Role of fine-needle aspiration cytology in peripartum/pregnancy-associated breast malignancy - Six cases with review of literature

Priyadarshini Dehuri; Debasis Gochhait; Durga Devi

doi:10.4103/mjmsr.mjmsr_9_20

ORIGINAL ARTICLE

Year : 2020 | Volume : 11 | Issue : 2 | Page : 59-64

Role of fine-needle aspiration cytology in peripartum/pregnancy-associated breast malignancy - Six cases with review of literature

Priyadarshini Dehuri¹, Debasis Gochhait², Durga Devi²
¹ Department of Pathology, IMS and SUM Hospital, Bhubaneswar, Odisha, India
² Department of Pathology, JIPMER, Puducherry, India

Date of Submission	28-Feb-2020
Date of Acceptance	14-Oct-2020
Date of Web Publication	25-May-2021

Correspondence Address:
Dr. Debasis Gochhait
Department of Pathology, JIPMER, Room No 2023, Institute Block, Puducherry - 605 006
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/mjmsr.mjmsr_9_20

Abstract

Background: The incidence of pregnancy associated breast cancers is on the rising trend in different parts of the world. There are occasional studies dealing with the fine needle aspiration cytology (FNAC) and clinicopathological characteristics of these tumors. Objectives: To study the cytomorphology and clinicopathological characteristics of pregnancy associated breast cancers and review the existing literature on the pathological characteristics. Methods: This is a retrospective study which includes cases of breast cancer which were diagnosed during peripartum period. FNAC was performed for all the cases from primary and metastatic sites along with correlation of the clinicopathological characteristics. Results: In the study group, 4 cases were lactating at the time of diagnosis, 1 patient presented at 37 weeks of her pregnancy and another patient presented 1 week after ruptured tubal ectopic pregnancy. Histologically two cases of infiltrating duct carcinoma -not otherwise specified (IDC-NOS), one case of invasive duct carcinoma with mucinous differentiation, one case of invasive duct carcinoma with concomitant lactating adenoma and one case each of metaplastic carcinoma and malignant phyllodes tumor. Only a single case was found to be positive for both the estrogen and progesterone receptors and another case only for estrogen receptors. None of the cases were found to positive for Her -2 neu. Conclusion: FNAC still serves as a reliable diagnostic measure inspite of the close mimics, especially when combined with cell block preparation. Further documentation of the clinicopathological features is essential for establishing the prognostic parameters and treatment guidelines for these peripartum breast cancers.

Keywords: Breast carcinoma, delayed diagnosis, fine-needle aspiration cytology, pregnancy

How to cite this article:
Dehuri P, Gochhait D, Devi D. Role of fine-needle aspiration cytology in peripartum/pregnancy-associated breast malignancy - Six cases with review of literature. Muller J Med Sci Res 2020;11:59-64

How to cite this URL:
Dehuri P, Gochhait D, Devi D. Role of fine-needle aspiration cytology in peripartum/pregnancy-associated breast malignancy - Six cases with review of literature. Muller J Med Sci Res [serial online] 2020 [cited 2023 Mar 21];11:59-64. Available from: https://www.mjmsr.net/text.asp?2020/11/2/59/316698

Introduction

Breast lumps are commonly encountered in pregnant females which often turn out to fibroadenoma, lactating adenomas, or galactoceles and less commonly as mastitis, granulomatous inflammation, or benign cysts. The clinical impression of breast carcinoma becomes far fetched considering the higher frequency of the above-mentioned benign or inflammatory lesions. Hence, the diagnosis of breast cancers in pregnancy is often delayed. Although the incidence of pregnancy-associated breast cancers (PABCs) is very low, estimated at 1 in 3000 pregnancies,^[1] breast cancers lead the list of malignancies seen during pregnancy surpassed only by cervical cancers.^[2] Only 10% of breast cancers diagnosed in women aged <40 years have been reported to be associated with pregnancy.^[3] However, the rising incidence of PABC in the different parts of the world^[2] has alerted pathologists and clinicians worldwide.

The suggested etiopathological factors for the development of these malignancies are the elevated levels of estrogen and progesterone, insulin-like growth factor, and leptin in pregnant state.^[4] These tumors have been shown to be enriched with the expression of major hormone-regulated genes involved in cell proliferation, metabolism, and tumor aggressiveness. In the Indian setting, there is only a single study which deals with the clinicopathological characteristics of PABC.^[5] Moreover, the cytomorphological aspects have not been dealt with. Hence, further documentations are necessary for understanding the behavior of this group of malignancy and hence standardize treatment options.

Aims and objectives

The aim and objective of this study is to study the cytomorphology and clinicopathological characteristics of PABCs and review the existing literature on the pathological characteristics.

Materials and Methods

The study undertaken is a record-based retrospective study. The data for this study are based on the histopathological records from January 2014 to June 2017. After screening 334 cases of breast cancer, 35 cases of breast cancer belonging to the age group of 20–35 years were recovered. Out of these 35 cases of breast cancer in young females, six cases were associated with pregnancy or lactation. Fine-needle aspiration cytology (FNAC) was performed for all the six cases after clinical evaluation. The histopathological grading assigned for the cases was as per the Elston and Ellis modification of Scarf Bloom Richardson scheme. The immunohistochemical stains used for the hormonal receptor status of the breast cancers belonged to Dako manufacturers (Monoclonal Rabbit Anti-Human antibody). The interpretation of estrogen and progesterone receptor (PR) status was done by the Alred score which includes both the proportion and intensity of staining of the tumor cells. The Her-2neu status was interpreted following the American Society of Clinical Oncology-College of American Pathologists guidelines for Her-2neu test recommendations, 2013. The other immunohistochemical stains used were Ki-67, p53, Pan cytokeratin, and Vimentin. The results were considered positive for p53 only if >10% of the malignant cells showed nuclear staining. All the immunohistochemical stains were performed on tissue blocks prepared from the resection specimens except one case where the stains were performed on cell blocks prepared from the FNAC material.

Results

The total number of breast cancer cases in the age group of 20–35 years was 35 out of which six cases could be grouped under PABCs. The mean age at the presentation was 29.3 years. Left side breast was more commonly affected (4/6 cases). Bilateral breast cancer was observed in a single case of disseminated malignancy which had presented with metastatic disease. A positive family history of breast cancer in first-degree relative was found in a single case where the patient presented at 35 years of age with a palpable lump in the breast along with axillary lymphadenopathy [Table 1]. However, molecular studies for BRCA status have not been performed.

Table 1: Clinical history of study subjects

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Amongst the total six cases of PABCs, there was one case of invasive duct carcinoma with concomitant lactating adenoma [Figure 1] two cases of infiltrating duct carcinoma (IDC)-not otherwise specified (IDC-NOS), one case of invasive duct carcinoma with mucinous differentiation [Figure 2]a, [Figure 2]b, [Figure 2]c, and one case each of metaplastic carcinoma and malignant phyllodes tumor [Figure 3]a, [Figure 3]b, [Figure 3]c and detail of all cases in [Table 2]]. One case of infiltrating duct carcinoma with mucinous differentiation showed positive results for both estrogen and PRs, while none of the cases were found to positive for Her-2 neu. A single case of infiltrating duct carcinoma (IDC-NOS) showed positive staining for p53. The cases of metaplastic carcinoma and invasive duct carcinoma with concomitant lactating adenoma were negative for all the three hormone receptors.

Figure 1: (a) Tumor cells with moderate pleomorphism along with numerous apoptotic bodies (Papanicolaou, ×100). (b) The gross image of the tumor shows a homogenous circumscribed tumor. (c) The histopathology section (H and E) shows tumor in the left field coexisting with lactating adenoma in the right side corner of the field

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Figure 2: Figure: (a) The Hematoxylin and Eosin (H&E) stained Cytology smear shows tumor cells in clusters admixed with pools of mucin. (b) Hematoxylin and Eosin (H&E) stained cytology smears show tumor cells with fat infiltration. (C) The histopathology section (H&E stain) shows predominant areas of IDC admixed with extracellular mucin

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Table 2: Pathological features of the cases included in study

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Figure 3: (a) Smears show tumor cells in fragments and chunks with moderate to marked pleomorphism (Papanicolaou, ×100). (b) The dark staining benign epithelial cells admixed with tumor cells (Papanicolaou, ×100). (c) The biopsy confirmed a malignant phylloides tumor with marked pleomorphism in the left side of the image, benign ductal epithelial cells were also seen (right side of the image)

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Discussion

Conventionally, PABC has been defined as those breast cancers which are detected during pregnancy or within 1 year postpartum. The reported incidences based on studies vary from 0.7% by Gogia et al.^[5] to 15% by Beadle et al.^[6] In our study, 6/35 breast cancer cases in females of the age group 20–35 years were associated with pregnancy. Although mid to late thirty's has been the suggested average age of PABCs, 4/6 cases in this study were younger than 30 years at the time of diagnosis. A study by Gooch et al. found advanced age at first pregnancy to be associated with increased risk of PABC, especially in BRCA mutants.^[7] This study includes a case with a positive family history of breast cancer with unknown BRCA1 status.

Although core biopsy has been advocated as the diagnostic modality for the detection of breast cancer,^[8] the role of FNAC needs to be emphasized here as it is a rapid, safe, and fairly reliable means of excluding malignancy in suspicious breast lumps during pregnancy and postpartum. A high index of clinical suspicion and cytomorphological expertise is the prerequisite for such cases. The cytomorphological features which helped us to diagnose ductal carcinoma were dispersed population of pleomorphic cells with high nucleocytoplasmic ratio, coarse chromatin, and prominent nucleoli. There was a lack of a milky/lipoproteinaceous background in most of the cases. The prime cause of concern regarding the accurate interpretation of aspirate smears is the cytological atypia that accompanies the secretory changes of glandular epithelium in pregnancy and lactation. The cytology smears in these cases often show highly cellular smears with dispersed population of cells showing prominent nucleoli along with lipo-proteinaceous milky background.^[9] These features often lead to a false-positive diagnosis of malignancy. In such situations, appreciating smooth contour of nuclear membrane with evenly dispersed, bland chromatin could avoid over diagnosing malignancy. The presence of singly scattered atypical epithelial cells and absence of a lipoproteinaceous milky background favors a malignant pathology. Historically radiologic interpretation of breast lumps in pregnancy has been met with many challenges, though recently there have been documentations of 70%–90% sensitivity rates of mammographic screening of cancers.^[10] However, considering the difficulties that are encountered in the radiologic interpretation of breast lumps in pregnancy, ultrasound-guided FNAC yields significantly better results.

In this study, core biopsy was indicated for the diagnosis only in one case where FNAC was reported as “suspicious of malignancy.” This was the case of an infiltrating duct carcinoma with coexisting lactating adenoma [Figure 1a-c]. Lactating adenoma is a well-known mimicker of malignancy on cytological smears. Literature search reveals occasional report of the coexistence of these two pathologies.^[11] The cytology smears of the case included in our study were very cellular comprising of clusters of tumor cells with mild-to-moderate pleomorphism in a dirty necrotic background [Figure 1a]. Many of the individual tumor cells showed vacuolated cytoplasm along with scattered mitotic figures were also noted. Since multiple needle passes were taken from the lump, there were some smears which showed lactation induced changes without any significant pleomorphism in the ductal epithelial cells.

Invasive duct carcinoma contributes a major share of the histological diagnoses of PABCs in most studies. In the largest Indian study by Gogia et al.,^[5] all the cases were of infiltrating duct carcinoma. Similarly, it constituted 80% of the total cases in the study by Basaran et al.^[12] Ives et al.^[13] reported 85% cases as invasive ductal carcinoma and 4.7% cases of invasive lobular carcinoma. Shousha^[14] have stressed on two histomorphological features which they observed to be associated with breast cancers seen in pregnancy and lactating females. They are cancerization of lobules and presence of foci of mucinous carcinoma. Two of our cases showed foci of mucinous differentiation, but we did not find cancerization of lobules as a major feature.

PABCs are usually large-sized tumors having higher grades,^[15] frequent lymphovascular invasion with nodal metastases in 60%–70% cases.^[16] Shousha^[14] observed a high rate (80%) of axillary nodal metastases. However, the incidence was still lower when compared to axillary nodal metastases seen in age-matched controls (90%) without any history of pregnancy and lactation. Hence, they have suggested the young age of the patients as the likely determining factor for the high rate of metastases rather than the association of pregnancy or lactation.

Basaran et al.^[12] found estrogen receptor (ER)/PR positivity in 70% of their cases. Gogia et al.^[5] also observed high rates (56%) of ER/PR receptor expression contrary to most other studies, for example, Gentilini et al.^[17] who reported ER and PR positivity of 36.8%. However, Shousha^[14] reported some interesting findings regarding the hormone receptor expression. They observed that tumors associated with pregnancy were less likely to be ER positive (20%) than the tumors associated with lactation (80%). Similarly, for ERs, none of the cases associated with pregnancy showed any reactivity, while 60% of the lactation-associated cases showed positivity.

Her-2 neu receptor positivity rates of 36%–42% have been documented in PABC by Amant et al.^[16] which has no significant difference to the positivity rates in nonpregnant breast cancer patients. The authors have also reiterated the fact that the pathological features of breast cancers associated with pregnancy are influenced by the age of the patient rather than due to the association of pregnancy. Reed et al.^[18] concluded that a substantial proportion of cases ranging from 44% to 58% of PABCs were Her-2neu positive. On the other hand, Shousha^[14] observed that none of the breast cancers presenting during pregnancy and lactation tested positive for Her-2 neu. However, all the cases of breast cancer which were diagnosed shortly after pregnancy and postlactation showed Her-2 neu positivity.

The role of other prognostic markers such as p53 has also been studied with the help of immunohistochemical stains. In the study by Shousha,^[14] none of the cases associated with pregnancy and lactation have shown positive staining with p53, although it has been always linked with aggressive tumor behavior in breast cancers. Among the six cases of cancer in our study, one case of invasive duct carcinoma (IDC-NOS) showed positive staining for p53 which was also found to be triple negative for the hormone receptors along with a positive family history of cancer.

Of late, no significant difference has been suggested in the prognosis of PABCs as compared to their nonpregnant counterparts, especially when they present early.^[19] However, PABCs have been proved to have poor overall and disease free survival.^[20]

Bad prognosis has been attributed to late presentation by patients which is also accompanied by large-sized tumors^[6] with nodal metastases.^[21] In this context, we would like to highlight a contradictory finding in one of our cases here which presented with metastatic disease involving skull and abdominal wall without clinically detectable mass in the breast or palpable axillary lymph nodes. The diagnosis was made by ultrasound-guided FNAC from the breast nodule.

A multidisciplinary approach is recommended for the treatment of these breast cancers with the options of surgery, chemotherapy, and radiotherapy applicable as per the gestational age or the time of presentation.^[22] While radiotherapy can be considered in the first and second trimesters, chemotherapy can be administered in the second and third trimesters with a judicious decision on the doses. In the present study, three cases underwent modified radical mastectomy followed by radiotherapy. Adjuvant chemotherapy was administered in one case of invasive duct carcinoma with axillary lymph node metastasis. The case of invasive duct carcinoma with concomitant lactating adenoma underwent breast conservation surgery with axillary node dissection followed by radiotherapy. The patient with malignant phyllodes also underwent surgery. All the above five cases had an uneventful postoperative period and have been so till date. One case with disseminated malignancy was treated with palliative chemotherapy, but unfortunately, the patient died within 1 month of presentation in the hospital.

Conclusion

Early diagnosis holds the key for reducing the morbidity and mortality of breast cancers associated with pregnancy. Hence, urgent attention is warranted for the diagnosis of palpable breast lumps in pregnancy or lactational period so as not to miss a malignancy. Ultrasound-guided FNAC still serves as a reliable diagnostic measure, especially when combined with cell block preparation. Core biopsy can be reserved for indeterminate cases.

Owing to the extreme rarity of PABCs, large scale data on the interrelationship of various prognostic parameters and pathological characteristics are lacking. This has restricted the understanding of the behavior and characteristics of these tumors. Hence, further documentation of the clinicopathological features is essential for establishing the prognostic parameters and treatment guidelines for these cancers.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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