffuse growth of OBC. There was no significant difference in total survival rate and disease-free survival rate between ALND+mastectomy, ALND+XRT and ALND alone (Wang et al., 2013).

6.2 Systemic therapy

According to the NCCN guide, hormone receptor positive patients should be treated with endocrine therapy. HER-2 positive patients are treated with adjuvant targeting, but should considered economic reasons. According to study by Wang et al. (2011), the effect of combined radiotherapy and chemotherapy is much better than that of simple treatment. Therefore, we should make reasonable and integrate strategy of radiotherapy, chemotherapy, targeted therapy and endocrine therapy.

7 Prognosis

The prognosis of OBC became worse according with more lymph nodes, what’s more, hormone receptor, HER-2 gene amplification(Xin et al., 2014), cancer pathological types, the number of axillary lymph nodes, whether the occurrence of supraclavicular metastasis are related to prognosis of OBC. In a retrospective analysis of Guiyun Sohn M D, it is shown that lymph node status and tumor size do not have much effect on the survival rate of patients when the lymph node staging is relatively late. This is also irrelevant with the malignant results of occult breast cancer (Guiyun et al., 2014). Therefore, there was no difference between the five year survival rate and ten year survival rate of OBC and N-OBC in stage Ⅲ (Sun et al., 2014).

Authors’ contributions

Z.D.W. read and approved the final manuscript. G.Z.F. wrote and translated the manuscript. Z.Z.W, L.W.Q, Y.S.R, Z.J.Y and Z.B.Z collected materials. All authors read and approved the final manuscript.

Acknowledgments

This work was supported by the Science Innovation Project (201716) and fund for Heilongjiang provincial science and Technology Department (YS17C22).

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