Section 2 Special Topics

#### **Chapter 9**

## Primary Central Nervous System Lymphoma: Focus on Indian Perspective

*Praful Pandey, Ahitagni Biswas, Saphalta Baghmar, Mukesh Patekar and Ranjit Kumar Sahoo*

#### **Abstract**

Early suspicion, withholding steroids, stereotactic biopsy, and high-dose methotrexate (HD-MTX) are essential for the treatment of primary CNS lymphoma (PCNSL) making its management in lower-middle-income countries (LMIC) challenging. Novel radiological methods, clinician awareness about the disease, and utilization of drugs like thiotepa and ibrutinib which can be given on an outpatient basis may allow better management of these patients in resource-poor settings. Combined with a late presenting demographic, this results in poorer outcomes in the Indian subcontinent as compared to its western counterparts. In this review, we summarize the currently available data on PCNSL in the Indian subcontinent. We also review the current standard of care for PCNSL and present potential modifications or research areas that may potentially improve outcomes in LMIC.

**Keywords:** primary central nervous system lymphoma, PCNSL, lower middle income countries, LMIC, methotrexate, TEDDI, ibrutinib

#### **1. Introduction**

WHO 2016 classification for lymphomas [1] defines primary central nervous system lymphoma as a rare and aggressive form of extranodal diffuse large B-cell lymphoma (DLBCL) involving the brain, leptomeninges, or eyes without any systemic involvement. However, this entity responded poorly to conventional DLBCL regimens [2, 3] despite using radiotherapy or dexamethasone to enhance CNS efficacy. Further evidence supporting PCNSL as a distinct entity comes from studies showing unique GEP signatures [4] and transcriptomics (with heavy reliance on NF-KB) [5] compared to its nodal counterparts.

PCNSL is predominantly a disease of the elderly [6] and presents with focal deficits followed by features of raised intracranial pressure [7]. Initially suspected on MRI, it is typically diagnosed by a stereotactic biopsy or by cerebrospinal fluid evaluation in exceptional circumstances [8]. Modern management is based on HD-MTX based polychemotherapy followed by consolidative therapy in the form of WBRT, standard-dose chemotherapy or high-dose chemotherapy followed by stem cell transplantation. Rituximab addition may improve outcomes [9]. Novel ibrutinib-based combinations are used in relapsed settings and are being evaluated in the frontline settings as well [10].

In the LMIC, the lack of availability of HD-MTX and neurosurgical suites make management of PCNSL difficult. Novel MRI-based sequences, ibrutinib-based regimes, and utilization of consolidative WBRT may ease the burden. This review details the epidemiological, clinical, and radiological features of PCNSL with a focus on the Indian subcontinent. Furthermore, the current standard of therapy and potential modifications for easier delivery in the LMIC is also detailed.

#### **2. Epidemiology**

#### **2.1 Incidence**

Overall, the age-adjusted incidence rate (SEER database) of PCNSL is .47 cases per 10,000,000 people per year [11].

The incidence is increasing in elderly males for unclear reasons. Variations in CD4 subpopulations could be a likely cause [12].

From India, only two studies have reported temporal incidence trends. One study reported a 3.5 increase in the number of cases without any change in the proportion of all CNS neoplasms from 1980 to 2003 [13]. Another study done at a single center in northern India found no temporal variation in incidence [14].

#### **2.2 Place in the lymphoma landscape**

PCNSL accounts for 4% of all primary CNS tumors as per western data [15]. Two Indian studies, however, report a more conservative estimate of 0.92–0.95% [13] and 1.2% [14].

PCNSL is an uncommon NHL accounting for 4–6% of all extranodal lymphomas [11] and less than 1% of all NHLs as per western literature. A study from Southern India reports that PCNSL accounts for 9.6% of all primary extranodal lymphomas and roughly 3% of all NHLs [16].

#### **2.3 Demographics**

**Table 1** contains the demographic details of PCNSL patients recruited in Indian studies.

In Western settings, non-HIV infected PCNSL is typically diagnosed at 45– 65 years of age (median age of diagnosis in the fifth decade) with no gender predilection [6, 17–19]. However, the Indian demographic differs in having a younger affected population (median age at diagnosis ranging from 42 to 59 years) with slight male preponderance [13, 14, 20–31]. These changes are more likely from different population demographics rather than inherent disease biology, given that individuals aged more than 60 or 65 consistently amount to less than 9% and 7% of the total Indian population respectively [32].

HIV-infected individuals are also a younger cohort (Median age: 37 years) with a male preponderance [12].

Among transplant recipients: CNS involvement is present in 15% of all NHL cases [33] and is associated with a poorer prognosis [34]. However, amounting to only 0.9% of all PCNSL cases, this subset is not well studied [12].

#### **2.4 Global vs. Indian burden of HIV in PCNSL**

The prevalence of HIV in PCNSL patients is estimated to be 6.1% globally, with significant variation among nations [35]. Prevalence in India is significantly lesser


#### *Primary Central Nervous System Lymphoma: Focus on Indian Perspective DOI: http://dx.doi.org/10.5772/intechopen.101235*


*Lymphoma*

*Primary Central Nervous System Lymphoma: Focus on Indian Perspective DOI: http://dx.doi.org/10.5772/intechopen.101235*

[35], with some studies not reporting even a single case [14, 25–27, 30]. Similarly, PCNSL accounts for 2.5% of all CNS lesions in HIV-positive patients compared to 10–17% in the western population [36]. Autopsy series show similar findings with the only published Indian series reporting no cases of PCNSL over 8 years [37] while western studies report the share to be between 1.4 and 3% [38, 39]. Shorter survival among AIDS patients in the Indian subcontinent could be the likely cause [40].

#### **3. Clinical features and diagnosis**

#### **3.1 Presenting features**

The most common presenting features reported are focal neurological deficits, neuropsychiatric symptoms, headache from raised intracranial pressure (ICP), seizures, and ocular symptoms [7]. Diagnosis may not be evident at presentation, with one study reporting a median time lag of 70 days from symptom onset to neuroimaging [41]. Personality changes and visual hallucinations are usually detected late, and a lower threshold to pursue neuroimaging is needed [41].

#### **3.2 Clinical evaluation**

Any suspected case of PCNSL should undergo neuroimaging in the form of a contrast-enhanced MRI of the brain and spine, CSF analysis unless contraindicated (ideally before stereotactic biopsy), slit-lamp examination, and testicular examination (in males) [42].

In some cases, pathological evaluation of ocular material or CSF may diagnose. In most cases, however, a stereotactic biopsy is needed [43]. The stark difference in the initial management of PCNSL, compared to high-grade gliomas, underlines the importance of early clinical suspicion and radiological expertise.

#### **3.3 The Indian scenario**

**Table 1** contains the clinical features of patients enrolled in studies in Indian settings.

In the Indian subcontinent, delayed health-seeking behavior combined with high initial misdiagnosis rates leads to a high disease burden at presentation. Median time from symptom onset to diagnosis is reported around 3.5–5 months in Indian studies [20, 24, 29, 44], compared to 2.5–3 months in western studies [7, 41].

Delayed health-seeking behavior is evident if we compare clinicoradiological features at index presentation. While two studies report focal neurological deficits as the most common presenting feature [20, 29], most studies report headache from raised ICP as the index presentation [14, 21–23, 27, 28, 30, 31], which is typically a late feature in the western literature. Furthermore, while most western patients are ambulatory and capable of self-care at presentation [7], roughly 2/3rd of Indian patients are ECOG performance status (ECOG-PS) three or worse in retrospective [22, 25, 29] and prospective [44] studies. Similarly, multifocal lesions, reported in 25% of patients at presentation as per western literature [7], are seen in 30–82% of all patients presenting in the Indian settings [20, 22, 24–29, 31, 44]. However, some studies do give estimates nearing their western counterparts [14, 23, 30], perhaps highlighting differential health-seeking behavior.

Erroneous evaluation and emergent management are also common. Indian studies report misdiagnosis rates as high as 54% [20] to 100% [29], and inadvertent open surgical resection in 36-57% [20, 44] of PCNSL patients compared to 25% in

western literature. In addition, inadvertent steroids are given before diagnosis in up to 2/3rd patients referred from primary care [20] although prospective studies document only 9% requiring corticosteroid therapy for life-threatening indications [44].

These delays and errors result in a patient population with advanced disease and a poorer prognosis. While the proportion of patients with LDH elevation (1/3rd) and CSF Protein elevation (2/3rd) are similar in Indian [22, 25, 28, 29, 31] and western studies [45], fewer patients are IESLG low risk in the Indian settings with concomitant better outcomes [22, 25, 29]. However, the MSKCC risk classification seems to underestimate the risk in the Indian population because of its weightage to older age [28, 31].

#### **4. Treatment modalities and outcomes**

**Table 2** shows treatment details and outcomes of important studies from the Indian subcontinent.

#### **4.1 Survival outcomes**

#### *4.1.1 Evolution of treatment modalities*

Left untreated, PCNSL has a uniformly dismal prognosis (median OS = 2 months) [46]. Only marginally better are conventional DLBCL regimes with response rates ranging from 19 to 59% and less than half patients surviving at two years from diagnosis [2, 3]. A significant improvement in prognosis comes from modern multidrug regimens incorporating high-dose methotrexate (HD-MTX) with appropriate consolidation (2 years OS of 80% and a five-year OS of 77%) [47]. More recent regimes utilizing autologous stem cell transplantation as consolidation report twoyear OS as high as 81% [48].

#### *4.1.2 Outcomes reported in India*

Indian studies report modest outcomes. Up to 20% of PCNSL patients never receive therapy [20, 22, 29]. A single-institution reported a median EFS of 20.4 months and a median OS of 31.7 months at a median follow–up of 34 months with HD-MTX-based multiagent regimes and Rituximab and consolidative WBRT. [20] A prospective phase 2 trial evaluating response adapted radiotherapy showed a median OS of 19 months, underlining the necessity of consolidative WBRT to optimize outcomes [44]. A study evaluating the importance of HD-MTX therapy in the Indian setting [28] reported a median OS of 8 months, 13 months, and 23 months in WBRT, R-CHOP with WBRT, and HD-MTX with WBRT, respectively. Thus, there is a scope for improvement in the outcomes of PCNSL seen in the Indian sub-continent.

#### **4.2 Long term toxicity**

Studies using HD-MTX-based induction and WBRT consolidation report 15% long-term neurotoxicity rates [49]. However, no such delayed sequelae are documented in prospective studies using abbreviated WBRT [50, 51]. On the other hand, regimes using ASCT as consolidation report continuous cognitive improvement until 12–18 months after completion of therapy [48].


#### *Primary Central Nervous System Lymphoma: Focus on Indian Perspective DOI: http://dx.doi.org/10.5772/intechopen.101235*


 *Treatment administered and long term prognosis of PCNSL patients enrolled in Indian studies.*

#### *Lymphoma*

#### *Primary Central Nervous System Lymphoma: Focus on Indian Perspective DOI: http://dx.doi.org/10.5772/intechopen.101235*

In the Indian setting, reliable estimates of long-term neurological toxicity are lacking given that most of the reported literature does not have adequate follow-up or assessment [22, 25–27, 30, 31]. However, limited studies report severe long-term neurotoxicity rates of 10–33%, with elderly patients and WBRT recipients at a higher risk [20, 28, 29].

#### **5. How can we improve?**

PCNSL requires multi-disciplinary care in resource-intense settings to optimize outcomes. However, in lower-middle-income countries (LMIC), the main barriers to applying modern evidence-based management of PCNSL are the lack of neurosurgical facilities and oncology units capable of handling HD-MTX.

#### **5.1 Improving diagnosis**

#### *5.1.1 Better radiological support*

Radiological differential diagnosis of PCNSL includes high-grade gliomas, tumefactive demyelinating lesions, metastasis, and granulomatous diseases/infections. Although, the radiological appearance of PCNSL is very distinctive with homogenous contrast enhancement, optic pathway, and cranial nerve infiltration, a predilection for deeper structures, lesser necrosis, and nearly no bleeding, many studies still report diagnostic difficulties while using conventional MRI only [52]. This differentiation is crucial because while PCNSL requires stereotactic biopsy followed by systemic chemotherapy, high-grade gliomas are usually treated with upfront gross total resection. With 40% of patients responding, prior steroid usage compounds this problem with high false-negative biopsy rates [53]. Thus, early radiological suspicion may allow many patients to undergo appropriate management in the form of no inadvertent steroid therapy, stereotactic biopsy, and early institution of HD-MTX-based therapy.

#### *5.1.2 Conventional MRI sequences*

Diffusion-weighted imaging is an essential diagnostic tool. PCNSL shows more restricted ADC than high-grade gliomas, given its higher cellular density and N: C ratio. However, solid portions of high-grade gliomas may mimic [52]. Therefore, a different measure," Relative minimum ADC," is often used given its reasonable diagnostic certainty [54]. Furthermore, dynamic contrast-enhanced MRI adds to ADC's diagnostic performance as well [55].

Another crucial diagnostic aid is the <sup>1</sup> H-magnetic resonance spectroscopy (<sup>1</sup> H-MRS). Choline to creatine ratio, a marker of membrane turnover, is identical for PCNSL and high-grade gliomas. However, N-acetyl aspartate peaks (NAA), a marker of neuronal damage, may have variable results. The lipid peak arises from necrosis in GBM and release of fatty moieties via lymphocytes in PCNSL, making lipid resonance without necrosis the most specific finding [56]. <sup>1</sup>

H-MRS may allow assessment of other peaks as well. Conventional 1.5 T MRI cannot differentially assess glutamate (Glu) and glutamine (Gln) peaks, and there is no difference in Glutamate + Glutamine/ Creatinine peaks among PCNSL and highgrade gliomas. However, because of impaired Glutamate internalization in highgrade gliomas, glutamate to glutamine conversion is upscaled. Thus, 3 Tesla MRI machines which can differentially quantify glutamate and glutamine, allow

assessment of Glu/Glu + Gln ratios which are reproducibly different in PCNSL and high-grade gliomas [57].

#### *5.1.3 Newer MRI based modalities*

Amide proton transfer weighted studies (based on 3 T MRI machines) also detect endogenous mobile proteins and peptides predominantly seen in the cytoplasm. PCNSL, with its high N:C ratio and thus, a low concentration of mobile proteins, shows much shows limited hyperintensities as compared to heterogenous hyperintensities much larger than the gadolinium-enhancing areas in high grade gliomas [55].

Dynamic susceptibility contrast-enhanced MRI can differentiate based on different tumor microenvironments. PCNSL lacks florid neovascularization compared to high-grade gliomas, as assessed by FVIII staining on resected specimens [58]. Contrast enhancement stems from breakage of the blood-brain barrier rather than increased vascularity resulting in a relatively lower rCBV than high-grade gliomas [59]. Neovascularization of surrounding infiltrated tissue can result in a specific shoulder-like pattern of signal intensity and enhance diagnostic performance [60]. Prospectively validated studies report an rCBV threshold of 2.56 having >90% sensitivity and specificity [54].

#### *5.1.4 Machine learning: better analysis of conventional MRI meta-data*

Fundamental differences of neovascularization and necrosis between PCNSL and high-grade gliomas may lead to subtle differences in imaging, which, although may not be evident to the human eye, are picked by metadata-based machine learning (ML) models. A recent meta-analysis assessing the utility of ML models for PCNSL diagnosis reports 0.878 as the lowest AUC across eight studies [61]. Another prospectively validated model reported an AUC of 0.978 using only T1 weighted images [62]. ML-based algorithms have advantages of being open access, easily accessible, and minimal reliance on novel machines or software. However, overfitting of models compromising external validity and prompting institutespecific algorithms is a challenge.

#### *5.1.5 Metabolic imaging*

Given its high cellular density, PCNSL shows intense homogenous FDG uptake (as opposed to heterogeneous uptake in high-grade gliomas) with SUVmax values around 12–14 (2.5 times of normal gray matter). However, surrounding physiological gray matter uptake hinders accurate assessment [63]. A study assessing the diagnostic utility of PET/CT for PCNSL reported an optimal SUVmax cut-off of 15 with only a single false positive [64]. Another study reported that a SUVmax cut-off of 12 had 86% accuracy as a standalone modality and 95% when combined with CE-MRI with DWI [65].

The tumor/normal (T/N) ratio overcomes the reliance of SUVmax on plasma glucose concentrations. A study reported good diagnostic performance with a cutoff 2.0. Prior Steroids may hinder both SUVmax, as well as T/N ratio [66]. PET/CT has additional utility in ruling out secondary CNS lymphoma and a 7% additional yield over CT and bone marrow examination [67].

#### **5.2 Cerebrospinal fluid analysis**

CSF analysis may allow diagnosis without neurosurgical procedures and its associated complications in up to 40% of patients. Therefore, patients without *Primary Central Nervous System Lymphoma: Focus on Indian Perspective DOI: http://dx.doi.org/10.5772/intechopen.101235*

evidence of raised ICP should undergo CSF analysis with cytomorphology, flowcytometry, and PCR for IGHV rearrangements either before or at least 1 week after the stereotactic biopsy [42].

A recent systematic review of 27 studies evaluating CSF cytomorphology and flow cytometry across different lymphoid neoplasms with meningeal involvement reported around 0.3-42.9% positive results with dual testing. Furthermore, 48% and 89% of studies reported samples positive on cytomorphology or flow cytometry alone, respectively, highlighting the importance of co-testing [68]. Another study assessing only PCNSL patients reported 13.3% and 23.3% positivity rates with CSF cytomorphology and flow cytometry, respectively [69].

CSF cell fragility impairs the diagnostic performance of cytomorphology and flow cytometry. However, PCR-based analysis of IGHV rearrangements to assess clonality does not require intact cells and may circumvent this problem. A study assessing IGHV rearrangement status in CSF among patients with PCNSL reported a sensitivity of 54% and specificity of 97% among the 84% patients having CSF with extractable DNA. The positive predictive value was 93%, with a further rise if only therapy naïve patients were considered [70]. However, a study prospectively evaluating CSF of 282 patients with PCNSL reported 10% samples with positive IGHV rearrangement PCR but negative cytomorphology and 12% samples with positive cytomorphology but negative IGHV rearrangement analysis [71]. Thus, IGHV rearrangement analysis may be better suited as an add-on than a replacement.

Novel approaches such as digital droplet PCR (ddPCR) analysis of MYD88 mutations [72], IL-10 levels [73], Osteopontin levels [74], neopterin levels [75], and miR-21 levels [76] may allow further diagnostic aid and potential negation of neurosurgical procedures in the future. Specifically, a meta-analysis reported that CSF IL-10 levels have a sensitivity of 81%, specificity of 97%, and an area under ROC of 0.95 at a cut-off of 6.88 pg/ml [77].

#### *5.2.1 Slit lamp and intra-ocular biopsy*

Like CSF analysis, Ocular involvement may also allow early diagnosis without reliance on neurosurgical procedures. Ocular involvement is seen in 15–25% of PCNSL patients, and slit-lamp examination is the diagnostic procedure of choice [78]. If involvement is suspected, a biopsy of vitreous fluid, choroid, or retina may allow histopathological diagnosis. Routine use of slit-lamp microscopy and a high index of suspicion is warranted given that more than 1/3rd of patients with ocular involvement are asymptomatic [79]. In cases with equivocal appearances, ocular ultrasound, fundus fluorescein angiography, and optical coherence tomography are adjunctive studies used for diagnosis [80].

Combined cytopathology, flow cytometry, and analysis of IGHV gene arrangement studies on multiple vitrectomy specimens have a combined sensitivity and specificity of 64% and 100%, respectively [81]. A chorioretinal biopsy is an option in suspicious cases with a normal vitreous biopsy [82].

Novel techniques may enhance diagnostic yields. For example, ARMS PCRbased MYD88 L265P mutation analysis is diagnostic in 86.7% FFPE samples of primary vitreoretinal lymphoma [83]. Techniques independent of DNA input such as ddPCR allow similar rates of MYD88 mutation detection from less invasive specimens like aqueous humor [72]. Lastly, elevated IL-10 levels or an IL-10/IL-6 ratio > 1 is suggestive but not diagnostic, and its utility as a standalone modality requires validation [78].

#### **5.3 Improving therapy**

#### *5.3.1 Non-methotrexate containing induction regimes*

High-dose methotrexate-based multiagent chemotherapy followed by consolidation with WBRT or autologous stem cell transplantation is the modern standard of care for PCNSL [42]. However, centers with facilities and experience for HD-MTX are lacking, necessitating the evaluation of alternative regime backbones.

Methotrexate doses of more than 3 g/m2 are needed to cross the BBB and doses as high as 8 g/m<sup>2</sup> have been used without any guiding prospective randomized data. A recent observational study has reported higher CR rates and PFS with higher dose HD-MTX (8 g/m2 ) [84]. An infusion time of 3 hours and 6 hours for doses of 3 g/m2 and 8 g/m<sup>2</sup> respectively allows better CNS penetration per unit dose, allowing enhanced efficacy and an attenuated toxicity profile [85]. 5–7 cycles of HD-MTXbased polychemotherapy spaced at 2 weeks intervals rather than 3-week intervals are associated with optimal oncological outcomes [86]. Leucovorin rescue is typically started 24 h after infusion and at least 12 doses are given at 6-hour intervals [51]. The utility of therapeutic drug monitoring remains to be proven in these settings with a recommendation for assessment at 24 h, 48 h, and 72 h after initial infusion [87].

Thiotepa, a lipid-soluble organophosphorus-derived alkylator, is a potential answer. Evidence suggests that Methotrexate is optimally given in doses more than 3.5 g/m<sup>2</sup> over shorter infusion times (3 h) at a gap of 2–3 weeks for 5–8 cycles [42]. High dose cytarabine (Ara-C) addition to HD-MTX therapy led to more than doubling of responses, likely from prolonged exposure to S-phase cytostatics [88]. Subsequently, the IESLG32 study evaluated Rituximab addition and autologous SCT's utility in PCNSL and added Thiotepa to a third induction arm (MATRIx regime), which outperformed both combination chemotherapy and chemoimmunotherapy arms [9]. Thus, with a 100% plasma-to-cerebrospinal fluid ratio, 30-min infusion time, and synergy with anti-metabolites, Thiotepa might be a convenient alternative to HD-MTX, and the comparative efficacy of Thiotepa-high-dose Ara-C vs. HD-MTX is worth exploring. Notably, a study using high dose Ara-C with Thiotepa after initial HD-MTX showed an increase in responses [89].

Single-agent temozolomide [90], topotecan [91], and temsirolimus [92] have also shown modest activity in relapsed PCNSL settings, and different combinations may be worth evaluating.

Frequent mutations in the BCR subunit CD79B and Toll-like receptor adaptor protein MYD88 suggest addiction of PCNSL to BCR signaling [93], making Ibrutinib an attractive option. However, since Ibrutinib-driven responses in ABC DLBCL last for less than a year [94], cotherapy with blood-brain barrier crossing synergistic drugs is prudent. Recent studies have built on this, and Ibrutinib-based combination regimes are a promising HD-MTX-free approach. While Ibrutinib is antagonistic with most anti-folate drugs, it is synergistic with etoposide, doxorubicin, Ara-C, and mitomycin C [95]. Additionally, doxorubicin, a broad spectrum lymphocytic but BBB impermeable agent, may be given as a liposomal formulation that maintains CSF concentrations throughout therapy duration, likely from a reservoir-like effect [96]. On these lines, the dose-adjusted TEDDi-R regime given after a 14-day run-in of ibrutinib monotherapy showed 86% complete responses in a phase 1b study with 18 patients [97]. Notably, the activity of this regime did not become dependent on the presence of the specific MYD88 L265P mutation. However, severe adverse effects in the form of grade 4 neutropenia, grade 4 thrombocytopenia, and invasive fungal infections (most commonly aspergillosis) were noted in 53%, 30%, and 50%, respectively. These rates of invasive fungal infections

#### *Primary Central Nervous System Lymphoma: Focus on Indian Perspective DOI: http://dx.doi.org/10.5772/intechopen.101235*

are not found in other studies evaluating Ibrutinib (with or without steroids), and monocyte BTK inhibition may be causative [98]. Recognizing the need for prophylaxis, a recent phase 1b trial reported 75% CR rates and no invasive fungal infections with DA-TEDDi R with Isavuconazole prophylaxis [95]. In the Indian settings, concomitant dose reduction of both ibrutinib and liposomal doxorubicin [99] makes Voriconazole prophylaxis an attractive option offering maintained efficacy and reduced financial toxicity.

Lenalidomide may offer a potentially less intensive ibrutinib-based option. Given its capability to expand NK-cell pools, Lenalidomide is known to be synergistic with Rituximab (R<sup>2</sup> -regimen) [100]. A proof-of-concept phase 2 study documented ORR and CR rates of 32% and 29%, respectively, in relapsed/refractory PCNSL with a tolerable safety profile [101]. Building on data from systemic DLBCL, ibrutinib and R<sup>2</sup> (IR<sup>2</sup> ) leads to complete responses in 1/3rd relapsed/ refractory PCNSL cases, and studies testing this regime in frontline settings are eagerly awaited [10].

Intrathecal delivery may enhance synergy between rituximab and lenalidomide. At conventional doses (375 mg/m<sup>2</sup> ), CSF compartment achieves only 0.1% of systemic rituximab concentrations [102]. Evidence suggesting that incorporation of systemic rituximab in lymphoma protocols does not impact the incidence of CNS relapse also points to potential inadequacy of intravenous rituximab in clearing the leptomeningeal compartment [103]. Given the acceptable safety profile of intrathecal rituximab in non-human primates [104], intrathecal rituximab-based combinations deserve consideration for further research. On these lines, a phase 1 study reported 25 mg as the optimal intraventricular dose (via ommaya reservoir) leading to an ORR of 60% and a CR rate of 40% with one parenchymal remission as well [105]. A subsequent study reported a CR rate of 43% in relapsed PCNSL when treated with a combination of intraventricular rituximab and methotrexate [106]. Thus, while intraventricular rituximab is an option with promising efficacy and cost benefits, larger studies are needed. Additionally, the utility of intrathecal rather than intraventricular therapy also requires consideration.

#### *5.3.2 Optimizing consolidation therapy*

More than 50% of PCNSL patients relapse within 5 years of therapy if treated with induction alone, necessitating some form of consolidation therapy [107]. The two largest comparative trials indicate comparable efficacy but lesser long-term neurotoxicity with HDT-ASCT than WBRT [108, 109]. While a longer follow-up may tell a different story [50], upfront HDT-ASCT for all PCNSL patients is not feasible for resource-limited settings.

In Indian settings, WBRT followed by HiDAC [107] remains the most common consolidation therapy. However, while western studies report comparable efficacy and lesser neurotoxicity by reduced dose WBRT [51, 110], studies in the Indian settings in our experience are less favourable [44].

Non-myeloablative chemotherapy may offer a balance of efficacy and cognition. For example, Etoposide-Cytarabine (EA regimen) showed efficacy comparable to historic WBRT treated cohorts in a single-arm phase 2 study. However, lack of randomized comparisons and high rates of grade ¾ hematological toxicity with the possible requirement of autologous stem-cell rescue are barriers to frequent utilization [111].

Maintenance with oral procarbazine, assessed in a phase 2 trial of elderly PCNSL patients, is a safe alternative, although randomized evidence is lacking [112]. Another study showed lesser relapse rates (non-randomized) with oral Temozolomide maintenance than WBRT, although atypical induction protocols

used in this study negatively impact the external validity of findings [113]. Lenalidomide maintenance is also a safe option in elderly patients, although the efficacy in this setting is yet to be proven [114].

### **6. Conclusion**

PCNSL, although morphologically like any other DLBCL, has distinct pathobiology and prognosis. The requirement of early radiological diagnosis and referral to a center equipped with neurosurgical facilities and safe administration of HD-MTX for every patient makes management of PCNSL challenging in resource-limited settings. Non-invasive methods of diagnosis and non-HD-MTX-based therapies need more research to allow PCNSL cases to be managed optimally in such settings.

#### **Author details**

Praful Pandey<sup>1</sup> , Ahitagni Biswas<sup>2</sup> , Saphalta Baghmar<sup>3</sup> , Mukesh Patekar<sup>4</sup> and Ranjit Kumar Sahoo<sup>1</sup> \*

1 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India

2 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India

3 Department of Medical Oncology, Max Vaishali and Noida, India

4 Department of Medical Oncology, Fortis Memorial Research Institute, Haryana, India

\*Address all correspondence to: drranjitmd@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Primary Central Nervous System Lymphoma: Focus on Indian Perspective DOI: http://dx.doi.org/10.5772/intechopen.101235*

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#### **Chapter 10**

## Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): Breast Imaging Perspective

*Fernando Collado-Mesa*

#### **Abstract**

Breast implant-associated anaplastic large cell lymphoma is a rare disease first described in 1997. Since then, its incidence has continued to increase. Current estimated lifetime risk in women with textured breast implants range from 1:1000 to 1:30,000. Most cases present with rapid and dramatic breast swelling resulting from peri-implant fluid collection. Palpable mass, pain, and skin lesions also occur. A high index of suspicion in patients who develop a seroma around the breast implant more than one year after implant placement is required. The combination of clinical history, physical exam findings, and appropriate imaging workup can lead to a timely and accurate diagnosis. The disease has excellent prognosis when it is diagnosed earlier, and complete surgery is performed. Radiologists, particularly those involved in breast imaging, can play an essential role in early diagnosis. This chapter presents an overview of the disease, including relevant imaging findings.

**Keywords:** breast implant-associated anaplastic large cell lymphoma, epidemiology, pathophysiology, diagnosis, treatment, prognosis, mammography, ultrasound, magnetic resonance imaging, fine needle aspiration, needle biopsy, positron emission tomography

#### **1. Introduction**

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare disease first described in 1997 when Keech & Creech published the first case report of anaplastic T-cell lymphoma in proximity to a saline-filled breast implant [1]. Following the initial report, additional case reports and case series of this entity have been published [2–4].

A possible association between breast implants and anaplastic large cell lymphoma was announced by the Food and Drug Administration (FDA) in 2011 [5], and in 2016, the World Health Organization (WHO) added BIA-ALCL as a provisionally recognized lymphoma to the family of existing ALCL [6].

In 2019 the FDA issued a safety communication stating, "all individuals who are considering a breast implant of any type be informed of the risk of developing BIA-ALCL". At the time, most cases of BIA-ALCL were reported to have Allergan's Biocell textured breast implants, thus, following an FDA recommendation, Allergan initiated a worldwide voluntary recall of their breast implant products in July 2019 [7].

The incidence of the disease has continued to increase with current estimates of the absolute risk for development of BIA-ALCL ranging from 1 in 3,817 to 1 in 30,000 [8].

BIA-ALCL is characterized by the development of peri-implant fluid collection that occurs >1 year after breast implant placement, and/or by a solid mass arising within the implant's fibrous capsule [9]. Median time since implant placement at diagnosis is estimated at 8–10 years [9].

Overall, the disease has an excellent prognosis, particularly if diagnosed and fully treated at early stage [10]. It is therefore important to increase awareness about this disease amongst health care providers in general and amongst radiologists and provide them with the relevant information for early diagnosis, referral, and treatment.

#### **2. Etiopathogenesis**

Although the etiology of BIA-ALCL remains poorly understood, there is evidence demonstrating a preponderance of patients with BIA-ALCL to have been exposed to textured breast implants, developed in the 1980s to reduce implant contractures, which in turn provides clues as to the pathogenesis of this condition [11, 12].

Texturing of the implant shell may lead to a greater inflammatory response of the surrounding fibrous tissue capsule eliciting an increased chronic antigenic stimulation, which in turn could potentially be responsible for the development of ALCL [12]. Other potential causes of chronic inflammation which have been postulated include lipopolysaccharide endotoxin, trauma to the breast pocket, viral infection, and allergens [13].

Currently, there is not enough data to determine whether ALCL may be found more or less frequently in individuals with silicone-filled breast implants compared to individuals with saline-filled breast implants [14].

The presence of germline and somatic mutations, which can increase the susceptibility of the host to BIA-ALCL has been postulated as a contributing factor [12].

Recent molecular studies have identified novel, activating mutations in the Janus kinase (JAK), and signal transducer and activator of transcription factor (*STAT3*) pathway as a major risk factor for the development of BIA-ALCL (the presence of germline and somatic mutations, which can increase the susceptibility of the host to BIA-ALCL). Aberrant *STAT3* signaling has been established as a mechanistic link between chronic inflammation in non–BIA-ALCL cancers, including B- and T-cell lymphomas, and amongst the latter systemic anaplastic large cell lymphomas (the presence of germline and somatic mutations, which can increase the susceptibility of the host to BIA-ALCL) and persistent *STAT3* activation has been definitively linked to improved tumor survival and cell proliferation, increased angiogenesis, and tumor metastasis [13].

#### **3. Epidemiology**

Current estimates suggest that each year over 1.8 million people worldwide receive breast implants for cosmetic or reconstructive purposes [15]. In July of 2019 the number of BIA-ALCL reported cases worldwide reached 573, with 320 those cases reported in the US [16]. The estimated lifetime risk of BIA-ALCL in women with textured breast implants range from 1:1,000 to 1:30,000 [17]. A reported

*Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): Breast Imaging… DOI: http://dx.doi.org/10.5772/intechopen.101084*

geographic variation of the risk is likely due to variable reporting and less likely to geographic or genetic predisposition [17].

#### **4. Clinical features**

Mean age at diagnosis is 53.2 ± 12.3 years [17]. Mean interval from implant placement to diagnosis is 10.7 ± 4.6 years [17]. However, this late-onset diagnoses may reflect delayed diagnosis or misdiagnosis.

Patients most commonly present with rapid onset of a spontaneous fluid collection (60–90%) or capsular mass (10–40%) [9]. Approximately 30% of patients report pain, and about 25% present with skin lesions, most commonly erythema, subcutaneous nodules, eruption, erosion, or ulcer [9].

Implant capsule contracture is present in approximately 30% of cases [9]. When this occurs, there is a preponderance of grade III and IV contracture, defined as clinically symptomatic and visible contracture of the implant capsule [18].

BIA-ALCL disseminates locally in a small proportion of cases [19]. When local dissemination takes place it most commonly involves the ipsilateral axillary lymph nodes [19]. The prevalence of lymphadenopathy at diagnosis ranges from 2–14% [19].

Distant disease is uncommon. There are case reports of and distant lymph nodes and bone marrow involvement [19]. Systemic symptoms, such as unexplained weight loss, fever, or night sweats, are also uncommon affecting approximately 8% of patients [19].

#### **5. Radiologic features**

#### **5.1 Mammography**

In general, mammography findings include nonspecific capsular thickening, and circumferential asymmetry around the implant (**Figures 1** and **2**) [19, 20].

#### **Figure 1.**

*63-year-old female with history of saline breast implants with textured surface placed 19 years ago presented with pain and swelling throughout the right breast and a palpable abnormality in the posterior third of the right breast at 7 o'clock for 1 month. Bilateral digital mammogram shows bilateral retro glandular saline breast implants. The right breast is larger than the left and shows a homogeneous and circumferential area of increased density (arrow) surrounding the implant, including the area of palpable abnormality noted by triangular marker in the posterior third of the right breast lower quadrants (source: Collado-Mesa et al. [20]).*

#### **Figure 2.**

*54-year-old female status post left breast mastectomy for DCIS and right breast prophylactic mastectomy, followed by immediate bilateral breast silicone implant with textured surface reconstruction 11 years ago presented with sudden onset of right breast swelling and enlargement with associated discomfort. She denied fever or general symptoms. Bilateral mammogram shows irregular contours of the right breast silicone implant with associated focal-peri-implant increased density (arrows) (source: Collado-Mesa et al. [20]).*

Unlike with primary breast cancer, mammography is not accurate for detection of either peri-implant effusion or mass-forming BIA-ALCL.

Overall, mammography has a lower sensitivity and specificity than both ultrasound and Magnetic Resonance Imaging (MRI) for any abnormality due to BIA-ALCL, at 73% and 50% respectively [21].

#### **5.2 Ultrasound**

Ultrasound (US) is the imaging exam of choice. Findings most commonly include a homogeneous peri implant effusion with inflammatory changes in the periprosthetic breast tissue (**Figures 3** and **4**).

#### **Figure 3.**

*63-year-old female with history of saline breast implants with textured surface placed 19 years ago presented with pain and swelling throughout the right breast and a palpable abnormality in the posterior third of the right breast at 7 o'clock for 1 month. Grey scale ultrasound shows right breast peri-implant fluid collection (arrow) (source: Collado-Mesa et al. [20]).*

*Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): Breast Imaging… DOI: http://dx.doi.org/10.5772/intechopen.101084*

#### **Figure 4.**

*Effusion-only BIA-ALCL in a 55-year-old woman after mastectomy for breast cancer. The initial breast implant was exchanged after 9 years; 7 years later, she experienced sudden new marked implant-associated swelling. Transverse US image shows a large seroma with septa surrounding the intact implant (arrow). US-guided fine-needle aspiration yielded cloudy yellow fluid, cytologic analysis of which demonstrated ALKnegative BIA-ALCL (source: Sharma B et al. [19]).*

When a solid mass is present, it frequently appears as an oval, hypoechoic, circumscribed mass, without hypervascularity (**Figure 5**) [19, 20]. Less frequently, it appears as a complex cystic and solid mass [19, 20].

Some cases may present with abnormal ipsilateral axillary lymph nodes, including the presence of nodal cortical thickening or diffusely hypoechoic without evident fatty hilus.

Amongst the commonly used breast imaging modalities, the highest sensitivity for detection of peri-implant fluid collection is reported for ultrasound (84%) [21]. Ultrasound is also reported to have the highest specificity for detection of solid mass (100%) [21].

#### **Figure 5.**

*63-year-old female with history of saline breast implants with textured surface placed 19 years ago presented with pain and swelling throughout the right breast and a palpable abnormality in the posterior third of the right breast at 7 o'clock for 1 month. Grey scale ultrasound shows a 4 × 1.4 × 2.4 cm mixed echogenicity, oval, partially, indistinct mass (arrow) abutting the fibrous capsule in the right breast at 7 o'clock, 5 cm from the nipple, corresponding to palpable abnormality (source: Collado-Mesa et al. [20]).*

#### **5.3 Magnetic resonance imaging**

Breast Magnetic Resonance Imaging (MRI) is the imaging test of choice after US, and it particularly add value when US results are indeterminate.

MRI findings include peri-implant tissue edema and effusion, as well as periimplant mass lesions, including small-volume mass components not detected with US. Enhancement with intravenous gadolinium contrast material may also help with characterization of some findings (**Figures 6**–**10**) [19, 20].

MRI also serves to evaluate for the presence of implant rupture when there is a silicone implant [19].

MRI is the imaging modality with the second highest sensitivity for periimplant fluid collection at 82% and with the second highest specificity for mass at 93% [21].

#### **Figure 6.**

*63-year-old female with history of saline breast implants with textured surface placed 19 years ago presented with pain and swelling throughout the right breast and a palpable abnormality in the posterior third of the right breast at 7 o'clock for 1 month. Breast MRI axial T2-weighted fat-saturated sequence shows right breast peri-implant fluid collection (arrow) (source: Collado-Mesa et al. [20]).*

#### **Figure 7.**

*63-year-old female with history of saline breast implants with textured surface placed 19 years ago presented with pain and swelling throughout the right breast and a palpable abnormality in the posterior third of the right breast at 7 o'clock for 1 month. Breast MRI axial T1-weighted fat saturated postcontrast subtraction shows a 4 × 1.7 × 2 cm oval heterogeneously enhancing mass (arrow) arising from the fibrous capsule in the right lower outer quadrant (source: Collado-Mesa et al. [20]).*

*Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): Breast Imaging… DOI: http://dx.doi.org/10.5772/intechopen.101084*

#### **Figure 8.**

*Mass forming BIA-ALCL in a 29-year-old woman with a right upper inner breast mass 3 years after bilateral breast augmentation with TRF-520 implants (Allergan). Axial gadolinium enhanced fat-saturated breath-hold volume MR image shows a large implant-associated lobulated mass with a central necrotic area and intense rim enhancement (arrow) infiltrating the pectoralis major muscle and threatening the intercostal muscles. Biopsy demonstrated BIA-ALCL (source: Sharma B et al. [19]).*

#### **Figure 9.**

*BIA-ALCL with chest wall invasion in a 29-year-old woman who underwent bilateral breast augmentation with TRF-520 implants (Allergan) and developed a right upper inner breast lump 3 years after surgery. Axial fast spin-echo T2-weighted image with breath holding 4 months later shows irregular surface of the implant (blue arrow) and rapid enlargement (estimated at 7 cm axially) of the lobulated mass (red arrow), which is characterized by a central necrotic area. Biopsy demonstrated large atypical CD30-positive cells infiltrating the fibrous tissue. The final diagnosis was BIA-ALCL (source: Sharma B et al. [19]).*

#### **Figure 10.**

*BIA-ALCL with chest wall invasion in a 29-year-old woman who underwent bilateral breast augmentation with TRF-520 implants (Allergan) and developed a right upper inner breast lump 3 years after surgery. Sagittal short* τ *inversion-recovery (STIR) image obtained 4 months later shows the mass (arrow) infiltrating the pectoralis major muscle and threatening the intercostal muscles. Biopsy demonstrated large atypical CD30 positive cells infiltrating the fibrous tissue. The final diagnosis was BIA-ALCL (source: Sharma B et al. [19]).*

### **6. Diagnosis and histologic features**

A high index of suspicion of BIA-ALCL is required to allow a timely diagnosis. Breast ultrasound should be obtained in patients with suspicious signs and symptoms such as breast swelling, palpable mass, pain, and skin lesions which have developed more than one year after implant placement (average 8–10 years).

If a peri-implant effusion is noted, then fine needle aspiration of at least 50 ml should be performed [22]. In cases where a peri-implant mass is present, either core needle biopsy or surgical excisional biopsy should be performed [22].

In cases with inconclusive findings on ultrasound, a breast MRI should be obtained [22].

#### **Figure 11.**

*Photomicrograph of ultrasound-guided core needle biopsy samples of solid mass showed in* **Figure 5** *shows most of the cells to be strongly and uniformly positive for CD30 (CD30 immunohistochemistry, ×60) (Source: Collado-Mesa et al. [20]).*

#### **Figure 12.**

*Effusion-only BIA-ALCL in a 55-year-old woman after mastectomy, axillary node dissection, implant reconstruction, chemoradiotherapy, and immunotherapy. After 9 years, the implant was exchanged; 7 years later, sudden new marked swelling of the right breast developed. At US, a large seroma surrounded the intact right breast implant; diagnostic aspirate yielded cloudy yellow fluid, which was ALK-negative at cytologic analysis. Immunohistochemistry slides show that the infiltrate is positive for CD30 (source: Sharma B et al. [19]).*

*Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): Breast Imaging… DOI: http://dx.doi.org/10.5772/intechopen.101084*

#### **Figure 13.**

*Photomicrograph of ultrasound-guided core needle biopsy samples of solid mass showed in* **Figure 5** *shows large and pleomorphic neoplastic cells with irregular nuclei, large prominent nucleoli, conspicuous mitotic activity, and moderate cytoplasm (hematoxylin and eosin [H&E], ×60) (source: Collado-Mesa et al. [20]).*

Samples should be sent for cytology, flow cytometry, immunohistochemistry for CD30 (**Figures 11** and **12**) and additional differentiation markers (CD2 – CD5, CD7, CD8, CD45, and ALK [19, 20, 22].

The presence of large neoplastic cells that have pleomorphic nuclei, abundant eosinophilic cytoplasm, and irregular cell membranes is required for diagnosis (**Figure 13**). Uniform CD30 expression, evidence of a single T-cell clone, and an absence of ALK expression are also observed [22]. Epithelial membrane antigen (EMA) is also often expressed by neoplastic cells [23]. "Hallmark cells" with eccentric kidney or horseshoe-shaped nuclei are not uncommonly seen [23].

If results are indeterminate, a referral to a cancer center is recommended. If results are negative, then it should be treated as a benign seroma. Patients with positive results require a disease workup [22].

#### **7. Staging**

The traditional staging for all lymphoma is the Ann Arbor classification. However, BIA-ALCL is not a classical non-Hodgkin lymphoma and it usually progress locally and/or regionally like a solid tumor; thus, it is better suited to the TNM system for staging solid tumors.


*Lymphoma*


#### **Table 1.**

*TNM stage classification of BIA-ALCL.*

The 2019 update of the National Comprehensive Cancer Network guidelines now include a TNM disease staging system based on clinical and pathological evaluation first proposed in 2016 by MD Anderson Cancer Center and which may be more applicable for predicting a prognosis and for evaluating treatment regimens in patients with BIA-ALCL [22].

In this TNM classification for BIA-ALCL the disease is considered extended (not localized) if there is tumor invasion beyond the fibrous capsule, spread to one or more regional lymph nodes, or spread to any organs/distant sites (**Table 1**).

#### **8. Treatment**

#### **8.1 Surgical treatment**

A surgical oncology consultation is not compulsory but may be beneficial for plastic surgeons unaccustomed to optimal surgical resection of a malignancy.

The goals of surgery are to remove the implant with the surrounding fibrous capsule and any associated capsule mass. Complete surgical excision prolongs both overall survival and event-free survival compared with all other therapeutic interventions [10].

All attempts should be made to gain complete surgical resection because retained or unresectable disease likely indicates the need for adjuvant treatments.

An estimated 2–4% of patients develop bilateral disease, and therefore surgeons may consider removal of the contralateral implant and capsule [10].

Currently, there is no clear role for radical mastectomy or sentinel lymph node biopsy. Full axillary dissection has been used rarely for gross involvement of multiple lymph nodes.

#### **8.2 Adjuvant treatments**

No data from prospective trials is available to guide management of patients with disseminated BIAS-ALCL. Current treatment is based on experiences from treating primary cutaneous and systemic ALCL.

*Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): Breast Imaging… DOI: http://dx.doi.org/10.5772/intechopen.101084*

Radiation therapy with 24–36 Gray (Gy) to the local or involved site is suggested for patients with local residual disease, positive margins, or unresectable disease with chest wall invasion [22].

Systemic therapy for patients with stage IIB-IV disease can be as combination anthracycline based chemotherapy or as a combination with brentuximab vedotin [22].

#### **9. Surveillance and prognosis**

In patients with complete response to treatment, surveillance should include history and physical exam and either a CT chest, abdomen, and pelvis with contrast or a whole-body PET-CT every 6 months for two years and then as clinically indicated (**Figures 14** and **15**) [22].

BIA-ALCL has shown to have an excellent prognosis when the disease is diagnosed earlier (localized disease), and when complete surgery, consisting of explantation, capsulectomy, and removal of any associated capsule mass, is performed [9, 10].

Compared to stage I disease, stage II and stage III disease have a rate of disease events and recurrence which are 2.6-fold higher and 2.7-fold higher respectively [10].

Patients with T1–T3 disease have 0% rate of disease events following complete surgical excision as compared to T4 disease have a 14.3% in patients with T4 disease [10]. Local recurrence is most common if incomplete resection or partial capsulectomy took place [10].

A study of causes of death in patients diagnosed with BIA-ALCL showed that all the patients who died had incomplete surgical excision or did not receive targeted therapy [24]. The study also reported delay in diagnosis or treatment for an average of 1–2 years [24]. Direct extension into the chest wall leading to respiratory failure was a common cause of death [24]. Other less commonly reported causes of death included stem cell transplant complication and development of a second unrelated lymphoma [24].

#### **Figure 14.**

*63-year-old female with history of saline breast implants with textured surface placed 19 years ago presented with pain and swelling throughout the right breast and a palpable abnormality in the posterior third of the right breast at 7 o'clock for 1 month. Screen capture of a whole body 18F-FDG PET/CT shows FDG activity of SUV 10.56, corresponding to a soft tissue mass (arrow) in the lower outer quadrant of the right breast adjacent to the implant measuring 3.2 × 4.8 cm × 2.5 cm (source: Collado-Mesa et al. [20]).*

#### **Figure 15.**

*63-year-old female with history of saline breast implants with textured surface placed 19 years ago presented with pain and swelling throughout the right breast and a palpable abnormality in the posterior third of the right breast at 7 o'clock for 1 month. Screen capture of a whole body 18F-FDG PET/CT obtained 6 months after bilateral breast explantation and total capsulectomy shows no abnormality (source: Collado-Mesa et al. [20]).*

#### **10. Conclusion**

In the absence of infection or trauma, the development of a new peri-implant effusion more than one year after breast implant placement should prompt consideration for the diagnosis of BIA-ALCL As the clinical symptoms are often nonspecific, radiologists, particularly those involved in breast imaging, play an important role in its diagnosis,. While mammography may demonstrate subtle abnormalities, ultrasound and MRI have higher sensitivity and specificity. Diagnosis requires sampling of peri-implant fluid or mass and or lymph node. Suspicion of BIA-ALCL should be communicated to the pathologist, and immunohistochemistry for CD30 ordered. Once diagnosed, oncology referral and multi-specialty team care including plastic surgery and radiation therapy is recommended. Prompt diagnosis and complete treatment appear to lead to excellent prognosis.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): Breast Imaging… DOI: http://dx.doi.org/10.5772/intechopen.101084*

#### **Author details**

Fernando Collado-Mesa University of Miami Miller School of Medicine, Miami, Florida, United States of America

\*Address all correspondence to: fcollado@med.miami.edu

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

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[5] Reports of Anaplastic Large Cell Lymphoma (ALCL) in Women with Breast Implants: FDA Safety Communication. 2011. Available from https://wayback.archive-it. org/7993/20170111070030/http://www. fda.gov/MedicalDevices/Safety/ AlertsandNotices/ucm240000.htm [Accessed: 2021-08-02]

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[7] US Food and Drug Administration. The FDA requests allergan voluntarily recall natrelle biocell textured breast implants and tissue expanders from the market to protect patients: FDA safety

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[10] Clemens MW, Medeiros LJ, Butler CE, et al. Complete surgical excision is essential for the management of patients with breast implantassociated anaplastic large cell lymphoma. Journal of Clinical Oncology. 2016;**34**(2):160-168

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[13] DeCoster RC, Clemens MW, Di Napoli A, Lynch EB, Bonaroti AR, Rinker BD, et al. Cellular and molecular mechanisms of breast implantassociated anaplastic large cell lymphoma. Plastic and Reconstructive Surgery. 2021;**147**(1):30e-41e

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[14] US Food and Drug Administration. Questions and answers about breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). Available from https://www.fda.gov/medical-devices/ breast-implants/questions-and-answersabout-breast-implant-associatedanaplastic-large-cell-lymphoma-bia-alcl [Accessed: 2021-08-02]

[15] International Society of Aesthetic and Plastic Surgery: International Survey on Aesthetic/Cosmetic Procedures performed in 2018. Available from https://www.isaps.org/ wp-content/uploads/2019/12/ISAPS-Global-Survey-Results-2018-new.pdf [Accessed: 2021-08-02]

[16] US Food and Drug Administration. Medical device reports of breast implant-associated anaplastic large cell lymphoma. Available from https://www. fda.gov/medical-devices/breastimplants/medical-device-reports-breastimplant-associated-anaplasticlarge-celllymphoma [Accessed: 2020-02-18]

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[20] Collado-Mesa F, Yepes MM, Net JM, Jorda M. Breast implant-associated anaplastic large cell lymphoma: Brief overview of current data and imaging findings. Breast Disease. 2021;**40**(1): 17-23

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[24] Abi-Rafeh J, Safran T, Al-Halabi B, Dionisopolous T. Death by implants: Critical analysis of the FDA-MAUDE database on breast implant-related mortality. Plastic and Reconstructive Surgery. Global Open. 2019;**7**(12):e2554

### **Chapter 11**

Lymphoma and the Microenvironmental Cross-Talk between Sex Hormone Receptors and Epstein-Barr Virus in Predicting Lymphoma Clinical Status

*Ahed J. Alkhatib*

### **Abstract**

Lymphoma is a significant clinical entity because of its high incidence and complicated etiology and pathology. In this chapter, we discussed lymphoma in general and made focus in our previous studies in which we found unique features linking the interaction of EBV with sex steroid hormones in lymphoma cells. Sex steroid hormones included estrogen receptor and progesterone receptors that were investigated for their expression in malignant lymphoid cells. The localization of EBV in malignant lymphoid cells was also investigated. The two main types of lymphoma, Hodgkin Lymphoma, and non-Hodgkin lymphoma, were investigated for the interaction of EBV with sex steroid hormones. Unique features were obtained in terms of a bridge-linking estrogen receptor with EBV in Hodgkin lymphoma and progesterone receptor with EBV in non-Hodgkin lymphoma. The interactions between EBV and lymphoma are classic, but the reasons beyond this are not well established. The results of our studies highlighted new features by the existence of expressed sex steroid receptors. We think that the dissociation of combination between sex steroid hormones and EBV bears the link to design new therapeutic strategies for lymphoma.

**Keywords:** lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, EBV, estrogen receptor, progesterone receptor

#### **1. Introduction**

#### **1.1 An overview of lymphoma**

Lymphoma is a term used to describe a group of lymphoproliferative malignant disorders that arise from lymphatic T- and B-cells [1]. Lymphoma is a group of malignancies that affect the lymphatic system [2]. The organs, tissues, and veins of the lymphatic system are part of the immune system and are important for battling disease and infection throughout the body [3]. When lymphocytes (the lymphatic

system's white blood cells) become malignant, they proliferate abnormally, forming tumors and squeezing out healthy cells [3].

#### **1.2 Types of lymphoma**

Lymphoma has traditionally been divided into the two types: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). However, it is now recognized that Hodgkin lymphoma is just one of many forms of lymphoma and that non-Hodgkin lymphoma is a largely meaningless phrase that encompasses all the disease's other subtypes [4]. Non-Hodgkin lymphoma is a diverse collection of over 40 lymphoproliferative tumors with varying patterns of behavior and treatment responses [5]. Non-Hodgkin lymphoma has a lower prognosis than Hodgkin lymphoma, and prognosis is determined by histologic type, stage, and treatment [6].

There are over 70 different forms of lymphoma. Some grow slowly (sometimes known as low-grade or indolent), while others grow quickly (referred to as highgrade or aggressive). Lymphoma has no known causes; however, several factors have been linked to an increased chance of having the disease. Hodgkin lymphoma and non-Hodgkin lymphoma are the two types of lymphomas. Hodgkin's lymphoma is a type of cancer that affects the lymphatic system [7, 8].

#### **2. Hodgkin lymphoma**

HL is a type of lymphoma that affects roughly 9000 adults and children in the United States each year. Hodgkin lymphoma can occur anywhere lymphocytes are detected in the body. However, lymph nodes in the chest, neck, and beneath the arms are where it usually starts. HL differs from all other kinds of lymphoma in several ways, the most notable of which is the existence of a cell known as the Reed-Sternberg cell. A Reed-Sternberg cell is a big, unusual cell that does not defend the body against infection. It is called for the two scientists who found it. When it multiplies improperly, it creates a tumor within a lymph node and attracts inflammatory cells. Chemotherapy and/or radiation therapy may be used to treat HL. A stem cell transplant may be considered in some circumstances, particularly if the disease does not respond to early treatment or returns after an initial response [9].

Hodgkin lymphoma is also known as Hodgkin's disease. It usually begins in a type of B cell that is found in the bone marrow. Hodgkin's disease is considered one of the most curable forms of cancer, especially if it is diagnosed and treated early. Several types of treatment can be used against Hodgkin lymphoma, including chemotherapy, immunotherapy, and stem cell transplantation [10]. Hodgkin lymphoma, often known as Hodgkin's disease, is a type of lymphoma. It usually starts in a specific type of B cell located in the bone marrow. Hodgkin's disease is one of the most treatable types of cancer, especially when detected and treated early [11]. Chemotherapy, immunotherapy, and stem cell transplantation are among the treatments available for Hodgkin lymphoma [12]. The presence of big aberrant tumor cells known as Hodgkin Reed-Sternberg cells distinguishes it. Hodgkin lymphoma can affect both children and adults; however, it is most diagnosed in young adults aged 20 to 34. Classic Hodgkin lymphoma and nodular lymphocyte-dominated Hodgkin lymphoma are the two primary subtypes of Hodgkin lymphoma. Classic Hodgkin lymphoma affects more than 90% of Hodgkin lymphoma cases [13].

*Lymphoma and the Microenvironmental Cross-Talk between Sex Hormone Receptors… DOI: http://dx.doi.org/10.5772/intechopen.101055*

Classical Hodgkin lymphoma is divided into five types as follows [14, 15]:


#### **3. Non-Hodgkin lymphoma (NHL)**

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of cancers, with B-cell origin in roughly 80% of cases (B-NHL). The presentation, clinical characteristics, prognosis, and therapeutic response of B-NHL are all different. Diffuse large B-cell lymphoma (DLBCL) is the most frequent histologic subtype, accounting for about a third of cases in the United States, followed by follicular lymphoma, which accounts for about a quarter of occurrences [16]. Other histologies are far less prevalent. Rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone are used to treat about 60% of DLBCL patients (R-CHOP). Most patients who relapse after or are refractory to initial therapy, on the other hand, succumb to their condition. Over the last decade, new therapeutic research has concentrated on molecules that target the cell surface, internal pathways, and the microenvironment, rather than cytotoxic chemotherapy drugs. The chimeric anti-CD20 monoclonal rituximab changed B-NHL therapy, extending survival in the majority of subtypes. However, resistance builds with time, necessitating the use of additional techniques aimed at other targets [17].

#### **3.1 Primary central nervous system lymphoma (PCNSL)**

PCNSL (primary central nervous system lymphoma) is an uncommon extranodal non-Hodgkin lymphoma that is distinct from systemic diffuse large B-cell lymphomas. PCNSL is diagnosed at a median age of 65 years, and its prevalence is quickly increasing among the elderly. A total of 20% of all PCNSL patients are above the age of 80. Age, in particular, has been recognized as a poor prognostic factor for PCNSL. Elderly patients have a worse prognosis than younger patients and are more susceptible to iatrogenic toxicity; as a result, they are a distinct and vulnerable therapeutic class. The goal of this study was to provide a better understanding of the epidemiology, clinical features, diagnosis, prognosis, and therapy of PCNSL in the aged population by summarizing the current research. Notably, PCNSL is becoming more common in immunocompetent elderly patients, particularly men. Imaging guided stereotactic biopsy is the gold standard for the diagnosis of CNSL. Certain biomarkers have been described that can aid establish a diagnosis when stereotactic biopsy is not possible or conclusive. Even though numerous prognostic grading systems exist, and several prognostic markers have been discovered in PCNSL patients, the elderly have a very dismal prognosis. Furthermore, treating older individuals remains difficult; while a novel agent is unlikely to be utilized as a curative monotherapy, a combination of novel medicines with polychemotherapy or with other innovative therapies may have therapeutic potential [18].

#### **3.2 Cutaneous lymphoma**

Primary cutaneous lymphomas are a diverse category of extranodal non-Hodgkin lymphomas that are restricted to the skin at the time of diagnosis [19]. In 2005 [20], the European Organization for Research and Treatment of Cancer (EORTC) and the World Health Organization (WHO) developed a cutaneous lymphoma consensus classification, which was recently updated [21]. Unlike nodal non-Hodgkin lymphoma, which is mostly B-cell originated, about 75% of primary cutaneous lymphomas are T-cell derived, with two-thirds of them being categorized as mycosis fungoides (MF) or Sézary syndrome (SS) [20, 22, 23]. According to the Surveillance, Epidemiology, and End Results (SEER) registry, the incidence of cutaneous T-cell lymphomas (CTCL) has been growing and is now 6.4 per million people, with the greatest incidence rates seen among men and African Americans [23]. When compared to non-Black individuals with MF, there are several major distinctions, including a female predominance, a younger age of onset, and probably worse results [24, 25]. While CTCL can arise in adolescents and young adults, it is a rare occurrence that is generally linked to histopathologic MF variations [26].

#### **4. Lymphoma diagnosis**

Lymphoma is diagnosed primarily through pathologic examination of an acceptable tissue specimen in the right clinical situation, which may include morphologic, immunophenotypic, and cytogenetic studies as needed. Individual lymphomas are treated differently, necessitating an accurate and specific diagnosis to provide appropriate patient care [27]. The choice of biopsy procedure and place is a common practical challenge in patients suspected of having lymphoma. For initial diagnosis, surgical biopsy is preferred because the bigger tissue sample collected enables for investigation of processes that may involve the lymph node or extranodal mass in a variety of ways, as well as immunophenotypic, cytogenetic, and molecular analysis [28]. Fine needle aspiration may not allow for the study of histologic architecture, and it may not yield enough tissue for a thorough analysis, including the determination of biologic subtype [29]. In some cases, fine needle aspiration can confirm relapsed illness, although even in these cases, a core needle or surgical biopsy is preferred [30]. Core needle biopsy may allow for nodal architecture study, but it collects less tissue than surgical biopsy, perhaps missing a heterogeneous process and providing less material for thorough testing. Only in clinical scenarios where a surgical biopsy is not possible, a core needle biopsy is suggested for first diagnosis. Despite the WHO classification's established definitions, an experienced hematopathologist will modify about one-fifth of lymphoma diagnoses, with the rate varied among the different forms of lymphoma [31, 32]. Expert pathology review is recommended and should be regarded standard of care because proper therapy is fundamentally dependent on correct pathologic diagnosis. When the diagnosis of lymphoma is unclear, medical imaging can be helpful in staging, but a definitive diagnosis of lymphoma and determination of the histologic subtype require pathological examination [27]. Though not conclusive, [18F]-fluoro-2 deoxyglucose positron emission tomography (FDG-PET) imaging can identify aggressive from indolent lymphomas based on standard uptake value assessment and can help predict indolent lymphoma transformation (usually DLBCL). When transformation is suspected, PET can be used to choose an acceptable biopsy site where the standard uptake value is the highest and thus, transformation is most likely to be present; however, marked FDG avidity does not rule out transformation and does not eliminate the necessity for diagnostic biopsy [33].

*Lymphoma and the Microenvironmental Cross-Talk between Sex Hormone Receptors… DOI: http://dx.doi.org/10.5772/intechopen.101055*

#### **5. Viruses and lymphoma**

Hepatitis C virus (HCV) is well known for its role in the etiology of chronic non-A, non-B viral hepatitis, liver cirrhosis, and hepatocellular cancer; it has also been linked to a number of extra-hepatic "autoimmune" disease presentations. A causal link between HCV and non-Hodgkin lymphoma (NHL) was proposed just lately, and it has sparked a lot of research and debate. HCV appears to be implicated in the pathogenesis of at least a proportion of patients with NHL, based on epidemiological data, developing scientific investigations, and clinical observations. HCVassociated lymphomas are classified as marginal zone lymphoma (splenic, nodal, and extranodal), small lymphocytic lymphoma/chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, lymphoplasmacytic lymphoma, and diffuse large B-cell lymphoma. Surprisingly, some HCV-associated NHLs appear to respond well to antiviral medication, giving clinical evidence for the link as well as the possibility of innovative therapeutic intervention [34].

Patients with HIV infection have a much higher rate of lymphoma than the normal population. Multiple factors appear to contribute to the increased risk of lymphoma, including the retrovirus's transforming properties, the disease's immunosuppression and cytokine dysregulation, and, most importantly, opportunistic infections with other lymphotrophic herpes viruses such as Epstein-Barr virus and human herpesvirus 8. Lymphomas are classified histologically into three groups: (1) those that occur in immunocompetent people, (2) those that occur more specifically in HIV-positive patients, and (3) those that occur in patients with various types of immunosuppression. The great majority of instances are aggressive lymphomas. They usually present with advanced stage, bulky cancer with a large tumor load and extranodal involvement. Clinical outcomes appear to be worse than those seen in the general population with similar severe lymphomas. The risk of developing lymphoma in the context of HIV infection has decreased, and the clinical result has improved since the advent of highly active antiretroviral therapy [35].

Epstein-Barr virus (EBV) is a common virus that affects over 90% of the world's population [36]. It was discovered to be linked to the development of EBV-associated lymphoproliferative diseases, hemophagocytic lymphohistiocytosis (HLH), and solid tumors, among other things, after being identified as an oncogenic virus in a Burkitt's lymphoma cell line [37]. *In vitro* infection and transformation of quiescent B cells into lymphoblastoid cell lines (LCLs) have proven EBV's carcinogenic potential [36]. The ability of EBV to create a lifelong latent infection in B-lymphoma cells has been established as a key mechanism of EBV-induced lymphomagenesis. During EBV latency, the expression of highly immunogenic proteins is suppressed, while viral lytic proteins are increased, impairing antigen processing by infected cells, and destroying the cellular molecular signaling machinery and metabolism, allowing tumor cells to escape immune surveillance and grow and survive. The most frequent indolent and second most common non-Hodgkin lymphoma subtype is follicular lymphoma (FL) [38]. Follicular lymphoma with EBV is a poorly understood disease that is infrequently reported [39]. Even though Asians have a higher incidence of EBV-associated cancers than Westerners, EBV-positive FL has been observed in the Chinese community on a rare basis. EBV is also the most frequent virus linked to HLH, a rare condition characterized by severe, life-threatening hyperinflammation. The decreased function of cytotoxic T lymphocytes and natural killer (NK) cells is the fundamental pathophysiology of HLH, resulting in uncontrolled immunological activation, hypercytokinemia, and macrophage proliferation. With a fatality rate of up to 50%, EBV-associated HLH is thought to be particularly common in Asia [40]. This may occur prior to, concurrently with, or after EBV-positive lymphoproliferative diseases [40]. T-cell and

NK-cell lymphomas account for the bulk of HLH-related cancers. The majority of B-cell lymphoma associated HLH cases have been observed in Asians [37].

#### **6. Microenvironmental interactions between lymphoma and EBV and sex hormones**

The hypothesis of cross-talks between hormone receptors such as the estrogen receptor (ER) and the progesterone receptor (PR) in breast cancer has recently been revealed to have major effects on breast cancer. Many researches, including ours, have previously proven the associations of Epstein-Barr virus (EBV) with lymphoma. We wanted to see if "EBV cross-talk with sex hormones plays a role in dictating the kind of lymphoma, Hodgkin's Lymphoma (HL) or non-Lymphoma Hodgkin's (NHL)" in this work. In lymphoma patients representing HL and NHL, we looked at the expression of sex hormones, ER, and PR, as well as EBV. The expression of these biomarkers in lymphoma cases was assessed using immunoperoxidase staining. Our data revealed that EBV cross-talk with ER is strongly linked with HL (p < 0.05), but its cross-talk with PR is significantly associated with NHL (p < 0.05). The findings of this study suggest that EBV acts as the conductor of an orchestra, orchestrating the events of lymphoma through various interactions with sex hormones. This could pave the way for novel lymphoma treatment options [41].

Grywalska and Rolinski [42] highlighted in their review study that the Epstein-Barr virus (EBV) has been linked to cancer pathogenesis. EBV is a member of the Herpesviridae family, and through the expression of multiple genes, it has developed ways to maintain the integrity of the viral genome and to escape from the host's immune system during the latent stage of infection. This expression promotes the development of cancers. EBV can infect a wide range of cells, resulting in a variety of diseases, including B-cell lymphoma [43].

Several studies have reported the link between EBV infection and Hodgkin Lymphoma (HL) [42], and the presence of EBV in Hodgkin/Reed-Sternberg (HRS) was confirmed by researchers such as Weiss et al. [44] and Takeuchi et al. [45]. On the other hand, non-Hodgkin Lymphoma (NHL) includes a variety of lymphomas such as Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) [46, 47].

Dolcetti [48] stated in his work that EBV has the power to alter the microenvironment to make it more conducive to cell transformation. EBV can boost the synthesis of a variety of substances that help lymphoid cells grow and/or survive while also allowing them to avoid immune system reactions. There is a complicated interplay between EBV-infected lymphoid cells and the tumor microenvironment that has the therapeutic potential against EBV-driven lymphoid malignancies.

There are few therapeutic alternatives in the treatment of lymphomas caused by EBV that can affect the virus within malignant cells. However, in most instances, no variations in therapy options have been found based on whether EBV is present. As prospective therapeutic methods, existing therapeutic techniques have focused on interfering with biological components of EBV to target lymphomas associated with EBV [49]. EBV-explicit methodologies include reinforcing the antiviral-/antitumorresistant reaction with antibodies or EBV explicit cytotoxic T-lymphocytes, initiating lytic viral qualities to render tumor cells immune to antiviral treatments, and inhibiting downstream prosurvival or antiapoptotic pathways that may be triggered by dormant EBV proteins. EBV-explicit cytotoxic T-cell imbuements have shown to be effective in EBV-related post-transplantation lymphoproliferative disorder (EBVPTLD) and extending such assenting immunotherapies to additional EBVrelated cancers is a hot topic of investigation [49]. Other EBV-related lymphomas, in contrast to EBV-PTLD, have progressively constrained, less immunogenic kinds of

#### *Lymphoma and the Microenvironmental Cross-Talk between Sex Hormone Receptors… DOI: http://dx.doi.org/10.5772/intechopen.101055*

viral antigens to restoratively target with assenting immunotherapy. Furthermore, the threatening EBV-positive tumor cells of HL are dispersed during a thick layer of administrative T-cells, macrophages, and other cells, which may compromise supportive immunotherapy's antitumor efficacy [50]. Continuous preclinical and clinical assessments are areas of continuous methodology to overcome these impediments. Some emerging approaches to treating EBV-related lymphomas include combining specialists that trigger lytic viral replication with anti-herpes virus operators or using small particle inhibitors to block deterioration pathways that are constitutively triggered by EBV. EBV antibodies appear to be generally promising for the treatment or prevention of EBV-related cancers, as opposed to required EBV contamination avoidance [51]. Preliminary EBV vaccination trials in patients with residual or low-mass EBV-related malignancies, or for the counteractive effect of EBV-PTLD in EBV-seronegative patients awaiting strong organ transplantation, are moving forward [52]. In many cases, the treatment of EBV-positive lymphomas is identical to that of EBV-negative lymphomas with similar histologies [53]. Special cases include experimental conventions and situations where a responsive immunotherapy method is available [54, 55]. When EBV-positive lymphomas appear in the context of immunosuppression, boosting the invulnerable deformities can help with lymphoma treatment [56, 57]. Antiretroviral treatment is routinely used in HIV-related lymphomas, but potential pharmaceutical interactions and the effects of chemotherapy on the ability to maintain HAART treatment in terms of sickness, heaving, and mucositis must be considered when antiretroviral treatment is planned [58, 59]. In any case, antiretroviral therapy alone is insufficient for the treatment of EBV-related lymphomas in HIV patients. This contrasts with AIDSrelated Kaposi sarcoma, where initiating antiretroviral medication in patients who are asymptomatic or insignificantly symptomatic and antiretrovirally innocent is frequently a regular practice [60, 61]. Select instances with EBV-PTLD may benefit from immunosuppressive reduction as a stand-alone treatment or as part of a therapeutic plan [62, 63]. The therapeutic choices for lymphomas associated with EBV are like those for lymphomas that are EBV-negative. Existing therapy methods, on the other hand, include addressing biological elements of EBV and may require further research to be firmly established.

#### **7. Conclusions**

This study showed that new therapeutic strategies are of great potential based on the interactions of EBV, lymphoid malignant cells, and sex steroid hormones, ER or PR. Our studies showed interesting features by identifying the impacts of interaction of progesterone receptors with EBV leading to the development of NHL, while the interaction of EBV with ER led to the development of HL. These features are unique and give the bases of designing new therapeutic lines that inhibit the binding of EBV with sex steroid hormones to participate in lowering the incidence of lymphoma.

*Lymphoma*

#### **Author details**

Ahed J. Alkhatib1,2

1 Department of Legal Medicine, Toxicology and Forensic Medicine, Jordan University of Science and Technology, Jordan

2 International Mariinskaya Academy, Department of Medicine and Critical Care, Department of Philosophy, Academician Secretary of Department of Sociology, Jordan

\*Address all correspondence to: ajalkhatib@just.edu.jo; drahedalkatib@yahoo.com; ahed.alkhatib64@yahoo.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Lymphoma and the Microenvironmental Cross-Talk between Sex Hormone Receptors… DOI: http://dx.doi.org/10.5772/intechopen.101055*

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## *Edited by Yusuf Tutar*

Lymphoma is a group of malignant diseases caused by the clonal proliferation of lymphocytes. Current treatment options include chemotherapy, radiotherapy, and bone marrow/stem cell transplantation. Development of new treatment options for cancer medications include small molecules and monoclonal antibodies for immunotherapy. In addition, the discovery of new phytochemical agents used in complementary and alternative medicine adds perspective to the treatment of lymphoma. This book highlights recent developments in the treatment of lymphoma. Chapters discuss different types of lymphomas, such as follicular lymphoma, gastrointestinal lymphoma, splenic B-cell lymphoma, and others, as well as the available treatment options for each.

Published in London, UK © 2022 IntechOpen © Dr\_Microbe / iStock

Lymphoma

Lymphoma

*Edited by Yusuf Tutar*