Comparison of tumor size,histopathological grade,and molecular subtype of breast cancer at a single center study

Abstract

BACKGROUND:

Breast cancer (BC) is the second most frequent cancer-related death among women worldwide. Factors influencing BC patients’ survival include histopathological grade, histopathological type, stage, hormonal receptors, and number of mitotic images.

OBJECTIVE:

To compare the tumor size, histopathological grade, and molecular type of BC patients.

METHODS:

This was an observational analytic retrospective study. The population was BC patients at Dr. Wahidin Sudirohusodo Hospital from 2017 to 2021. The Kruskal–Wallis test was used to compare statistically between tumor size, histopathological grade, and molecular subtype. Significance was set at p < 0.05.

RESULTS:

The study included 784 patients. Most were aged 50–59 years (34.8%), with tumor size 4c (37.0%) and moderate grade (66.1%), and the most common molecular subtype was luminal A (34.2%). Bivariate analysis using the Kruskal–Wallis test found no significant difference in molecular subtypes based on tumor size (p = 0.079), but significant differences existed in molecular subtype by histopathological grade (p = 0.005) and tumor size by histopathological grade (p < 0.001).

CONCLUSIONS:

Significant differences existed between histopathological grade by tumor size and molecular subtype. Early diagnosis and prompt treatment of BC patients are important to prevent morbidity and mortality.

1. Introduction

Breast cancer (BC) accounts for more than 1 in 10 new cancer diagnoses in women each year, making it the most prevalent malignancy. It is the second most frequent cancer-related death among women worldwide [1]. In the United States, invasive BC affects 1 in 8 women (12.4%) over their lifetime. According to data from GLOBOCAN, an estimated 58,256 new cases of BC are diagnosed each year in Indonesia, accounting for 30.9% of all female cancer cases, and it is the most common cause of death (38.95%) [2]. In 2020, more than 2.3 million new instances of BC and 685,000 fatalities occurred. The International Agency for Research on Cancer and partner institutions predict more than 3 million new instances of BC per year by 2040 [3].

Today, women with a primary diagnosis of BC have a good prognosis with good survival rates overall [4]. However, despite great efforts in BC research over the past 20 years, a significant proportion of patients will still develop metastatic disease. Unfortunately, metastatic BC is still not curable. BC patients’ chances of survival are influenced by a variety of factors, such as age above 50, tumor size, and whether they receive complete therapy for their tumors; tumors larger than 5 cm are thought to have lower survival rates [5]. According to the College of American Pathologists, the histopathological grade, TNM stage, histopathological type, hormone receptors, and amount of mitotic imaging in the histopathology are prognostic markers that influence a patient’s chance of surviving BC [6]. The American Joint Committee on Cancer (AJCC) staging method is frequently used to categorize cases of breast cancer. The main tumor size (T), nodal involvement (N), and metastasis (M) are determined by clinical and pathological evaluations and are used in the 7th edition of the AJCC Staging Manual [7]. The BC stage is then determined using the TNM classification, ranging from stage I to stage IV[8]. The 5-year relative survival rate for stage III breast cancer, which fluctuates at each stage, is 86%, according to the American Cancer Society in 2022 [9].

Table 1

Characteristics of participants

Variable	Characteristic	n (%)
Age (years)	20–29	1 (0.1)
	30–39	35 (4.5)
	40–49	175 (22.3)
	50–59	273 (34.8)
	60–69	233 (29.7)
	≥70	67 (8.6)
Tumor size	1	2 (0.3)
	2	47 (6.0)
	3a	117 (14.9)
	3b	50 (6.4)
	4a	56 (7.1)
	4b	222 (28.3)
	4c	290 (37.0)
Histopathological grade	Low (grade I)	90 (11.5)
	Moderate (grade II)	518 (66.1)
	High (grade III)	176 (22.4)
Molecular subtype	Luminal A	268 (34.2)
	Luminal B	94 (12.0)
	Her-2	219 (27.9)
	Basal-like/triple-negative	203 (25.9)

Table 2

Comparison of tumor size and histopathological grade with molecular subtype

Variable	Molecular subtype				p-value
	Luminal A	Luminal B	Her-2	Basal-like/triple-negative
Tumor size
1	0	0	0	2
2	21	6	10	10
3a	39	20	24	34
3b	16	7	14	13	0.079∗
4a	18	6	16	16
4b	71	24	64	63
4c	103	31	91	65
Histopathological grade
Low (grade I)	35	12	27	16	0.005 ∗
Moderate (grade II)	182	72	124	140
High (grade III)	47	10	68	51

Table 3

Comparison of tumor size with histopathological grade

Tumor size	Histopathological grade			p-value
	Low	Moderate	High
1	0	1	1
2	17	26	4
3a	22	95	0
3b	2	21	27	<0.001∗
4a	9	36	11
4b	17	155	50
4c	23	184	83

This study aimed to compare tumor size, histopathological grade, and molecular subtype of BC patients at Dr. Wahidin Sudirohusodo Hospital from 2017–2021 as reference data to better evaluate, detect, and treat BC.

2. Methods

This was an observational analytic retrospective study. The population consisted of female patients with BC who were admitted at Dr. Wahidin Sudirohusodo Hospital, Indonesia, between January 2017 and December 2021. The Hasanudin University Faculty of Medicine Ethics Committee approved this study (no. 702/UN4.6.4.5.31/PP36/2022). The inclusion criteria were being a woman with BC, having a complete examination in the form of laboratory and histopathological examinations, not having previous treatment or surgery, and having complete data about tumor size, histopathological grade, and subtype. The exclusion criteria were BC patients with other synchronous cancers or incomplete medical record data.

Age at BC diagnosis, TNM-classified tumor size, molecular subtype, and histopathological grade were among the medical record data used for the study. The classification of tumor size was based on the 7th edition of the AJCC staging system: I, II, IIIa, IIIb, 4a, 4b, and 4c [8]. The histopathological grade was based on histological findings that were low (grade I), moderate (grade II), or high (grade III) [10]. Molecular subtype classifications were according to the St. Gallen Consensus 2013: luminal A, luminal B, Her-2, or basal-like/triple-negative [10,11].

The data were collected and statistically analyzed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). The Kruskal–Wallis test was used to compare statistically between tumor size, histopathological grade, and molecular subtype. Significance was set at p < 0.05.

3. Results

In total, 784 patients with BC were included in this study. Based on the age of presentation, the most cases were found in the group aged 50–59 years (34.8%), and the fewest were in the age 20–29 years group (0.1%). Most patients had tumor size 4c (37.0%), and the fewest had tumor size 1, with 2 samples (0.3%). Most had moderate histopathological grades (66.1%), and the fewest had low grades (11.5%). The most common molecular subtype was luminal A (34.2%), and the least common was luminal B (12.0%). Table 1 shows the participants’ characteristics.

The Kruskal–Wallis test was used to assess any differences in molecular subtype based on the tumor size category. Based on the result of p = 0.079, no significant difference existed. The Kruskal–Wallis test was then run to determine any differences in molecular subtype based on histopathological grade category. Based on the result of p = 0.005, significant differences existed (Table 2). For tumor size by histopathological grade, the result obtained was p < 0.001, indicating a significant difference (Table 3).

4. Discussion

In all subtypes, the most common tumor size was T4 (4a, 4b, and 4c), so most patients came with advanced cancer. This is in line with the findings of Rahmawati et al. [12], who reported that most cases of BC in Indonesia are advanced-stage tumors. Tumor size and histopathological grade were significantly correlated in this study, but not with molecular subtypes. The AJCC 7th edition stated that a relationship exists between tumor size and histopathological grade in BC [13].

Luminal A was the most frequent molecular subtype of BC in this study. The results of Rahmawati et al. [12], Widodo et al. [14], and Elesawy et al. [15] also showed the highest prevalence of luminal A. This can be explained by the findings of Kong et al. [16], who reported significant differences in the incidence and proportion of molecular subtypes, histopathological grade, TNM staging, and tumor location related to race or ethnicity. Another study stated that in BC, an ethnicity will have significantly different molecular subtypes compared to other ethnicities that are likely to occur due to differences in biological and social risk factors [17–20].

In this study, all subtypes were dominated by grade II (moderate) histopathological results. In the category of histopathological grade III (high grade/poorly differentiated), this was subtype Her-2 and triple-negative. Kadivar et al. [21] also found that the basal-like subtype had the highest percentage of grade III histopathology. They stated that the Her-2 subtype also tended to show grade III histopathological results. Another study found a significant relationship between histopathological grade and molecular subtype [22–25], where triple-negative and Her-2 molecular subtypes tended to be grade III histopathology [22]. This is in line with the findings of Elesawy et al. [15], who stated that both had a significant relationship (p = 0.035) with the basal-like molecular subtype tending to show Grade III histopathological results.

This study has some limitations, including the fact that the number of samples for each group was not homogeneous, which might have impacted the findings. Comparing lymph nodes, metastatic status, staging, and treatment status with survivability in future studies is recommended.

5. Conclusions

Generally, a significant difference existed between histopathological grade by tumor size and molecular subtype. Early diagnosis and prompt treatment of BC patients are important to prevent morbidity and mortality. Further analysis is recommended, including comparing other clinicopathological parameters such as age, menopausal status, lymph nodes, metastatic status, staging, and treatment status with survivability.