Diagnosis and treatment of metachronous multiple primary carcinoma: A case report and review of literature

Abstract

BACKGROUND

Multiple primary carcinoma (MPC) refers to two or more types of primary malignant tumors occurring simultaneously or sequentially in the same patient. Breast cancer is one of the most common malignant tumors affecting women. On the other hand, diffuse large B-cell lymphoma (DLBCL) is the most frequent form of non-Hodgkin’s lymphoma (NHL). In clinical practice, the simultaneous existence of metachronous primary breast cancer and lymphoma is rare. In this case, we highlight the significance of multidisciplinary management and advanced imaging techniques in the early identification and treatment of MPC cases.

CASE SUMMARY

In this study, we report a case of a 40-year-old female who was diagnosed with invasive ductal carcinoma of the breast (T3N1M0 stage IIIA LuminalB type) as the first primary cancer and DLBCL (stage IIIA) as the second primary cancer. The patient underwent the modified radical mastectomy for left breast cancer and received Rituximab, cyclophospha-mide, hydroxydaunorubicin, Oncovin (vincristine) and prednisolone regimen chemotherapy treatment for DLBCL. As of now, the patient is in stable condition. The successful diagnosis of the present patient highlights the need for multidisciplinary management and adoption of advanced imaging techniques to identify the second primary cancer, especially NHL.

CONCLUSION

Accurate diagnosis and management of metachronous MPC requires an interdisciplinary team and selection of an appropriate treatment plan.

Key Words: Multiple primary carcinoma; Metachronous; Breast cancer; Diffuse large B cell non-Hodgkin lymphoma; Case report

Core Tip: We report a case of a 40-year-old female diagnosed with invasive ductal carcinoma of the breast (T3N1M0 stage IIIA LuminalB type) as the first primary cancer and diffuse large B-cell lymphoma (DLBCL) (stage IIIA) as the second primary cancer. A modified radical mastectomy was selected for the treatment of left breast cancer and Rituximab, cyclophospha-mide, hydroxydaunorubicin, Oncovin (vincristine) and prednisolone regimen chemotherapy treatment to control DLBCL. At the last follow-up, the patient is in stable condition. In clinical practice, the simultaneous existence of metachronous primary breast cancer and lymphoma is rare. This case underscores the need for a multidisciplinary management approach and the adoption of advanced imaging techniques to facilitate early identification and treatment of rare multiple primary carcinoma cases.

INTRODUCTION

Breast cancer is one of the most common malignant tumors in women, which can be fatal, deteriorating the physical and mental health of women worldwide. In 2020, an estimated 2.3 million new cases of breast cancer were reported globally, accounting for 11.7% of all malignant tumors, making it the most prevalent malignant tumor among women, surpassing lung cancer[1]. Invasive carcinoma is the most common pathological type of breast cancer[2]. Non-Hodgkin’s lymphoma (NHL) is a malignant tumor of the lymphatic system, accounting for about 90% of lymphoma cases. Diffuse large B-cell lymphoma (DLBCL) is the most common NHL, affecting gastrointestinal tract, the neck and other lymphoid tissues or organs rich in lymphoid tissue. Environmental pollution caused by pollutants, such as food additives and pesticides, has contributed to the progressively rising incidence of lymphoma[3]. Simultaneous or metachronous primary breast cancer and lymphoma are rare in clinical practice. In this case report, we describe the diagnosis and treatment process of a patient with invasive ductal carcinoma of the breast as the first primary cancer and DLBCL as the second primary cancer. In addition, we identify similar clinical studies to comprehensively discuss the diagnosis and treatment options for multiple primary carcinoma (MPC) patients.

CASE PRESENTATION

Chief complaints

A 40-year-old female presented with a mass in the left breast during a physical examination in November 2017. There was no skin redness, fever, headache, vomiting, or tenderness. In the outpatient clinic, the patient received a breast ultrasound examination, which identified a solid mass in the left breast and bilateral axillary hypoechoic masses. Consequently, she was admitted for further treatment in December.

History of present illness

Physical examination revealed a mass in the left breast, without skin redness, fever, headache, or vomiting.

History of past illness

The patient denied any history of hypertension, coronary heart disease, diabetes, hepatitis, tuberculosis, or other infectious diseases.

Personal and family history

Her occupation and working conditions were free from industrial toxins, dust, radioactive substances and exposure history. In addition, she denied a history of smoking and drinking habits, family history of cancer and genetic disorders.

Physical examination

Physical examination did not find any systemic abnormalities except for a left breast lump with a Karnofsky performance status score of 1.

Laboratory examinations

Immunological examination: In November 2017, rotational resection of a breast mass was performed. Immunohistochemistry revealed CK5/6 (-), P63 (-), CD10 (-), E-cadherin (+), P120 (membrane+), ER (90%), PR (5%), HER-2 (0), P53 (+), P16 (-), epidermal growth factor receptor (-), and Ki-67 (60%) (Figure 1A). These tests suggested a diagnosis of invasive ductal carcinoma of the breast. Routine blood test, urinalysis, routine stool and liver and kidney function did not find any significant abnormalities.

Figure 1 Invasive ductal carcinoma of the breast. A: Immunohistochemistry revealed ER (90%), E-cadherin (+), PR (5%), P120 (membrane+), indicating a diagnosis of invasive ductal carcinoma of the breast; B: Breast ultrasound showed a solid mass in the left breast with a diameter of 2.4 cm.

Imaging examinations

Breast ultrasound revealed a solid mass in the left breast (BI-RADS 4b grade) with a diameter of 2.4 cm and lymph node ultrasound identified oval hypoechoic mass in the bilateral (Figure 1B). Abdominal ultrasound and chest computed tomography (CT) showed no abnormalities.

In August 2023, re-examination CT identified multiple enlarged lymph nodes in the abdominal cavity (Figure 2A-C). Subsequently, the pathological biopsy of the right abdominal mass was performed and immunohistochemical examination of the tissue found CD20 (+), CD3 (-), GATA3 (-), CK (Pan) (-), Ki-67 (80%) (Figure 2D). These results confirmed the diagnosis of DLBCL.

Figure 2 Metachronous diffuse large B-cell lymphoma. A-C: Computed tomography showed multiple enlarged lymph nodes adjacent to the abdominal aorta (A) and bilateral iliac vessels (B) and abdominal cavity (C); D: Immunohistochemical results showed that CD20 (+), Ki-67 (80%). These results suggested a diagnosis of diffuse large B-cell lymphoma.

FINAL DIAGNOSIS

A final diagnosis of metachronous MPC was made, with invasive ductal carcinoma of the breast (T3N1M0 stage IIIA LuminalB type) as the first primary cancer and DLBCL (stage IIIA) as the second primary cancer.

TREATMENT

In December 2017, a modified radical mastectomy was performed to treat left breast cancer together with four cycles of EC regimen chemotherapy (epirubicin + cyclophosphamide) from December 2017 to March 2018. In April 2018, she was administered with four cycles of chemotherapy using the docetaxel regimen.

In June 2018, a follow-up CT indicated the presence of proliferative lesions in the lung posterior right upper lobe, which were treated with radiotherapy with a scheduled target volume of 50 Gy/25 fractions in August and tamoxifen endocrine therapy applied afterwards. In November 2019, the patient underwent re-examinations, which confirmed no signs of tumor recurrence or metastasis. Breast ultrasound showed solid nodules in the right breast (BI-RADS class 3, suggestive of proliferative nodules) and tamoxifen was administered as endocrine therapy. In May 2021, magnetic resonance imaging of the abdominal and pelvic revealed no clear signs of tumor recurrence or metastasis. The patient continues to receive tamoxifen treatment combined with leuprorelin.

In August 2023, re-examination positron emission tomography (PET)-CT showed multiple enlarged lymph nodes in the abdominal cavity, which were considered manifestations of DLBCL based on immunological results as determined by a multidisciplinary team. According to the basic treatment principles of multiple primary tumors of the Chinese Society of Clinical Oncology Guidelines in 2024[4] and the National Comprehensive Cancer Network Clinical Guidelines in 2024[5], the patient was put on the standard first-line treatment Rituximab, cyclophospha-mide, hydroxydaunorubicin, Oncovin (vincristine) and prednisolone (R-CHOP) regimen chemotherapy, consisting of rituximab 600 mg/day 1, cyclophosphamide 1200 mg/day 1, doxorubicin 80 mg/day 1, vincristine 2 mg/day 1, and prednisone 100 mg/day 1-5. Subsequently, the patient developed neutropenia and fever, necessitating further dose adjustment.

From September to December 2023, the second to sixth cycles of R-CHOP chemotherapy were administered as follows: Rituximab 600 mg/day 1, cyclophosphamide 1000 mg/day 1, pirarubicin 70 mg/day 1, vincristine 2 mg/day 1, and prednisone 100 mg/day 1-5. After the second cycle of R-CHOP chemotherapy, CT revealed a significant reduction of the lymph nodes in the abdominal aorta, bilateral iliac vessels and abdominal compared to earlier tests. The therapeutic effect of the drugs was evaluated as the partial response (PR). However, the complete response (CR) was achieved on the sixth cycle of chemotherapy. In January 2024, the treatment was changed to rituximab 500 mg/day 0, etoposide 0.15 g/day 1-3, ifosfamide 8 g/day 2, carboplatin 0.5 g/day 2. These drugs achieved significant bone marrow suppression. In February 2024, the chemotherapy dosage was adjusted to rituximab 600 mg/day 0, etoposide 0.15 g/day 1-2, 0.1 g/day 3, ifosfamide 6.5 g/day 2, and carboplatin 0.4 g/day 2.

From April to June 2024, the patient underwent four cycles of chemotherapy comprising 600 mg zuberitamab and gemox regimen (gemcitabine 1.7 g/day 1, oxaliplatin 170 mg/day 1 q2w). After the last chemotherapy cycle, the patient developed grade III bone marrow suppression. In July, a follow-up CT showed a marked reduction in the abdominal tumor and the therapeutic effect evaluation was PR. The patient was administered with a fifth round of chemotherapy including 600 mg of zuberitamab and gemox regimen (gemcitabine 1.0 g/day, oxaliplatin 150 mg/day 1 q2w) and lenalidomide starting in July. Targeted combination chemotherapy was administered in August, which contained rituximab 600 mg/day, gemcitabine 1.2 g/day, and oxaliplatin 120 mg/day q2w. Since then, the patient has continued to use lenalidomide.

Rituximab 600 mg/day, gemcitabine 1 g/day, oxaliplatin 120 mg/day 1 q2w in November 2024. Targeted therapy with zebitumumab 600 mg was administered in January 2025.

The treatment regimen is presented in Table 1.

Table 1 The treatment regimen.

Date	Treatment management	Efficacy evaluation
December 2017 to April 2018	In December 2017, modified radical mastectomy for left breast cancer and 4 cycles of EC regimen chemotherapy from December 2017 to March 2018. In April 2018, 4 cycles of chemotherapy were administered using the docetaxel regimen	The therapeutic effect was evaluated as CR
June 2018 to May 2021	Radiotherapy for proliferative lesions with a PTV of 50 Gy/25 fractions for proliferative lesions in the lung posterior right upper lobe in August and tamoxifen endocrine therapy was taken after it. The patient continues to receive treatment with tamoxifen combined with leuprorelin in May 2021	The therapeutic effect was evaluated as CR
August 2023	Diagnosed as DLBCL. R-CHOP regimen chemotherapy was administered, consisting of rituximab 600 mg/day 1, cyclophosphamide 1200 mg/day 1, doxorubicin 80 mg/day 1, vincristine 2 mg/day 1, and prednisone 100 mg/day 1-5	The patient developed neutropenia and fever after chemotherapy and then the dose was adjusted
September 2023 to December 2023	R-CHOP chemotherapy rituximab 600 mg/day 1, cyclophosphamide 1000 mg/day 1, pirarubicin 70 mg/day 1, vincristine 2 mg/day 1, and prednisone 100 mg/day 1-5. After second cycle of R-CHOP chemotherapy, CT showed a significant reduction of lymph nodes in the abdominal aorta, bilateral iliac vessels and abdominal compared to before	The therapeutic effect was evaluated as PR
January 2024 to February 2024	In January 2024, the treatment was changed to rituximab 500 mg/day 0, etoposide 0.15 g/day 1-3, ifosfamide 8 g/day 2, carboplatin 0.5 g/day 2. Bone marrow suppression significantly occurred after chemotherapy. In February 2024, the chemotherapy dosage was adjusted to rituximab 600 mg/day 0, etoposide 0.15 g/day 1-2, 0.1 g/day 3, ifosfamide 65 g/day 2, and carboplatin 0.4 g/day 2	The CT in July showed a reduction in the abdominal tumor, and the therapeutic effect was evaluated as PR
April 2024 to August 2024	From April to June 2024, 4 cycles of chemotherapy using a combination of 600 mg zuberitamab and Gemox regimen. The patient developed grade III bone marrow suppression at last chemotherapy. The fifth round of chemotherapy which included 600 mg of zuberitamab and Gemox regimen and lenalidomide starting from July. Targeted combination chemotherapy was administered in August, specifically consisting of rituximab 600 mg/day, gemcitabine 12 g/day, oxaliplatin 120 mg/day q2w, lenalidomide chemotherapy has been used ever since	The therapeutic effect was evaluated as PR
November 2024 until now	Rituximab 600 mg/day, gemcitabine 1 g/day, oxaliplatin 120 mg/day 1 q2w in November 2024. Targeted therapy with zebitumumab 600 mg was be administered in January 2025	The therapeutic effect was evaluated as CR. Currently, the patient's condition remained stable

EC: Epirubicin + cyclophosphamide regimen chemotherapy; PTV: Planning target volume; CR: Complete response; DLBCL: Diffuse large B-cell lymphoma; R-CHOP: Rituximab, cyclophospha-mide, hydroxydaunorubicin, Oncovin (vincristine) and prednisolone; CT: Computed tomography.

OUTCOME AND FOLLOW-UP

In December 2017, the patient underwent a modified radical mastectomy of left breast cancer and the chemotherapy of EC × 4 and T × 4 scheme. There were no signs of tumor recurrence and metastasis and the therapeutic effect was evaluated as CR.

Examination of the proliferative lesions in the lung posterior right upper lobe in August 2018 following radiotherapy and endocrine therapy did not find any signs of tumor recurrence or metastasis and the therapeutic effect was evaluated as CR.

Following the diagnosis of DLBCL in August 2023, which was treated with the R-CHOP regimen chemotherapy, a follow-up abdominal CT after the second cycle of chemotherapy confirmed that the lymph nodes in the abdominal aorta, bilateral iliac vessels and abdominal were significantly resolved compared to earlier tests, and the therapeutic effect was evaluated as PR (Figure 3A-E). Notably, the therapeutic effect was only evaluated as CR at the sixth cycle of chemotherapy. The chemotherapy regimen was adjusted from February to June 2024, and converted to a combination of zuberitamab and gemox regimen which were administered for four courses. The CT examination conducted in July revealed a reduction in the abdominal tumor, and the therapeutic effect was evaluated as PR (Figure 3F-J). The patient received zuberitamab combined with gemox in the fifth stage of chemotherapy and targeted combination chemotherapy in August. The latest examination results shows that lymph nodes adjacent to the abdominal aorta and bilateral iliac vessels and abdominal cavity were significantly reduced (Figure 3K-O). The therapeutic effect was evaluated as CR. Currently, the patient's condition remained stable.

Figure 3 Treatment outcome of diffuse large B-cell lymphoma. A-E: Lymph nodes adjacent to the abdominal aorta (A) and bilateral iliac vessels (B) and abdominal cavity (C-E) were significantly reduced compared to before treatment; F and G: Multiple lymph node shadows can be seen near the abdominal aorta, bilateral iliac vessels, and abdominal cavity, partially fused into clusters; H-J: The abdominal lymph nodes were significantly shrunk and decreased compared to before treatment; K-O: The latest re-examination result shows that lymph nodes adjacent to the abdominal aorta (K) and bilateral iliac vessels (L) and abdominal cavity (M-O) were significantly reduced.

DISCUSSION

Clinically, MPC refers to the existence of two or more different types of primary malignant tumors occurring simultaneously or sequentially in the same patient. Each tumor originates from different tissues and organs and exhibits distinct pathological features, without metastasis or mutually transformation[6]. MPC can be divided into two types: Synchronous MPC and metachronous MPC. Synchronous MPC refers to the occurrence of the second primary cancer simultaneously or successively within 6 months of the first primary cancer. In contrast, metachronous MPC refers to the occurrence of the second primary cancer 6 months after the first primary cancer. The incidence rate of MPC is estimated at 0.73%-11.7%[7]. Most patients with MPC present a poor prognosis and its pathomechanism is not well understood. Several risk factors have been proposed for MPC, including immunodeficiency, viruses (especially EB virus), chemotherapy drugs, insecticides and organic solvents, ultraviolet radiation exposure, family history of lymphoproliferative diseases, and genetic susceptibility[8]. Compared to single cancer patients, MPC has a higher degree of malignancy and a poorer prognosis.

To identify similar cases, we conducted a search on PubMed database using the key words, "breast cancer", "lymphoma" and "multiple primary carcinoma" from 1963 to date. A total of 29 studies were identified, comprising 37 MPC patients with breast cancer and lymphoma (2 males and 35 females). Among them, 6 cases of metachronous MPC were identified (Table 2). All patients with metachronous MPCs were female, 4 with breast cancer as the first primary cancer and NHL as the second primary cancer. However, no DLBCL case was obtained. In the 31 cases synchronous MPC, the first primary cancer was breast cancer (including 2 males and 29 females); the second primary cancer was Hodgkin's lymphoma in 1 patient, NHL in 21 patients and DLBCL in 9 patients (Table 3). The number of patients with metachronous lymphoma with the first primary cancer being breast cancer is small in current literature. Breast cancer patients receiving adjuvant radiotherapy and chemotherapy tend to be susceptible to developing a second type of malignant tumor, including leukemia and NHL[9]. Although it is often considered a coincidence, some evidence suggests a possible pathophysiological relationship between the two tumors, which may involve a common genetic background or cause. It is also speculated that one disease may induce the other disease. Lymphoma is the most common tumor among MPC. Demirci et al[10] analyzed 222 cases of MPC related to lymphoma from 2001 to 2010, and found that the most common malignant tumors that occurred simultaneously or successively with lymphoma were breast cancer and lung cancer. Moreover, the second primary cancers were lymphoma and other hematological tumors, often occurring within 5 years after completion of treatment for the first primary cancer[10]. In this report, the patient was diagnosed with breast cancer (T3N1M0 stage IIIA LuminalB) and did not experience recurrence after treatment. A lymph node biopsy was conducted due to the presence of multiple enlarged lymph nodes in the abdominal cavity following surgery, leading to a diagnosis of DLBCL. Of note, the occurrence of DLBCL as the second primary cancer, appearing at five years and nine months after the initial diagnosis of the primary breast cancer is exceptionally rare in this metachronous MPC case.

Table 2 Reports of metachronous multiple primary carcinoma of breast cancer and non-Hodgkin lymphoma and treatment strategies.

Year	Patient description	Primary carcinoma	Second primary malignancy	Follow up management	Ref.
1983	A 52-year-old premenopausal white woman	Breast carcinoma	Aggressive, large cell lymphoma of the ileum (occur to twelve years after diagnosis and five years after the start of chemotherapy)	Treated for breast carcinoma with postoperative adjuvant chest wall irradiation, followed four and seven years later with therapy to spinal ports for palliation of metastatic disease. For the next three and a half years, she received oral cyclophosphamide on a daily basis to a total of more than 110 g	[12]
1989	A 51-year-old woman	Malignant lymphoma of the breast	Scirrhous carcinoma (two years after the operation)	For primary carcinoma modified radical mastectomy (Patey's method), in combination with chemotherapy (Cyclophosphamide, Vincristine, Prednisolone). for scirrhous carcinoma performed a modified radical mastectomy (Auchincloss' method), followed by chemotherapy (Tegafur)	[13]
1990	A 53-year-old female	Breast cancer (1980)	Malignant lymphoma of diffuse, small cell type (lymphoplasmacytic) (1988)	Radical mastectomy, followed by irradiation was performed in 1980	[14]
2002	A 70-year-old woman	A history of non-Hodgkin’s lymphoma and melanoma	Moderately differentiated infiltrating ductal carcinoma	Underwent a right breast lumpectomy with right axillary lymph node dissection	[15]
2015	A 55-year-old Caucasian woman	Simultaneous ductal carcinoma in situ of the right breast, and follicular lymphoma involving an inguinal lymph node and the left breast	Multifocal ductal carcinoma of the left breast and reappearance of the lymphoma in the left axillary lymph nodes (2 years later)	The patient underwent local excision and radiotherapy for the ductal carcinoma in situ, while a watch and wait strategy was adopted for the lymphoma. Two years later, underwent bilateral mastectomy, left sentinel node biopsy, and chemotherapy	[16]
2021	A 58-year-old woman	Breast cancer	Malignant lymphoma and colon cancer (2 years later)	Maliqnant lymphoma and colon cancer that occurred during breast cancer treatment	[17]

Table 3 Reports of synchronous multiple primary carcinoma of breast cancer and non-Hodgkin lymphoma and treatment strategies.

Year	Patient description	Primary carcinoma	Primary management	Second primary malignancy	Follow up management	Ref.
1998	An 87-year-old woman	Invasive lobular carcinoma of the breasts	Underwent breast conserving surgery with ipsilateral axillary lymph node dissection	Stage IV diffuse large B-cell lymphoma (REAL classification)	3 courses of combination chemotherapy, vincristine, cyclophosphamide, idarubicin and prednisolon (CIOP)	[18]
2004	A 53-year-old woman	Breast cancer	Complete axillary lymph-node dissection	Low grade lymphoma	Not mentioned	[19]
2006	A 63-year-old woman	Invasive, grade 1, ductal carcinoma	Radiotherapy to left breast and was started on tamoxifen. Chemotherapy with four courses of adriamycin, carmustine, cyclophosphamide, and melphalan	B cell lymphoma, with peripheral mantle cells	Chemotherapy with fludarabine and cyclophosphamide	[20]
	A 50-year-old woman	Grade 1 invasive ductal carcinoma	Mastectomy	B cell type non-Hodgkin’s lymphoma, mature, follicular (all follicular, grade 1)	Radiotherapy to the left breast and was started on tamoxifen (20 mg daily). Treated with six courses of chlorambucil and dexamethasone
	A 58-year-old woman	Ductal carcinoma in situ of the comedo type	Left mastectomy	Low grade follicular non-Hodgkin’s lymphoma	No systemic treatment
2008	A 50-year-old female	Infltratingductal carcinoma of mucinous type	Axillary lymph a node dissection. The patient refused further radiotherapy treatment for the breast carcinoma	Non-Hodgkin's lymphoma of axillary lymph nodes	Chemotherapy regimen for CLL (cyclophosphamide 300 mg and prednisolone 30 mg daily)	[21]
2010	74-year-old woman	Multicentric invasive ductal breast carcinoma	Modified radical right mastectomy with level 2 axillary lymph node dissection	SLL	Chemotherapy, radiation, traztuzumab and hormonal therapy	[22]
	74-year-old woman	Invasive lobular breast carcinoma	Wide local excision and sentinel node biopsy	Low-grade B cell lymphoma	6 weeks of adjuvant radiotherapy followed by an aromatase inhibitor
	79-year-old woman	Breast cancer	Modified radical right mastectomy with axillary mass excised in continuity with the whole breast	Classical Hodgkin lymphoma	Local irradiation was chosen as initial treatment
	54-year-old woman	Grade 2, invasive ductal carcinoma	Wide local excision and axillary node dissection	Small lymphocytic B cell lymphoma	The decision was made to treat the lymphoma as a priority; this patient also required radiation treatment to the breast and axilla as well as further chemotherapy for stage IIA breast carcinoma followed by hormonal treatment
2010	A 52-year-old woman	Invasive ductal carcinoma, grade 2 of 3 (moderately differentiated)	Right total mastectomy and right axillary node dissection	Stage 1A follicular lymphoma	An adjuvant chemotherapy regimen, which entailed four cycles of dose dense doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), followed by dose dense paclitaxel	[23]
2011	A 47-year-old female	Ductal car cinoma right breast	Modified radical mastectomy of right breast	B-cell non-Hodgkin lymphoma	Not mentioned	[24]
2012	A 72-year-old Japanese woman	Breast tumor	Surgical resection for the breast tumor	IVLBCL	7 courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) at 3-week intervals	[25]
2014	A 51-year-old woman	Invasive ductal carcinoma (grade III)	Left modified radical mastectomy with ipsilateral axillary lymph node dissection	Diffuse large B-cell lymphoma	Combination of treatment including surgical excision, chemotherapy, and bone marrow transplantation	[26]
2014	A 75-year-old Malay woman	PBLs	Modified radical mastectomy with level II axillary clearance	ILBCL	Rituximab, cyclophospha-mide, hydroxydaunorubicin, Oncovin (vincristine) and prednisolone (R-CHOP) chemotherapy regimen	[27]
2014	A 47-year-old Japanese female	Invasive ductal carcinoma of the right breast	Right mastectomy with sentinel lymph node biopsy and axillary lymph node dissection	Low grade B-cell lymphoma with plasmacytic differentiation	Spontaneous regression of the MALT lymphoma originally	[8]
2014	A 51-year-old woman	Invasive ductal carcinoma of the breast	Left mastectomy, axillary clearance and right lumpectomy	DLBCL	Epirubicin, vincristine, prednisone and cyclophosphamide (CHOP) chemotherapy with rituximab and planned to follow adjuvant endocrine therapy after chemotherapy	[28]
	A 47-year-old woman	Invasive ductal carcinoma of the breast	Right mastectomy and axillary clearance	DLBCL	6-8 cycles of R-CHOP chemotherapy and planned to follow trastuzumab for one year, and adjuvant endocrine therapy after that
2017	A 65-year-old man	Grade II invasive ductal carcinoma (stage IIA)	Modified radical mastectomy	MCL (stage I, group A)	6 courses of CHOP (A chemotherapy protocol consists of cyclophosphamide 12 g day 1, doxorubicin 80 mg day 1, vindesine 4 mg day 1, and prednisone 90 mg from day 1 to 5) for lymphoma and breast cancer. The patient was also administered endocrine therapy	[29]
2018	A 73-year-old female	Breast cancer	Not mentioned	DLBCL	Not mentioned	[30]
2020	An elderly woman	Grade 2 invasive ductal carcinoma with axillary lymphadenopathy	Mastectomy and axillary node dissection	SLL	Not mentioned	[31]
2019	A woman in her early 60	Invasive ductal carcinoma	Multidisciplina-breast radiotherapy	Diffuse large B-Cell lymphoma	3 coures of R-CHOP and 3 courses of R-CEOP	[32]
2021	A 72-year-old female	Invasive lobular carcinoma of the right breast Stage IIIA (pT2pN3cM0)	Right modified radical mastectomy followed by chemotherapy	Right inguinal lymph node + follicular lymphoma Stage 2 (intermediate risk)	The lymphomas were low grade, which the oncologist closely followed	[33]
	A 60-year-old female	Stage IIB (pT2pN2acM0)	Right mastectomy and right axillary LN dissection, followed by adjuvant chemotherapy and radiotherapy	Abdominal mesenteric lymph node + follicular lymphoma Stage 2 (intermediate risk)
	A 74-year-old female	Multifocal Stage IB (pT1CpN2acM0)	Left mastectomy and complete left axillary dissection followed by chemotherapy and radiotherapy	Follicular neoplasia in situ in two of her left dissected axillary LNStage 1 (low risk)
2021	A 78-year-old male	Breast mucinous carcinoma	Modified radical left mastectomy with lymph node dissection for mucinous carcinoma	Diffuse large B-cell lymphoma	Hormonal therapy with tamoxifen and chemotherapy with the R-CHOP protocol (cyclophosphamide, doxorubi cin, vincristine, and prednisone; given every 21 days for 6 cycles) in combination	[34]
2021	A 72-year-old female	T2N1Mx (stage 2) for the breast cancer	The patient underwent courses of CHOP (cyclophosphamide, doxorubicin, vincris-tine, prednisolone) chemotherapy and was planned for surgery	Chronic lympho cytic leukemia/SLL	The patient underwent courses of CHOP (cyclophosphamide, doxorubicin, vincris- tine, prednisolone) chemotherapy and was planned for surgery	[35]
2021	A 78-year-old woman	Breast invasive ductal carcinoma	Wide local excision of the breast mass with sentinel node biopsy	Abdominal DLBCL	R-CHOP regimen (rituximab 375 mg/m2, vincristine 14 mg/m2, doxorubicin 50 mg/m, cyclophosphamide 750 mg/m2, and prednisolone 100 mg orally). The tumor rapidly relapsed, and the patient received rituximab in combination with gemcitabine and vinorelbine chemotherapy (rituximab 375 mg/m2, gemcitabine 880 mg/m2, vinorelbine 25 mg/m2). Radiotherapy was then administered	[2]
2022	A 35-year-old woman	Invasive ductal carcinoma with no special type grade III (i.e., poorly differentiated) in the breast	Modified radical mastectomy for stage IIIA IDC	NHL	Received R-CHOP chemotherapy for stage I NHL	[1]
2022	A 72-year-old female	Infiltrating ductal carcinoma grade III of the right breast	Resection.	NHL, B cell type, high grade	RHCOP for 6 cycles to overcome lymphoma then received hormonal therapy afterwards	[11]
2024	A 54-year-old post-menopausal female	Breast cancer was staged as Stage IIA	Right breast-conserving surgery with axillary lymph node dissection	DLBCL as Stage IE	3 cycles of R-CHOP protocol. Recommended weekly paclitaxel for 12 cycles and trastuzumab and pertuzumab for 1 year. Endocrine treatment will be started once chemotherapy is completed	[3]

R-CHOP: Rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone; DLBCL: Diffuse large B cell lymphoma; RHCOP: Rituximab, cyclophosphamide, epirubicin, vincristin, and prednisone; NHL: Non-Hodgkin Lymphoma; SLL: Small lymphocytic lymphoma; MCL: Mantle cell lymphoma; ILBCL: Intravascular large B-cell lymphoma; MALT: Mucosa-associated lymphoid tissue; PBLs: Primary breast lymphomas; IVLBCL: Intravascular large B-cell lymphoma; CLL: Chronic lymphocytic leukemia.

Currently, the diagnosis of MPC is challenging, especially for patients with solid tumors as the first primary cancer and hematological or lymphatic system tumors as the second primary cancer. This is because patients present with symptoms such as high fever and lymph node enlargement, requiring that clinicians distinguish them from the recurrence of the first primary cancer or other febrile diseases. In this report, the patient was diagnosed with invasive breast cancer during physical examination and she underwent a modified radical mastectomy to treat the left breast cancer. Notably, the patient did not manifest any symptoms before the identification of NHL. A follow-up PET-CT examination performed five years and nine months after surgery revealed multiple soft tissue nodules in the abdominal aorta and right lower abdominal cavity, with mildly increased glucose metabolism and a PET-CT standard uptake value of 2.0, suggesting a high possibility of hematological disease. Lymph node pathological examination confirmed a diagnosis of DLBCL.

Patients with MPC show poor response to treatments and their prognosis is suboptimal. The pathogenesis of breast cancer complicated with lymphoma is proposed to be a result of antigen stimulation of cancer, low immune function of lymphoma patients, virus infection, chromosome abnormalities, living environment and bad personal lifestyle[11]. Recent studies have proposed a shared immunological predisposition which may underlie the co-occurrence of breast cancer and lymphoma, potentially mediated by therapy-induced antigenicity or genetic mutations common to both malignancies. Previously, Albain and Ultmann[12] reported a rare occurrence of ileocecal diffuse histiocytic lymphoma in a patient administered with large doses of an alkylating agent with radiation therapy for breast carcinoma. In the present case, the patient denied a similar family history and genetic history, and there was no industrial poisons, dust, radioactive substances and contact history in his occupation and working conditions; there was no abnormality in laboratory examinations. She received chemotherapy with EC × 4 and T × 4 regimen after the surgery, followed by radiotherapy for the proliferative lesions in the lung posterior right upper lobe followed by tamoxifen and leuprorelin treatment without interruption. Subsequently, she received six cycles of R-CHOP regimen chemotherapy treatment following the detection of DLBCL. However, she showed poor response to treatment and the treatment was converted to a combination of zuberitamab and gemox regimen and targeted chemotherapy as determined by a multidisciplinary team. We believe that it cannot be ruled out that the treatment of breast cancer with radiotherapy and the low immune function of the patient's body are the triggers; due to the high economic cost of genetic testing, the patient has not carried out the test, and it cannot be concluded whether chromosomal factors are the triggers of secondary primary cancer. In future, studies with longer follow-up are needed to determine whether this connection exists. Subsequent reviews performed once a year found no clear signs of tumor recurrence and metastasis and the patient's condition has remained stable. The diagnostic process adopted in the present case highlights the need for a multidisciplinary management team and application of PET-CT to identify the second primary cancer, especially NHL.

CONCLUSION

This case demonstrates that a correct diagnosis and staging, as well as the involvement of interdisciplinary team to determine the optimal treatment plan are crucial for effective management of metachronous MPC.