Blastoid Mantle Cell Lymphoma of the Palate: Report of a Rare Aggressive Entity and Review of the Literature

Abstract

Mantle cell lymphoma (MCL) is a well-defined, non-Hodgkin lymphoma of B-cell origin displaying diverse morphological phenotypes and variable disease course. The World Health Organization recognizes two aggressive histopathologic variants of this type of lymphoma: pleomorphic and blastoid MCL. To date, only few cases of MCL affecting the oral cavity have been reported. Additionally, the involvement of the oral and maxillofacial area by aggressive MCL subsets is considered extremely rare with only two patients reported in the English language literature to the best of our knowledge. Herein, we describe a 69 year-old male with a prior history of MCL of the right lateral pharyngeal wall developing a recurrent lesion extending to the palatal mucosa as diffuse ulceration and exhibiting histomorphological features of blastoid MCL. We also review the pertinent literature with emphasis on the diagnostic challenges and distinction between the different MCL variants.

Introduction

Lymphomas are a heterogeneous group of malignancies characterized by irregular proliferation of neoplastic cells carrying a phenotype of B-lymphocytes, T-lymphocytes or natural killer cells [1, 2]. Mantle Cell Lymphoma (MCL) is a rare, mature B-cell lymphoma firstly described in 1992 by Banks et al. and was adopted by the World Health Organization (WHO) in 2001 [1, 3–5]. It represents 3–10% of all non-Hodgkin lymphoma (NHL) cases [5], while its overall incidence (per 100,000) ranges between 0.50 and 1.0 [6, 7]. It most commonly involves male patients in their 7th decade of life [5, 6].

The cornerstone in MCL molecular pathogenesis is the genetic translocation t(11;14)(q13;q32) between immunoglobulin heavy chain (IGH) and CCND1 genes. The later encodes cyclin D1, which is well-known for participating in the cyclin D1–CDK4/6 complex, a cell-cycle promoter that induces pro-tumorigenic effects [5, 8]. However, evidence from previous studies suggests that the expression of CCND1 is not sufficient for the development of MCL and other genetic abnormalities take place [5, 8, 9].

MCL usually affects the lymph nodes, with the spleen and bone marrow being other significant sites of the disease [3, 5]. The gastrointestinal tract, lung, pleura and central nervous system (CNS) are also frequently affected [5], while, in the head and neck region, the Waldeyer ring is the most common extranodal site of involvement. Even though the development of MCL within the oral cavity is considered rare, several cases have been reported extending from the oropharyngeal area [10] or involving primarily the oral mucosa [11].

Conventional MCL is a monomorphic lymphoid proliferation composed by small- to medium-sized CD20(+), CD5(+), Cyclin D1(+) and CD23(−) cells with a centrocytic morphology displaying irregular nuclear contours, dispersed chromatin and inconspicuous nucleoli [5, 12]. Cells with morphological features of centroblasts, immunoblasts, paraimmunoblasts or transformed neoplastic cells are typically absent. Reactive bystander cells including epithelioid macrophages, T cells and follicular dendritic cells are occasionally present, while plasmacytic differentiation is considered uncommon in these neoplasms [5, 12, 13]. Architecturally, the diffuse pattern is most commonly encountered followed by the nodular, while the mantle zone arrangement, is rarely noticed solely and may complement the other growth patterns [5]. The tumor microenvironment is typically supported by hyalinized vessels.

Besides the classical MCL, several variants or disease subsets have been reported in the literature exhibiting specific morphological features and biological behavior, such as small cell variant (mimicking small lymphocytic lymphoma), marginal zone-like MCL (resembling marginal zone lymphoma), and in situ mantle cell neoplasia (associated with indolent course but rarely progressing to conventional MCL) [1, 4, 5]. Further, aggressive variants have been recognized, including blastoid and pleomorphic MCL [5, 12, 14]. To this date, the occurrence of these morphological variants of MCL in the oral cavity is considered extremely uncommon. Herein, we report a case of MCL relapse in the oral cavity exhibiting microscopic features of the blastoid variant. We also review all the reported cases of MCL affecting the oral mucosa and emphasize the diagnostic challenges associated with specific disease subsets.

Case Report

A 69 year-old Caucasian male was referred by the First Propaedeutic Department of Internal Medicine, School of Medicine to the Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian University of Athens, for evaluation of dysphagia and oropharyngeal pain of 20 days duration. The patient had also noticed an erythematous region nearby the uvula. No other symptoms were mentioned.

Medical history was significant for MCL stage IEA of the right lateral pharyngeal wall diagnosed 8 years before admission. Following 6 circles of R-CHOP chemotherapy and local radiotherapy, the patient was on regular follow-up by his hematologists-oncologists and had remained under full remission for approximately 6 years. Subsequently (two years prior to visit in the Oral Medicine Clinic), he developed two subcutaneous masses, one in the right upper arm measuring 5.6 × 2.8 × 5.3 cm and the other affecting the skin overlying the right mandible. Biopsy from both lesions was consistent with disease relapse and the patient underwent four cycles of R-COP chemotherapy followed by Hyper-CVAD/MTX-Ara-C regimen in addition to radiotherapy in both anatomic locations. Approximately two months after completion of this treatment, the patient displayed gradual deterioration of the disease with involvement of the left arm and the nasopharynx and developed hearing loss and breathing difficulties for which he was managed with monthly pulses of corticosteroids over the last 9 months. Temsirolimus was also initiated 1 month prior to the current visit.

Clinical examination revealed a depressed ulcerated area of 3 cm diameter, with slightly elevated erythematous margins, located on the left side of the soft palate and extending anteriorly to the hard palate and posteriorly to the uvula and left glossopalatine arch (Fig. 1). Computed tomography showed a mass in the left lateral oropharyngeal wall extending into the soft palate. Based on the clinical and radiographic examination, as well as patient’s medical history, a provisional diagnosis of MCL relapse was made.

Fig. 1.

Clinical examination revealed a large ulceration located on the left hard and soft palate, extending posteriorly to the uvula and left glossopalatine arch

An incisional biopsy of the palatal ulcerated lesion was performed (Fig. 2) and microscopic examination revealed a vaguely nodular and mostly diffuse proliferation of a medium-sized lymphocytic population extensively infiltrating the adjacent tissues. The neoplastic cells displayed a uniform lymphoblastic appearance with pale staining nuclei, inconspicuous cytoplasm and increased mitotic activity (> 30 mitoses/10 high-power fields). Foci of crash artifacts were also noticed. Finally, significant amounts of tingible body macrophages were observed, in addition to hyalinization of the blood vessels (Fig. 3a–e). Immunohistochemical evaluation was performed, disclosing diffuse positivity of the neoplastic cells for CD20, CD5 and Cyclin D1 (Fig. 4a–c). A diagnosis of MCL relapse with morphological features consistent with blastoid variant was rendered and the patient was referred to his hematologists-oncologists for further management. The patient was treated with ibrutinib resulting into remission in the affected sites. Three years later a new relapse was reported with involvement of the nasopharyngeal wall. New histopathologic examination of the affected area showed similar morphologic findings with the previous oral biopsy and immunohistochemical evaluation revealed diffuse positivity of the neoplastic cells for CD20, Bcl-2, Cyclin D1 and high expression of Ki-67 (> 50%), supporting the previous diagnosis of aggressive (blastoid) MCL (Fig. 5a, b). Additionally, Bcl-6, CD10 and MUM-1 were negative, while CD21 showed a weak positivity. The patient was subsequently lost to follow-up.

Fig. 2.

Macroscopic examination of the incisional biopsy specimen showing a tan soft tissue of 1.2 cm maximum diameter

Fig. 3.

Histopathologic findings (H&E; original magnification: ×200): a Oral mucosa specimen with surface ulceration infiltrated by a diffuse or vaguely nodular neoplastic proliferation; b Medium-sized and pale-staining cells with morphological characteristics of lymphocytes and scattered tangible-body macrophages in a stroma exhibiting vascular hyalinization. c Crash artifacts were also noticed. d Monomorphic oval shaped lymphocytes with finely dispersed chromatin intermixed with tangible-body macrophages. e High power view highlighting the cytological characteristics of the neoplastic population which exhibits an overall lymphoblastic appearance with increased mitotic activity. Perivascular hyalinization of a blood vessel is also noticed

Fig. 4.

Immunohistochemical evaluation (original magnification: ×200): Diffuse immunoreactivity of the neoplastic cells for CD20 (a), CD5 (b) and CCND1 (c)

Fig. 5.

Histopathologic findings of the new relapsed tumor in nasopharynx (original magnification: ×200): a Neoplastic proliferation of medium-sized lymphoid cells with blastoid features (H&E); b Immunohistochemical evaluation of Ki-67 showing > 50% immunopositivity

Discussion

To this date, few cases of MCL affecting the oral mucosa have been reported. A search in the “PubMed” and “Google Scholar” electronic databases about English language reports of oral MCL was conducted. Additional data were collected from the references of the publications retrieved. Cases with lack of sufficient information were excluded. Only lymphomas affecting the oral cavity were included and MCLs with exclusive involvement of the oropharynx (e.g. base of tongue, palatine tonsils, soft palate) were omitted. Additionally, cases that have been reported before the official recognition of MCL (2001) were also not included. To our knowledge, only 23 cases of oral MCL, including ours, have been published so far [10, 11, 15–28]. Table 1 summarizes the reported cases according to patients’ demographic characteristics, clinical and radiographic features, type of treatment and outcome. Table 2 presents the histopathologic subtype and the immunohistochemical and cytogenetic profile of these cases.

Table 1.

Demographic, clinical and radiographic characteristics, treatment and outcome of oral MCL cases reported in the English language literature

Authors/year	# of cases	Age/gender	Type	Symptoms	Clinical features	Site	Radiographic findings	Treatment	Outcome (follow-up)
Chuang et al. (2003) [15]	1	62/F	Primary	Sore throat	Swelling	Hard Palate	N.M	CT (R-CHOP)	NED (6 mos)
Kolokotronis et al. (2005) [16]	1	84/M	Primary	N.M	N.M	Hard Palate	N.M	CT (N.M.)	DOD (17 mos)
Tan et al. (2006) [17]	1	74/M	Relapse	N.M	Mass	Hard Palate	N.M	CT (R-DHAP)	DOD (18 mos from palatal relapse)
Rockacy et al. (2007) [18]	1	72/F	Primary	None	Mass	Floor of the Mouth	Plain film radiographs: non-significant findings	Observation	NED (12 mos)
Guastafierro et al. (2008) [19]	1	62/F	Primary	None	Mass	Tongue	MRI: mass on the right side of the tongue	CT (R-CEOP + Rituximab maintenance)	NED (53 mos)
Guggisberg and Jordan (2010) [20]	2	67/M	Primary	None	Mass	Palate	N.M	Declined	Alive with disease (24 mos)
		87/M	Primary	None	Mass	Palate	N.M	CT (N.M.)	DOD (8 mos)
Kyo et al. (2010) [21]	1	71/M	Primary	Unstable dentures	Swelling	Hard Palate and Oropharynx	MRI: palatine mass PET-CT: marked accumulation in palatal lesion, lymph nodes of the mediastinum and abdominal para-aortic region	CT (RCHOP)	N.M
Scheller et al. (2011) [22]	1	41/M	Primary	None	Swelling	Hard Palate	N.M	CT/RT	NED (48 mos)
Fitzpatrick et al. (2012) [11]	4	57/M	Primary	None	Swelling	Hard Palate	Various imaging studies of the head and neck (not specified): non-significant findings	CT (RCHOP)	NED (unknown)
		67/F	Relapse	None	Mass	Hard Palate	N.M	RT	NED (> 24 mos from palatal relapse)
		93/M	Primary	None	Mass	Hard Palate	N.M	N.M	NSF
		63/F	Unknown	None	Mass	Hard Palate	N.M	CT (N.M.)	NED (unknown)
Milgrom and Yahalom (2013) [23]	2	56/M	Primary	N.M	N.M	Hard Palate	N.M	RT	NED (16 mos)
		75/F	Primary	N.M	N.M	Hard Palate	N.M	RT	DOD (41 mos)
Dereci et al. (2015) [24]	1	71/M	Primary	Unstable dentures	Swelling	Hard Palate	N.M	CT (COP)	DOD (during CT-4 cycles)
Rajkumar et al. (2015) [25]	1	65/M	Primary	None	Swelling	Palate and Buccal Mucosa	Occlusal radiograph: palatal lesion—no resorption of the palatal bone Ultrasound of the neck and salivary glands: nonsignificant findings	Declined	NSF
Mundada et al. (2015) [26]	1	65/M	Primary	Dysphagia	Mass	Tongue	Computed Tomography: pedunculated lesion extending into the left oropharyngeal space	CT (R-BOP)	NED (unknown)
Ainscough et al. (2016) [27]	1	69/M	Primary	None	Swelling	Floor of the Mouth	N.M	Observation	NSF
Marcucci et al. (2017) [28]	1	80/M	Primary	N.M	Swelling	Palate, Floor of the Mouth, Tongue	MRI: masses affecting the parotid, palate, tongue, oropharyngeal area and floor of the mouth	N.M	DOD (4 mos)
Lukach et al. (2020) [10]	2	91/M	Primary	N.M	Swelling	Palate	Computed tomography: bilateral palatal mass	Declined	NSF
		59/F	Primary	N.M	Swelling	Palate and Tonsils (enlarged)	PET-CT: multi-site nodal and extra-nodal involvement	CT (Rituximab – CHOP -DHAP)	NED (18 mos)
Georgaki et al. (2020)	1	69/M	Relapse	Dysphagia	Ulceration	Oropharynx and Palate (Hard and Soft)	Computed tomography: oropharyngeal mass extending to the palate	Ibrutinib	Alive with disease—new relapse in nasopharynx (36 mos from palatal relapse)

N.M. not mentioned, CT chemotherapy, RT radiotherapy, NED no evidence of disease, DOD died of disease, NSF: no significant follow-up

Table 2.

Immunohistochemical and cytogenetic profile of oral MCL cases in the English language literature

Authors	# of cases	Histopathologic variant	Positive IHC stains	Weak IHC stains	Negative IHC stains	Cytogenetics
Chuang et al. [15]	1	Classic	CD20, CCND1, CD5, CD43, BCL2	–	CD10, CD23	–
Kolokotronis et al. [16]	1	Classic	N.M	N.M	N.M	N.M
Tan et al. [17]	1	Pleomorphic	N.M	N.M	N.M	N.M
Rockacy et al. [18]	1	Classic	CD20, CCND1, BCL2	–	–	–
Guastafierro et al. [19]	1	Classic	CD20, CCND1, CD5, CD19	–	CD10, CD23	t(11;14)(q13;q32)
Guggisberg and Jordan [20]	2	Blastoid	CD20, CCND1, CD5, CD43	–	CD10, CD23, CD21, BCL6	–
		Classic	CD20, CCND1, CD5, CD43	–	CD10, CD23, CD21, BCL6	–
Kyo et al. [21]	1	Classic	CD20, CCND1	CD5	CD10	tetraploid karyotype with t(11;14)(q13;q32)
Scheller et al. [22]	1	Classic	CD20, CCND1, CD43, KI67	CD5, κ and λ light chains	CD10, CD23, BCL6, CD30, EMA	t(11;14)(q13;q32)
Fitzpatrick et al. [11]	4	Classic	CD20, CCND1, BCL6, KI67 (30–40%)	–	CD5, CD10, CD3	t(11;14)(q13;q32)
		Classic	CD20, CCND1, BCL2	CD5, CD43	CD3	–
		Classic	CD20, CCND1		CD5, CD10, CD23, CD3, KI67	–
		Classic	CD20, CCND1, BCL2	CD5, CD43	CD3	–
Milgrom and Yahalom [23]	2	Classic	N.M	N.M	N.M	N.M
		Classic	N.M	N.M	N.M	N.M
Dereci et al. [24]	1	Classic	CD20, CCND1, CD5, BCL2, PAX5, IGM, KI67 (50%)	CD43, CD23, CD21	CD10, IGD	–
Rajkumar et al. [25]	1	Classic	CD20, CCND1, CD5, CD43	–	CD10, CD23, BCL6	–
Mundada et al. [26]	1	Classic	CD20, CCND1, CD5, BCL2, CD79A	–	CD10, CD23, CD3	–
Ainscough et al. [27]	1	Classic	N.M	N.M	N.M	N.M
Marcucci et al. [28]	1	Classic	CD20, CD5, Cyclin-D1	N.M	CD3, CD4, CD23
Lukach et al. [10]	2	Classic	CD20, CD5, Cyclin D1 (nuclear), BCL2, Ki67 (25%)	CD43, BCL6	N.M	N.M
		Classic	CD20, BCL2, Cyclin D1, SOX11	N.M	BCL6, CD43, CD5	N.M
Georgaki et al	1	Blastoid	CD20, CD5, Cyclin D1	–	–	–

N.M. not mentioned

As already mentioned, MCL occurs in patients with a median age of 60–70 years old, with a higher incidence in men [5, 29, 30]. The reported oral MCL cases presented in Table 1 show a similar median age (69.6) with a male predominance (16 males/7 females), while our patient also presented corresponding demographic features (male/69 years old).

Among the reported cases of oral MCL, the majority presented in the oral cavity as first presentations of disease leading to diagnosis, while only in three cases, including ours, involvement of the oral mucosa represented a relapse [11, 17]. Additionally, another oral MCL case reported by Fitzpatrick et al. [11] had a history of prior lymphoma of unknown type, which might have been MCL, but not verified as such. Clinically, oral MCL almost exclusively presents as a tumor mass or diffuse swelling with or without an ulcerated surface, while our case was the first one to occur as a diffuse depressed ulceration with no clinical evidence of an elevated lesion. Regarding location, the hard palate is the most commonly involved site (19 cases), followed by the floor of the mouth (3 cases), tongue (2 cases) and buccal mucosa (1 case). In the cases reported by Rajkumar et al. [25] and Marcucci et al. [28], MCL was multifocal. In our case, as well as in three previously reported cases [10, 21], MCL involved the oral cavity extending from the oropharyngeal area to the hard palate, which is considered a rare phenomenon. Usually, no symptoms are reported (11 cases), although unstable dentures (2 cases), sore throat (1 case) and dysphagia (2 cases, including ours) may be the initial symptoms leading to diagnosis. In our case, the ulceration as well as the simultaneous involvement of the oropharynx appeared to correlate with dysphagia symptoms.

Radiographic evaluation can be an important diagnostic tool. Among the reported cases of oral MCL, different types of radiographic examination were used in 10 cases [10, 11, 18, 19, 21, 25, 26, 28]. MRI and CT were performed in three cases each (including ours); two cases were evaluated by PET-CT, one by occlusal radiograph and ultrasound of the neck and salivary glands and one by plain film radiograph. The most commonly encountered radiographic finding was the presence of well-defined masses with no bone resorption, primarily affecting the oral cavity or extending from posterior oropharyngeal sites, while the occurrence of disseminated disease with simultaneous involvement of other nodal or extra-nodal sites outside the oral cavity was noticed in three cases [10, 21, 28]. In our case, a CT was performed and revealed that the lesion was extending from the pharyngeal wall to the oral mucosa.

Histopathologically, conventional MCL was most commonly encountered (20 of 23 cases). However, as already mentioned, uncommon cytological and architectural features may indicate a diagnosis of an aggressive MCL variant; our case is only the second reported blastoid MCL of the oral mucosa [20], in addition to a pleomorphic MCL [17], to this date (Table 2). Morphological features indicative of aggressive behavior include increased nuclear size, pleomorphism, elevated mitotic activity, chromatin dispersal, as well as a diffuse architectural arrangement of the neoplastic cells [5]. Additionally, epithelioid macrophages in these aggressive variants of MCL are more commonly observed and often exhibit a starry-sky appearance [5]. Both pleomorphic and blastoid MCLs share these features, therefore many authors consider these entities as the same subcategory of MCL [34]. Nevertheless, there is a morphological distinction between these two entities. More specifically, pleomorphic MCL displays larger and more pleomorphic cells with irregular nuclei, prominent nucleoli and pale cytoplasm, resembling diffuse large B-cell lymphoma [5, 15, 31]. On the contrary, the neoplastic cells of blastoid MCL are more monomorphic, medium-sized with oval shaped nuclei, finely dispersed chromatin, mostly inconspicuous nucleoli and mimic those of lymphoblastic lymphoma [5, 15, 31]. Additionally, the mitotic activity seems to be higher in blastoid MCL compared to pleomorphic MCL (> 20–30 mitoses per 10 hpf) [5, 31].

The first published aggressive MCL in the oral cavity affected a male patient with a prior history of pleomorphic variant of the appendix, displaying a metachronous diffuse mass of the hard palate showing similar histopathologic features [17]. Subsequently, a 67 year-old male patient with a blastoid MCL of the palate was reported, which is the only case of the literature of aggressive MCL initially involving the oral cavity [20]. Our patient is the third reported case of aggressive MCL affecting the oral cavity and the first blastoid variant presenting as a relapse.

The immunohistochemical profile of oral MCL cases is also presented in Table 2. CD20 and CCND1 were positive in every documented case (18 cases). BCL-2 was positive in all 8 cases in which it was performed. CD43 was positive in 50% of tested cases (5 out of 10), while it was weak in 4 cases and negative in 1 case. CD10 and CD23 were weakly or not at all expressed in every tested case, while BCL-6 was negative in 71% (5/7) of the cases. A potential difference between the generally encountered MCL immunophenotype and the immunoreactivity of oral MCL seems to be the expression of CD5. It was positively expressed in 60% of oral MCL cases, which is lower compared with the 73–96% positive expression in MCL cases reported in English literature [32, 33]. It is important to recognize CD5-negative MCL due to clinical and biological differences compared to classic MCL [34]. Lack of CD5 expression has been associated with indolent MCL and higher survival rate [34], even though it has also been considered to occur in the aggressive variants [5]. Our patient, as well as the previously reported case of blastoid oral MCL [20], showed CD5 positivity, while the immunopathological findings of the previously reported pleomorphic MCL of the palate were not discussed. The proliferation index Ki-67 is also helpful in cases of MCL and, even though the diagnosis of blastoid and pleomorphic variants is mainly based on the morphology, the aggressive nature of MCL could be supported by a high Ki-67 index. No other immunohistochemical marker has been reported to distinguish the two aggressive variants of MCL [5, 12, 31]. Among the previously reported cases of oral MCL, Ki-67 was tested in 4 patients and in none of the aggressive subtypes. Finally, the immunohistochemical markers CD200 and LEF-1 have also been correlated with specific variants of MCL with the former being associated with non-nodal leukemic variant and the later with the aggressive subtypes [5]. Our case underwent a relatively limited immunohistochemical panel evaluation due to the already disclosed diagnosis of refractory MCL and necessity for immediate management; however, the relapsing nature of disease, the morphological findings, as well as a subsequent biopsy showing similar features and high proliferation index (Ki-67 > 50%), are consistent with the diagnosis of blastoid MCL.

Among the oral MCL cases, cytogenetic examination was performed in 4 cases. Three of the reported cases showed t(11;14)(q13;q32) translocation [11, 19, 22]. In one case, a tetraploid karyotype with t(11;14)(q13;q32) translocation was observed [21], which has been correlated with aggressive MCLs (especially the pleomorphic MCL) [5]; nevertheless, in this specific case, histopathologic features of classic MCL were described. Cytogenetic evaluation was not performed in our patient due to the already existing diagnosis of MCL. However, during the initial MCL diagnosis, a cytogenetic study of the bone marrow was carried out showing an add(15)(q22), which is a rare molecular event in MCL patients that has never been reported in the literature of oral MCL cases.

Treatment of MCL should be personalized and dependent on the patient’s overall status and course of disease. Chemotherapy and/or radiotherapy are standard treatment modalities, while improvements have been achieved by using conventional chemotherapy along with autologous stem cell transplantation [35]. Lately, a gradual transition to targeted therapy, epigenetic modulation therapy, and immunotherapy has been initiated with lenalidomide (immunomodulatory agent), bortezomib (proteasome inhibitor), as well as ibrutinib and acalabrutinib (bruton kinase inhibitors) being recently used [36]. Different types of MCL management were chosen among the reported cases in Table 1. Chemotherapy was chosen as a treatment option in most cases (10); four patients received R-CHOP; three with unspecified regimen; 1 R-BOP (rituximab, bendamustine, vincristine, and dexamethasone); 1 COP (cyclophosphamide, oncovin, prednol); 1 R-DHAP (rituximab, dexamethasone, cytarabine and carboplatin). Radiotherapy (three cases), observation (two cases) and chemotherapy-radiotherapy combination (one case) were secondary options. Data on therapy were not available for two patients and in three cases the patients declined any treatment.

Regarding the management of aggressive variants of MCL, even though the clinical data are limited to draw safe conclusions, the use of ibrutinib with or without other chemotherapeutic agents is more efficient, especially during the initial six months [34]. In our case, different types of treatment were chosen due to the long period of the disease and the several involved sites. Our patient was treated with chemotherapeutic regimens (R-CHOP, R-COP, Hyper-CVAD/MTX-Ara-C), radiation therapy and lately with targeted therapy (ibrutinib). In the remaining two reported cases of aggressive MCL, one patient received a chemotherapeutic regimen [18], while the other refused any treatment [20].

MCL is generally characterized by poor prognosis with a median survival of 3–5 years [20, 28, 35]. The MCL International Prognostic Index (MIPI) [37] identifies clinical prognostic factors and patients’ risk by considering the clinical (age, Eastern Cooperative Oncology Group performance status—ECOG PS) and laboratory features (LDL activity, WBC count). Other histopathologic and molecular findings implicated in the biological behavior include the Ki-67 and proliferation signature score; mitotic activity; blastoid or pleomorphic appearance; cytogenetic complexity; TP53 mutation, overexpression or loss; and CDKN2A deletion, while loss of SOX11 expression is associated with indolent disease. Among 18 cases of oral MCL with follow-up and reported outcomes (Table 1), 10/18 had no evidence of disease at the time of the last available follow-up (ranging from 6 to 53 months), 2/18 patients, including ours, were alive with disease (for at least 2 years), while 6/18 died of disease (after 4 to 41 months). Noticeably, the percentage of patients succumbing to the disease (33.3%) is lower than the percentage of death cases in sizeable cohorts of MCL from various anatomic locations [38, 39]. For example, Fu et al. [38] reported that 56.39% and 58.25% of MCL patients died of disease between years 1995–2013 based on Surveillance, Epidemiology, and End Results (SEER) database (7555 patients) and Texas Cancer Registry (TCR) database (2055 patients), respectively. In a more recent review by Wu et al. [39], focusing exclusively on MCL patients younger than 65 years in SEER databases between years 1995–2016, the total number of patients dying of disease was 2155 (out of 4892), accounting for 44.1% of total cases. The observed better survival trend for oral MCL is also in accord with a previously recorded better 5-year overall survival (approximately 63%) in primary MCL tumors of head and neck region, compared to other nodal or extranodal sites [40]. However, the limited follow-up data and the small size of oral MCL cohort should be acknowledged.

In our case, initial remission in the affected site was achieved after treatment; however, a new relapse involving the nasopharynx was diagnosed after three years, showing again an aggressive blastoid phenotype. Regarding the other two aggressive oral MCLs previously reported, in the blastoid MCL by Guggisberg and Jordan [20], the patient was alive 2 years after diagnosis despite refusing treatment, while the patient with pleomorphic MCL by Tan et al. [17] died of disease 1.5 and 3.5 years after palatal relapse and initial diagnosis, respectively.

Conclusion

To date, only few cases of oral MCL have been reported in the English literature, precluding any safe conclusions about specific features of oral MCLs compared to their counterparts in other anatomic sites. Despite their rarity and the limited follow-up, oral MCL cases appear to follow a trend for better survival, as previously reported for head and neck involvement in general, compared to nodal or other extranodal primary locations. Interestingly, only in a very limited number of these cases, including ours, did oral involvement represent a sign of MCL relapse; however, patients with medical history of lymphoma should always be thoroughly examined, as their oral lesions could be manifestations of their already diagnosed malignancy of the lymphoreticular system. Additionally, the pathologist should be familiar with rare morphologic variants of the disease, especially considering their correlation with a different biologic behavior. Since there are only 3 reported cases (including ours) of a blastoid or pleomorphic MCL in the oral cavity, the characteristics and behavior of these variants at this particular anatomic location remain unknown; nonetheless, their aggressiveness and worse prognosis at other sites justifies their recognition and separation from other types of MCL. Reporting of more cases of oral MCL with recognition of specific variants is encouraged.

Author Contributions

All authors contributed to the study conception and design. All authors read and approved the final manuscript. Conceptualization: MG, VIT, NGN; Methodology: MG, VIT, NGN; Formal analysis and investigation: MG, VIT, NGN; Writing—original draft preparation: MG, VIT, EP; Writing—review and editing: EP, PP, NGN; Supervision: NGN.

Funding

The authors did not receive support from any organization for the submitted work. No funds, grants, or other support was received.

Data Availability

Department of Oral Medicine & Pathology and Hospital Dentistry, School of Dentistry, National and Kapodistrian University of Athens, Greece.

Declarations

Conflict of interest

The authors have no conflicts of interest to declare that are relevant to the content of this article.

Ethical Approval

Ethics approval was waived by the local Ethics Committee of School of Dentistry, National and Kapodistrian University of Athens, Greece in view of the retrospective nature of the study and the fact that all procedures were part of the routine care, based on institutional regulations.

Informed Consent

No informed consent was obtained due to retrospective nature of the case and since only intra-oral images and pathology slides were used. No consent was obtained from the participant due to retrospective nature of the case and since only intra-oral images and pathology slides were used.