Complete response of extramedullary relapse in breast of acute T lymphoblastic leukemia after bone marrow transplantation to chemoradiotherapy: a case report and literature review

Background Relapse of acute lymphoblastic leukemia (ALL) occurring in the breast after allografting is extremely rare, with only 22 reported cases in the literature thus far. Further, the lack of a systemic analysis provides little information about this entity. We present a case of isolated extramedullary relapse from acute T lymphoblastic leukemia (ATLL) after allogeneic hematopoietic stem cell transplantation (HSCT). Case presentation A 32-year-old Chinese woman diagnosed with ATLL with myeloid antigen expression received HSCT from her human leukocyte antigen (HLA)-matched sister and presented with two lesions in her right breast 6 months later. Pathology investigation revealed breast relapse, with complete remission on the basis of bone marrow findings. Combined modality treatment including chemotherapy and local radiotherapy helped achieve complete remission with mild side effects. Conclusion The findings from this case indicate that the breast is a potentially involved extramedullary site of relapse for ALL patients after HSCT. In the case of a newly developed breast lump in such patients, clinicians consider local relapse even if the bone marrow findings indicate remission. Combined modality treatment will contribute to better local control and improve prognosis.


Background
Relapse of acute lymphoblastic leukemia (ALL) occurring in the breast after allografting is extremely rare, with only 22 reported cases in the literature thus far [1][2][3][4][5][6][7][8]. Isolated extramedullary relapse (IEMR) in the so-called sanctuary sites after hematopoietic stem cell transplantation (HSCT) is rarely encountered in clinical practice, especially in the breast [4]. Given the paucity of data surrounding this phenomenon, the optimal treatment for relapse of ALL in the breast has not been identified yet. Systemic chemotherapy is generally used. Herein, we describe a rather rare case of IEMR in the breast after HSCT for acute T lymphoblastic leukemia (ATLL) in which combined modality treatment contribute to better local control and improve prognosis.
Six months after HSCT, the patient complained of a hard lump in the inner upper quadrant of the right breast.  nelarabine (1500 mg/m 2 , 2310 mg d1, 3, 5, q28d) and one cycle of chemotherapy with VCP (vincristine, cyclophosphamide, and prednisone) -VP (vincristine, and prednisone) -VCP -VP, the large lump shrank to 15.6 mm × 5.5 mm. However, the small nodule showed no changes and caused pain. Positron emission tomography-computed tomography (PET/CT) demonstrated a moderately FDG (fluorodeoxyglucose) -avid nodule (standardized uptake value: 4.6) in the outer upper quadrant of the right breast and no focal uptake in the other sites (Fig. 3). Subsequently, the patient underwent simple intensity-modulated radiotherapy (sIMRT). The whole right breast received a dose of 40 Gy/2 Gy/20 f with a concurrent dose of 50 Gy/2.5 Gy/20 f (Fig. 4) to the FDG -avid lump in the outer upper quadrant. The dose volume histogram showed excellent dose coverage to the target volume and minimal dose to the surrounding normal tissue (Fig. 5). After irradiation of 14 f, the patient did not experience pain, and the lump in the outer upper quadrant disappeared. Furthermore, intensive evaluation of the bone marrow including cytologic, flow cytometry, and molecular examination revealed CR. The postradiotherapy breast ultrasound also confirmed that the FDG -avid lump disappeared. Thus, radiotherapy resulted in CR with mild related side effects. Thereafter, the patient received four cycles of chemotherapy with decitabine (25 mg d1-5, q28d). The last evaluation of the bone marrow, conducted 18 months after HSCT, indicated CR (Fig. 6). The breast ultrasound conducted on April, 2016, 1 year after radiotherapy, still demonstrated CR.

Discussion
The most common sites of extramedullary relapse (EMR) from ALL are the testis and central nervous system [9]. IEMR of the breast in ALL after allogeneic HSCT is extremely rare. According to the reports by Bekassy et al. [10], the incidence of breast relapse after HSCT in leukemia was 0.09 %. IEMR in the breast usually manifests as bilateral multiple nodules without specific radiologic  [7]. In our case, involvement of only the right breast was an uncommon finding.
The most essential explanation is the protective graftversus-leukemia effect on the bone marrow [11]. However, for extramedullary sites such as the central nervous system and testis, the effect of chemotherapy is compromised owing to the blood-brain or -testis barrier.
Besides, allogeneic T cells can hardly reach these locations [12]. Philadelphia positive ALL is considered a high-risk indicator of relapse and dismal prognosis [7]. Horowitz et al. pointed out that the presence of GVHD was associated with a relatively lower risk of relapse in ALL after allogeneic HSCT [13]. Our patient did not develop GVHD, partially illustrating the occurrence of breast IEMR.  Additionally, individuals who developed EMR before HSCT had a much higher risk of relapse in extramedullary site [14,15]. Another explanation for IEMR is that blast cells have a high affinity to extramedullary locations because of specific adhesion molecules or receptors [6].
PET/CT was valuable in detecting EMR after HSCT even in uncommon sites [16]. In terms of a sensitive, whole-body imaging modality, PET/CT was helpful in accurate staging and evaluation of leukemia burden. As described in our case, PET/CT demonstrated that the larger lesion disappeared after chemotherapy, while the smaller one was still FDG -avid. Therefore, further intervention should be initiated to improve local control. The application of PET/CT is encouraged in cases of EMR after HSCT for accurate disease staging, delineating treatment strategies, and response evaluation.
SET-CAN fusion gene was first described in 1992 by von Lindern M et al. [17,18] in a case of acute undifferentiated leukemia. SET-CAN positivity generally indicates resistance to chemotherapy, especially to high dose of glucocorticoids [19]. Van Vlierberghe P et al. pointed out SET-CAN boosted the progression of ATLL by activation of HOXA and inhibition of T cell differentiation [20]. Besides, SET-CAN is a valuable index in the minimal residual disease (MRD) monitoring for its high sensitivity. SET-CAN was positive at first visit in our patient and turned to negative when she suffered breast relapse, indicating that the bone marrow was CR and the breast relapse was EMR. In comparison with its B-lineage ALL counterpart, IEMR in the breast in ATLL after HSCT is exceedingly rare. Howrey et al. described the case of a 15-year-old girl who received an umbilical cord blood transplant for refractory, relapsed T-cell ALL, and developed breast IEMR on day +373 after transplantation. Despite local radiotherapy to the breast mass, bone marrow relapse occurred over the next several weeks and the patient eventually died of progressive disease on day 140 after breast IEMR [21]. Firas et al. described the case of a 27year-old woman with common T-ALL with a normal karyotype who developed IEMR in the left breast and left axillary lymph nodes on day +345 after allogeneic HSCT. Local radiotherapy helped achieve CR. However, on day +519 after HSCT, she experienced myocardial infiltration, and subsequent systemic chemotherapy induced CR. On day +707 after HSCT, relapse in the kidneys and bone marrow occurred. The patient died shortly thereafter [2]. In our patient, the HSCT was effective (CR at least 18 months after HSCT). However, long-term surveillance should be performed to monitor treatment outcomes.
Even though patients with EMR due to leukemia after allogeneic HSCT usually demonstrate a dismal prognosis, frequently followed by multiple relapses, they tend to show long-term survival [10,15]. The optimal treatment remains uncertain owing to the rarity of IEMR after HSCT and the lack of large-scale retrospective studies [2]. Multiple factors such as the interval between IEMR and HSCT, patient age, performance status, and prior treatment strategy must be taken into consideration before a definite therapeutic algorithm is established [10,15,22,23]. In the published cases, cases of IEMR in the breast demonstrated varying sensitivity to radiotherapy. In the study by Fadilah et al., a patient with B-precursor ALL presented with bilateral breast and ovarian recurrence on day +172 after HSCT. Radiotherapy of 40 Gy to the breasts resulted in only partial remission. Subsequent chemotherapy with mitoxantrone, cytosine, and arabinoside and infusion of donor lymphocytes contributed to CR. Moreover, multidisciplinary intervention achieved at least 10 months of disease-free survival [5]. However, in the case presented by Conter et al., the breast IEMR showed strong radiosensitivity at 30 Gy/15 f plus mild chemotherapy, which brought about rapid disappearance of the tumor [24]. In the case described by Firas et al., 12 fractions of radiotherapy to the 10 cm tumor in the left breast and 3 cm left axillary lymph node helped achieve CR [2]. Radiotherapy might play an essential role in local control of breast IEMR. One study reported that the lack of radiotherapy at the first relapse in the right breast in a patient with ALL following allogeneic HSCT resulted in a second relapse in the same breast [25]. In our case, the two lesions in the right breast showed great heterogeneity. The larger one responded to chemotherapy well while the smaller one did not. The smaller lesion was resistant to chemotherapy but radiosensitive. This heterogeneity emphasized the importance of combined modality treatment in the elimination of leukemia cells to the greatest extent.

Conclusions
The breast is a potentially involved site of relapse for ALL patients after HSCT even without evidence of bone marrow recurrence. For newly developed breast lumps in ALL individuals after HSCT, we should consider the possibility of local relapse despite bone marrow remission. Close follow-up is critical because early detection of tumor progression and timely intervention can guarantee a better prognosis. This case is novel in that it is rare and because it illustrates the value of PET/CT in disease evaluation and determining the best intervention. In future, multicentric clinical trials should be conducted to establish a consensus regarding this unique disease.