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Non- Hodgkin lymphoma of the lips: A rare entity
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Non- Hodgkin lymphoma of the lips: A rare entity ⁎
I. Kaplana,b,c,d, , A Shustera,c, G. Frenkela, G. Avishaib, I. Allone, V. Raisera a
Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel Rabin Medical Center, Petah-Tikva, Israel Goldschleger School of Dental Medicine, Tel-Aviv University, Israel d Sackler School of Medicine, Tel-Aviv University, Israel e Barzilai Medical Center, Ben-Gurion University Ashkelon, Beer Sheva, Israel b c
A R T I C LE I N FO
A B S T R A C T
Keywords: Lymphoma MALT Lip Oral mucosa Malignancy
Aim: To investigate clinico-pathological features of lymphoma of the lips, and review the literature. Materials and Methods: Retrospective analysis and review of English literature, 1996-2016. Results: Analysis included 23 cases, 7 new cases and 16 from literature, 12 M: 11 F, age 7–82 years. Four occurred in children, mean age 10.1; 19 in adults, mean 61.1 years. The lower lip was involved in the majority of cases (16, 69.56%). 14 (60.87%) were isolated to the lips, 8 (34.78%) were multifocal. Nine (39.13%) occurred in association with Sjogren's syndrome, of which one also had Hashimoto thyroiditis. IgG4-related disease and HIV were reported in one case each. The lip salivary glands were involved in most cases (19, 82.6%); 3 (13.6%) showed only cutaneous involvement. The typical presentation was single or multiple nodules (15, 65.21%), with surface ulceration in only two (8.69%). Constituent symptoms were absent in all cases, paresthesia was reported in one (4.34%). The majority (18, 78.26%) was extranodal marginal zone B-cell lymphoma - mucosa-associated lymphoid tissue lymphoma (EMZB-MALT), and one case each was mantle cell, NK-T cell, CD30 positive and plasmablastic lymphoma. Conclusion: The lips seem to have a unique pattern of non-Hodgkin lymphoma dominated by EMZB-MALT lymphoma, rarely other types. In more than half, neither Sjogren's syndrome nor other chronic inflammation was identified. Lesions tend to present as asymptomatic slowly progressing, non-ulcerated submucosal masses. Lymphoma should be considered even in the absence of constituent symptoms, as most cases showed none. Although the number of reported cases is rather small, disease course is usually prolonged and prognosis seems to be good.
1. Introduction Non-Hodgkin lymphoma (NHL) is a diverse group of malignant tumors of hematologic origin, which may occur in lymph nodes or as extra-nodal lesions. Oral extranodal tumors comprise only 2–3% of NHL, and the majority of these are of B-cell origin (Triantafillidou et al., 2012). Mucosa-associated lymphoid tissue (MALT) lymphoma had been first reported by Isaacson and Wright (1983), and in the World Health Organization classification, it has been classified as extranodal marginal zone B-cell lymphoma of MALT (EMBZ-MALT). It is relatively rare among NHLs, representing only 0.2–8% of total B-cell lymphomas, in various reports (Lopez-Jornet and Bermejo-Fenoll, 2005; Ryu et al., 2009).
The majority of EMBZ-MALT occurs in the gastric mucosa. The head and neck is the second most frequent location, including salivary glands, thyroid and oral mucosa. Oral mucosal NHLs are most frequently located in the gingiva-buccal complex and palate according to some reports (Shah et al., 2011; van der Waal et al., 2005), while according to Sirsath et al. (2014), the mobile tongue was the most frequent location. Other oral locations are only rarely involved. A correlation with auto-immune diseases such as Sjogren's syndrome (SS) and Hashimoto thyroiditis has been established, as well as a link to infection with Helicobacter pylori (especially in relation to gastric EMBZ-MALT) (Berrebi et al., 1998). Although the minor salivary glands of the lips are affected by SS, EMBZ-MALT of the lips, either in SS patients or as isolated non-syndromic cases, has rarely been described.
Abbreviations: DLBCL, diffuse large B cell lymphoma; EMZB, extranodal marginal zone Bcell lymphoma; MALT, mucosaassociated lymphoid tissue lymphoma; NHL, nonHodgkin lymphoma; SS, Sjogren's syndrome ⁎ Corresponding author at: Institute of Pathology Tel-Aviv Sourasky Medical Center, Tel-Aviv and Rabin medical Center, Petah-Tikva Israel. E-mail address: [email protected] (I. Kaplan). https://doi.org/10.1016/j.acthis.2019.151449
0065-1281/ © 2019 Elsevier GmbH. All rights reserved.
Please cite this article as: I. Kaplan, et al., Acta Histochemica, https://doi.org/10.1016/j.acthis.2019.151449
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A search of the English language literature (Pubmed, Scholar Google) between 2000 and 2016 was conducted using the terms lymphoma and lip. The archives of pathology have been searched for cases with a diagnosis of lymphoma and a location in the lip. The patients' files have been searched for additional information and follow-up. The study was performed in accordance with ethical requirements (both Israeli and GCP-ICH standards) of clinical trials. IRB approval is not required for case series.
Predisposing factors for lymphoma were recognized in less than half of the cases: 9 (39.13%) cases occurred in patients diagnosed with SS, of which one also had a diagnosis of Hashimoto thyroiditis, one case had IgG4-related disease and one case occurred in an HIV positive patient. The minor salivary glands of the lip were involved in the majority of cases (19, 82.6%), in 3 (13.04%) cases only cutaneous involvement was reported. The lesions presented clinically as single or multiple nodules in 16 cases (69.56%), diffuse swelling in 1 (4.34%) and with no mucosal abnormality in 4 (7.39%). Only 2 cases (8.69%) reported surface ulceration. Additional signs included paresthesia in one case (4.34%). Constituent symptoms (fever, weight loss, night sweats) were not reported in any of the cases analyzed. The majority of cases (18, 78.26%) were typed as EMZB-MALT (Figs. 2 and 3) and one case each mantle cell, NK-T cell, CD30 positive (Fig. 4) and plasmablastic lymphoma.
3. Results
4. Discussion
3.1. New case series
The NHL's are a heterogeneous group of malignancies, originating from lymphoid tissue, which can be separated by distinct epidemiology, etiology and clinical characteristics. For each type, a unique pattern of morphology and immunophenotyping can be described. The sub-classification of NHL is based on cell of origin (B cell, T cell, or natural killer (NK) cell) and the stage of maturation (Sharma et al., 2014). In terms of incidence, the disease accounts for 5.1% of all cancer cases and 2.7% of all cancer deaths (Sharma et al., 2014). It is generally more frequent in males. There is much controversy regarding the most frequent locations for intra-oral NHL; while in some series the gingivo-buccal complex and palate were described as the most frequent locations (Shah et al., 2011; van der Waal et al., 2005), others reported the jaws, palate, vestibule and gingivae (Kemp et al., 2008). A series of head and neck NHLs described about a third of cases involving the jawbones and the remaining involving soft tissue, but only single cases in the palate or tongue (Walter et al., 2015). In contrast, in a different series the mobile tongue was described as the location in the majority of cases (Sirsath et al., 2014), while the Waldeyer's ring area was reported as the location for 50% of extra-nodal NHL in the head and neck (Triantafillidou et al., 2012). In spite of these wide differences between reports regarding location of oral NHL, there is no controversy as to NHL of the lips - it has rarely been described to occur in this location in any of these reports, with only 16 cases in the literature since the year 2000. The vast majority of oral NHL are of B-cell lineage. Of these, the majority (58%) are classified as diffuse large B cell lymphoma (DLBCL), 15% follicular lymphoma, 13% EMZB-MALT, 8% plasma cell tumors, and 5% small lymphocytic lymphoma/chronic lymphocytic leukemia (Kemp et al., 2008). Of the different subtypes of NHL, EMBZ-MALT is generally among the least frequent types, accounting for only 2.1–8.2% of cases (Ryu et al., 2009), but among oral NHL it is the second or third in frequency, with DLBCL consistently being the dominant subtype (Kemp et al., 2008). In contrast, among the cases of NHL of the lips reported in the literature, as well as in the present new series, over 80% of cases were EMBZ-MALT, with only single cases of DLBCL, CD30 positive large cell lymphoma, plasmablastic, NK-T and mantle cell lymphomas. Mucosa associated lymphoid tissue (MALT) is not present in normal minor salivary glands, nor is it recognized in the lip mucosa or skin. Chronic inflammation or autoimmune diseases, such as SS may lead to the formation of acquired MALT, and give rise to EMBZ-MALT in some cases (Kolokotronis et al., 2005). However, in contrary to the expectation that EMBZ-MALT of the lips would develop from acquired MALT tissue, in both the literature and the present series, of a total of 24 cases only 9 (37.5%) occurred in association with SS and a single case with IgG4 disease, but still the majority involved the minor salivary glands. Thus, the potential origin remains enigmatic, and the cause
There is only sparse information regarding clinical presentation, diagnosis, disease course and outcome in cases of lymphoma of the lips. Therefore, the objective of the present study is to present clinical and pathological features of a new case series and to review the literature. 2. Materials and methods
The new case series includes 7 female patients, age 59–92 years, mean 75 (Table 1). The clinical presentation in all cases was of submucosal, non-ulcerated firm masses, described as slowly progressing (Fig. 1). The majority (7, 85.71%) were asymptomatic, only one patient (anaplastic CD30+ large cell lymphoma) presented partial lip paresthesia. None presented systemic signs and symptoms (such as fever, night-sweats or weight loss). The lesions involved the lower lip in 5 cases and upper lip in two, all but one were isolated to the lip. The pre-biopsy clinical differential diagnosis was mucocele or benign salivary gland tumor in all but one case. Only a single case (14.2%) developed in association with SS, with no other autoimmune or other recognizable contributing factor in the remaining cases. Seven cases (85.71%) were typed as EMZB-MALT (Figs. 2 and 3), and one as anaplastic CD30 positive large cell lymphoma (Fig. 4). EMBZ-MALT cases stained diffusely positive for CD20, with a subpopulation positive for CD3 and CD43. Bcl-2 and CD23 were focally positive only in remnants of germinal centers. CD5, Bcl-6, cyclinD1 and CD10 were negative, and Ki67 was lower in the tumor cells than within the remnants of germinal centers. The case of large DLBCL CD30 lymphoma showed a diffuse population of large lymphoid cells, effacing the structure of the salivary gland. The large cells were diffusely positive for CD20 and CD30, with only a small fraction of cells positive for CD3, Bcl-6 and CD10. In all 7 cases, surgical excision of the masses was performed. Additional treatment modalities were reported in two cases: chemotherapy and local radiotherapy in one case, and chemotherapy with CD20 monoclonal antibody (Mabthera) in one case. Recurrent disease was documented in only one case with EMZBMALT that presented as a local recurrence, which had been locally resected and the patient remained free of disease for 5 additional years. 3.2. Analysis of the new case series and cases from the literature The literature search yielded 14 articles reporting 16 cases of NHL of the lips. Combined with the 7 new cases the analysis included 23 cases. The patients included 12 males and 11 females, age 7–82 years. Four of these occurred in 7–14 years old children, mean 10.1 years; 18 were adults, 27–82 years old, mean 61.1 years, with an overall mean age of 51.8 years. The majority 16 (69.56%) of cases involved the lower lip, upper lip in 4 (17.39%), both lips in 2 (8.69%) cases and the commissure area (where both lips are joint) in 1 (4.34%). In 14 (60.87%) cases the disease was isolated to the lips, and in 8 (34.78%) it was multifocal. 2
LL LL& submandibular gland LL&UL LL LL, Palate, base of tongue, vocal cords LL UL
F/9 M/82 M/27 F/60 F/64
M/43 F/33
F/58 F/7 F/62
F/53 F/51 F/55
M/57
Moayedi et al. (2012) Nicola et al. (2009)
Park et al. (2013) Ryu et al. (2009) Shwetha et al. (2014)
Van Mello et al. (2005)
Villa et al. (2010)
3
LL LL UL LL LL
F/59 F/87 F/82 F/82 F/66
F/79
F/71
Present Case 6
Present Case 7
Mass, 1 cm
NA Firm mobile mass, 2 cm Firm mass, 0.5 cm. Mass, 1 cm, Mobile, firm mass, 0.5 cm Mass, 3 cm, paresthesia
Mass, 1.1 cm
Ulcer
Painless mass, 1 cm Multiple nodules 2 masses, 6 and 8 cm No mucosal abnormality Multifocal and recurrent masses Mass Swelling with ulceration, 4 cm Diffuse swelling Mass,1.5 cm 2 Non-tender masses 1and 1.3 cm No mucosal abnormality No mucosal abnormality No mucosal abnormality
Mass, 1 cm
Clinical presentation
No
No
Yes/ Previous NHL No Yes No No
No
No
Yes Yes Yes
No Yes Yes
No Yes/ Hashimoto
No No / IgG4 disease No Yes No
No
SS / other autoimmune or hematologic condition
EMZB-MALT - extranodal marginal zone B cell lymphoma of Mucosa associated Lymphoid Tissue. DLBC - diffuse large B cell lymphoma. Hep - hepatitis. HP - Helicobacter Pylori. FOD - free of disease. FU - follow up. NA - not available. NHL - non-Hodgkin lymphoma. PB – plasmablastic lymphoma. PCR – polymerase chain reaction. SG - salivary glands. SS - Sjogren's syndrome.
UL first presentation and later involved LL
LL and vestibule
UL
M/14
Zambrano et al. (2006) Present Case 1 Present Case 2 Present Case 3 Present Case 4 Present Case5
Commissure
LL LL LL
LL LL LL&UL
LL
M/11
Bombeccari et al. (2011) Crandley et al. (2011) Hayashi et al. (2015) Kawasaki et al. (2014) Keszler et al. (2013) Kojima et al. (2006)
Location Lower lip = LL Upper lip = UL
Gender /age (yrs)
Source
Table 1 Summary of clinical and pathological data, cases from literature and new case series combined.
EMBZ- MALT
DLBC CD30+
EMZB- MALT, PCR(+) EMBZ- MALT EMBZ- MALT EMBZ- MALT EMBZ- MALT EMBZ- MALT
NK-T cell lymphoma EMZB- MALT EMZB- MALT Isolated to lip EMZB- MALT Suspected EMZBMALT EMZB- MALT CD 30 (+) T-cell
PB lymphoma EMZB MALT
EMZB- MALT Mantle cell EMZB- MALT EMZB- MALT EMZB- MALT
EMZB- MALT
Type of NHL
No/Isolated to lips
Yes/Isolated to lip
No/Cutaneous only, Isolated to lip No/Cutaneous only, Isolated to lip Yes/Isolated to lip Yes/Isolated to lip Yes/Isolated to lip Yes/Isolated to lip Yes/Isolated to lip
Yes/Not isolated Yes/NA Yes/Previous NHL of groin
No/Multifocal cutaneous Yes/Isolated to lip Yes/Isolated to lip
Yes/Isolated to lip Yes/Multifocal Yes/Isolated to lips Yes/Isolated to lip Yes/Multifocal only in upper aerodigestive tract No/Multifocal Yes/Isolated to lip
Yes/Isolated to lip
Involvement of SG/other organ involvement
Chemotherapy and radiotherapy, survived 9yrs; died of unrelated reasons Surgical resection, no FU available
Chemotherapy and Mabthera; 11yrs FOD Surgical resection, FOD 1yr Surgical resection, no FU Surgical resection, FOD 2yrs Surgical resection, no FU available
No information
Negative for viruses
No information
No information Habitual chewing, HP, Hep B,C; HIV(-) No information
HIV(+) HP(+)
Habitual chewing, HP(-) Colon carcinoma HP, Hep B,C; HIV(-) HP(+) No information
Habitual chewing, HP(-)
Additional information
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Fig. 1. Similar clinical presentation in three cases, showing non-ulcerated submucosal masses of the lower lip. In the right panel, there is a scar visible from a previous resection, with recurrent lesion in the same area.
Fig. 2. A: EMBZ-MALT lymphoma: At low magnification, a dense cellular infiltrate can be observed, with no remnants of normal salivary gland tissue (scale bar 500 μ). A small myoepithelial island can be observed (square frame) A cytokeratin stain aids in recognizing the myoepithelial proliferation, infiltrated by small lymphoid cells B: EMBZ-MALT lymphoma: Left panel shows diffuse proliferation of mostly medium-sized cells with small irregular nuclei (centrocyte-like), as well as cells with well-defined borders and abundant pale cytoplasm (monocytoid). Invasion of blood vessel walls by the tumor cells can be observed. Right panel shows mostly small and regular cells, resembling small mature lymphocytes. A thin capsule defines the borders of the mass. (scale bars 100 μ).
Fig. 3. a EMBZ-MALT lymphoma: CD20 is strongly and diffusely expressed, with a subset of T-cells expressing CD3. Aberrant co-expression of CD43 by CD20 positive small B cells is present. CD23 is positive in the remnants of germinal center but negative in the malignant lymphoid infiltrate (scale bars 500 μ). b EMBZ-MALT: BCL-6 is only positive in remnants of germinal centers, but negative in the rest of the infiltrate, while Bcl-2 demonstrates non-germinal center staining. Ki67 shows higher index in the germinal center area than in the tumor population (scale bars 500 μ).
female predominance. In general, they have an indolent prolonged course, and only a minority may disseminate to other locations, usually after prolonged disease free intervals (Ryu et al., 2009; Lopez-Jornet and Bermigo-Fenoll, 2005). Most of the NHL of the lips fall within these general characteristics, although a subgroup (4 cases) have been reported in children, thus, age distribution seems to have 2 peaks, one
for onset of malignant transition in this particular environment is yet unknown. The present analysis suggests that the lips seem to have a unique pattern of NHL, which deserves separate recognition and further investigation. Most cases of EMBZ-MALT occur in adults, over the age of 60, with a
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Fig. 4. a DLBC-CD30 positive lymphoma: A dense infiltrate of large atypical, pale lymphoid cells with vesicular nuclei is demonstrated. CK7 stain (inset) helps to identify small epithelial islands, remnants of the salivary glands, which could not be visualized in the hematoxylin and eosin stained slides (scale bar X100). b DLBC-CD30 positive lymphoma: Strong membranous CD30 staining in the majority of cells supports the diagnosis. (scale bar 100 μ).
variants. Expression of CD30 in DLBCL is reported to correlate with better survival and prognosis (Sotomayor et al., 2014). In the literature and the present series combined, only 2 (8.7%) of cases were CD30 positive DLBCL, thus it is a rare event among lymphomas of the lips, in contrast to other organs. Although no conclusions can be drawn from single cases, the CD30 positive case from the present series seemed to fall into the pattern characterized by a relatively less-aggressive behavior as described in CD30 positive DLBCL in other locations, since the patient survived for 9 years post-diagnosis and died of unrelated causes. In recent years, a large amount of information has come through, regarding specific genetic changes for many types of lymphoma. Testing for these characteristic markers may help in diagnosis, although they are not required for every case, and a thorough review of these is beyond the scope of this study. Cytogenetic testing has not been performed in the new cases presented or in the majority of cases reviewed from the literature. In general, translocations observed in EMZB-MALT lymphomas such as t(14;18) (IGH-MALT1) and t(11;18) (API2-MALT1) are uncommon in those lymphomas in the head and neck area (Streubel et al., 2004), therefore the diagnosis is mainly based on the morphology and immunophenotype of the neoplastic lymphocytes.
around age 10 and a second peak around age 60. All EMBZ-MALT of the lips seem to have a prolonged and indolent disease course, and should be treated in a conservative manner. The histologic characteristics of salivary glands EMZB-MALT lymphoma include proliferation of marginal zone B cells around the ductal epithelium, the formation of solid sheets of marginal zone B cells, and prominent lympho-epithelial lesions (Ryu et al., 2009). The cytological characteristics in EMZB-MALT are variable: small to medium-sized cells with small irregular nuclei (centrocyte-like) are common, but in other cases abundant pale cytoplasm with well-defined cell borders (monocytoid) may be encountered, as well as cells resembling small mature lymphocytes. Occasionally, larger cells, which resemble centroblasts or immunoblasts, as well as plasma cells, may be observed (Bacon et al., 2007). EMBZ-MALT lymphoma at many sites (including salivary glands) is associated with the presence of lympho-epithelial islands, which become infiltrated by aggregates of neoplastic lymphoid cells. These features are helpful in the diagnosis, with cytokeratin stains aiding in their recognition. In addition, a diffuse dense infiltrate of CD20 positive cells, associated with destruction of the normal parenchyma of the glands are features supporting lymphoma. Immunohistochemistry is a very important tool in the diagnosis of lymphoma. Unfortunately, a specific immunohistochemical marker for EMZB-MALT lymphoma does not yet exist, thus, the diagnosis relies on recognition of the morphological characteristics and the combined phenotypic results of immunostainings (Bacon et al., 2007). The neoplastic cells stain positive for CD20 and IgM, and negative for IgD, CD5, CD10, Bcl-6 and cyclin D1. There may be an admixed population of CD3 positive reactive T cells. Immunoglobulin light-chain restriction may also be demonstrated, especially in plasma cells. If present, light-chain restriction is helpful in the exclusion of reactive changes. Another feature observed in around 50% of cases is aberrant co-expression of CD43 by CD20 positive small B cells. If present, this phenotype can serve as a strong indication for lymphoma (Bacon et al., 2007). The pattern of negative immunoreactivity for stains mentioned above also serves to rule-out other types of small B-cell lymphoma, such as follicular lymphoma, which is usually Bcl-6 and CD10 positive (Bacon et al., 2007). CD 23 and Bcl-6 would be negative in EMZBMALT, but may be helpful in identifying any residual germinal centers, which stain positive for both these markers, but are negative in the transformed neoplastic cells in EMZB-MALT lymphoma. Proliferation index, evaluated by staining with Ki67 (MIB-1) is usually high in the reactive follicles, and lower in the neoplastic cell population (Bacon et al., 2007). This finding correlates well with the indolent nature of this type of lymphoma Diffuse large B-cell lymphoma (DLBCL) is in general the most common and one of most heterogeneous types of NHL. DLBCL is subclassified by morphology, pattern of immunophenotype and molecular analysis, into distinct subtypes/entities in the current World Health Organization classification (Hu et al., 2013). Centroblastic, immunoblastic, and anaplastic are the most common morphological
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M., Li, L., Møller, M.B., Piris, M.A., Li, Y., Go, R.S., Wu, L., Medeiros, L.J., Young, K.H., 2013. CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP consortium program study. Blood. 121, 2715–2724. Isaacson, P., Wright, D.H., 1983. Malignant lymphoma of mucosa-associated lymphoid tissue: a distinct type of B-cell lymphoma. Cancer. 52, 1410–1416. Kawasaki, G., Yanamoto, S., Kawano, T., Yoshitomi, I., Yamada, S., Rokutanda, S., Fujita, S., Ikeda, T., Umeda, M., 2014. Soft masses occurring simultaneously in the upper and lower lips. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 117, 147–152. Kemp, S., Gallagher, G., Kabani, S., Noonan, V., O’Hara, C., 2008. Oral non-Hodgkin’s lymphoma: review of the literature and World Health Organization classification with reference to 40 cases. Oral. Med. Oral. Pathol. Oral. Radiol. Endod. 105, 194–201. Keszler, A., Adler, L.I., Gandolfo, M.S., Masquijo Bisio, P.A., Smith, A.C., Vollenweider, C.F., Heidenreich, A.M., de Stefano, G., Kambo, M.V., Cox, D.P., Narbaitz, M., Lanfranchi, H.E., 2013. MALT Lymphoma in labial salivary gland biopsy from Sjogren’s syndrome: importance of follow-up in early detection. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 115, e28–33. Kojima, M., Sugihara, S., Iijima, M., Ono, T., Yoshizumi, T., Masawa, N., 2006. Marginal zone B cell lymphoma of minor salivary gland representing tumor forming amyloidosis. J. Oral Pathol. Med. 35, 314–316. Lopez-Jornet, P., Bermejo-Fenoll, A., 2005. Oral mucosal non-Hodgkin’s lymphoma. Oral. Oncol. EXTRA. 41, 101–103. Moayedi, Y., Venos, E.S., Ghaffar, H., Gough, K.A., Hicks, L.K., 2012. Paying more than lip service to an oral lesion: a case of plasmablastic lymphoma. BMJ Case Rep. https://doi.org/10.1136/bcr-2012-006452. Nicola, P., Palombi, M., Fratoni, S., Trawinska, M.M., Scaramucci, L., Ales, M., Tendas, A., Cupelli, L., Perrotti, A., de Fabritiis, P., 2009. Primary MALT lymphoma of the upper lip mucosa: an exceptionally rare localization. Int. J. Hematol. 39, 130–131. Park, J.H., Shin, H.T., Lee, D.Y., Ko, Y.H., 2013. Natural killer (NK)/T-cell lymphoma presenting with recurrent lip swelling. Int. J. Dermatol. 52, 762–773. Ryu, M.H., Han, S., Che, Z., Min, Y., Yoo, K.H., Koo, H.H., Yang, W.I., Kim, H.S., 2009. Pediatric mucosa-associated lymphoid tissue (MALT) lymphoma of lip: a case report and literature review. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 107, 393–397. Shah, G.H., Panwar, S.K., Chaturvedi, P.P., Kane, S.N., 2011. Isolated primary extranodal lymphoma of the oral cavity: A series of 15 cases and review of literature from a
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Non- Hodgkin lymphoma of the lips: A rare entity ⁎
I. Kaplana,b,c,d, , A Shustera,c, G. Frenkela, G. Avishaib, I. Allone, V. Raisera a
Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel Rabin Medical Center, Petah-Tikva, Israel Goldschleger School of Dental Medicine, Tel-Aviv University, Israel d Sackler School of Medicine, Tel-Aviv University, Israel e Barzilai Medical Center, Ben-Gurion University Ashkelon, Beer Sheva, Israel b c
A R T I C LE I N FO
A B S T R A C T
Keywords: Lymphoma MALT Lip Oral mucosa Malignancy
Aim: To investigate clinico-pathological features of lymphoma of the lips, and review the literature. Materials and Methods: Retrospective analysis and review of English literature, 1996-2016. Results: Analysis included 23 cases, 7 new cases and 16 from literature, 12 M: 11 F, age 7–82 years. Four occurred in children, mean age 10.1; 19 in adults, mean 61.1 years. The lower lip was involved in the majority of cases (16, 69.56%). 14 (60.87%) were isolated to the lips, 8 (34.78%) were multifocal. Nine (39.13%) occurred in association with Sjogren's syndrome, of which one also had Hashimoto thyroiditis. IgG4-related disease and HIV were reported in one case each. The lip salivary glands were involved in most cases (19, 82.6%); 3 (13.6%) showed only cutaneous involvement. The typical presentation was single or multiple nodules (15, 65.21%), with surface ulceration in only two (8.69%). Constituent symptoms were absent in all cases, paresthesia was reported in one (4.34%). The majority (18, 78.26%) was extranodal marginal zone B-cell lymphoma - mucosa-associated lymphoid tissue lymphoma (EMZB-MALT), and one case each was mantle cell, NK-T cell, CD30 positive and plasmablastic lymphoma. Conclusion: The lips seem to have a unique pattern of non-Hodgkin lymphoma dominated by EMZB-MALT lymphoma, rarely other types. In more than half, neither Sjogren's syndrome nor other chronic inflammation was identified. Lesions tend to present as asymptomatic slowly progressing, non-ulcerated submucosal masses. Lymphoma should be considered even in the absence of constituent symptoms, as most cases showed none. Although the number of reported cases is rather small, disease course is usually prolonged and prognosis seems to be good.
1. Introduction Non-Hodgkin lymphoma (NHL) is a diverse group of malignant tumors of hematologic origin, which may occur in lymph nodes or as extra-nodal lesions. Oral extranodal tumors comprise only 2–3% of NHL, and the majority of these are of B-cell origin (Triantafillidou et al., 2012). Mucosa-associated lymphoid tissue (MALT) lymphoma had been first reported by Isaacson and Wright (1983), and in the World Health Organization classification, it has been classified as extranodal marginal zone B-cell lymphoma of MALT (EMBZ-MALT). It is relatively rare among NHLs, representing only 0.2–8% of total B-cell lymphomas, in various reports (Lopez-Jornet and Bermejo-Fenoll, 2005; Ryu et al., 2009).
The majority of EMBZ-MALT occurs in the gastric mucosa. The head and neck is the second most frequent location, including salivary glands, thyroid and oral mucosa. Oral mucosal NHLs are most frequently located in the gingiva-buccal complex and palate according to some reports (Shah et al., 2011; van der Waal et al., 2005), while according to Sirsath et al. (2014), the mobile tongue was the most frequent location. Other oral locations are only rarely involved. A correlation with auto-immune diseases such as Sjogren's syndrome (SS) and Hashimoto thyroiditis has been established, as well as a link to infection with Helicobacter pylori (especially in relation to gastric EMBZ-MALT) (Berrebi et al., 1998). Although the minor salivary glands of the lips are affected by SS, EMBZ-MALT of the lips, either in SS patients or as isolated non-syndromic cases, has rarely been described.
Abbreviations: DLBCL, diffuse large B cell lymphoma; EMZB, extranodal marginal zone Bcell lymphoma; MALT, mucosaassociated lymphoid tissue lymphoma; NHL, nonHodgkin lymphoma; SS, Sjogren's syndrome ⁎ Corresponding author at: Institute of Pathology Tel-Aviv Sourasky Medical Center, Tel-Aviv and Rabin medical Center, Petah-Tikva Israel. E-mail address: [email protected] (I. Kaplan). https://doi.org/10.1016/j.acthis.2019.151449
0065-1281/ © 2019 Elsevier GmbH. All rights reserved.
Please cite this article as: I. Kaplan, et al., Acta Histochemica, https://doi.org/10.1016/j.acthis.2019.151449
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A search of the English language literature (Pubmed, Scholar Google) between 2000 and 2016 was conducted using the terms lymphoma and lip. The archives of pathology have been searched for cases with a diagnosis of lymphoma and a location in the lip. The patients' files have been searched for additional information and follow-up. The study was performed in accordance with ethical requirements (both Israeli and GCP-ICH standards) of clinical trials. IRB approval is not required for case series.
Predisposing factors for lymphoma were recognized in less than half of the cases: 9 (39.13%) cases occurred in patients diagnosed with SS, of which one also had a diagnosis of Hashimoto thyroiditis, one case had IgG4-related disease and one case occurred in an HIV positive patient. The minor salivary glands of the lip were involved in the majority of cases (19, 82.6%), in 3 (13.04%) cases only cutaneous involvement was reported. The lesions presented clinically as single or multiple nodules in 16 cases (69.56%), diffuse swelling in 1 (4.34%) and with no mucosal abnormality in 4 (7.39%). Only 2 cases (8.69%) reported surface ulceration. Additional signs included paresthesia in one case (4.34%). Constituent symptoms (fever, weight loss, night sweats) were not reported in any of the cases analyzed. The majority of cases (18, 78.26%) were typed as EMZB-MALT (Figs. 2 and 3) and one case each mantle cell, NK-T cell, CD30 positive (Fig. 4) and plasmablastic lymphoma.
3. Results
4. Discussion
3.1. New case series
The NHL's are a heterogeneous group of malignancies, originating from lymphoid tissue, which can be separated by distinct epidemiology, etiology and clinical characteristics. For each type, a unique pattern of morphology and immunophenotyping can be described. The sub-classification of NHL is based on cell of origin (B cell, T cell, or natural killer (NK) cell) and the stage of maturation (Sharma et al., 2014). In terms of incidence, the disease accounts for 5.1% of all cancer cases and 2.7% of all cancer deaths (Sharma et al., 2014). It is generally more frequent in males. There is much controversy regarding the most frequent locations for intra-oral NHL; while in some series the gingivo-buccal complex and palate were described as the most frequent locations (Shah et al., 2011; van der Waal et al., 2005), others reported the jaws, palate, vestibule and gingivae (Kemp et al., 2008). A series of head and neck NHLs described about a third of cases involving the jawbones and the remaining involving soft tissue, but only single cases in the palate or tongue (Walter et al., 2015). In contrast, in a different series the mobile tongue was described as the location in the majority of cases (Sirsath et al., 2014), while the Waldeyer's ring area was reported as the location for 50% of extra-nodal NHL in the head and neck (Triantafillidou et al., 2012). In spite of these wide differences between reports regarding location of oral NHL, there is no controversy as to NHL of the lips - it has rarely been described to occur in this location in any of these reports, with only 16 cases in the literature since the year 2000. The vast majority of oral NHL are of B-cell lineage. Of these, the majority (58%) are classified as diffuse large B cell lymphoma (DLBCL), 15% follicular lymphoma, 13% EMZB-MALT, 8% plasma cell tumors, and 5% small lymphocytic lymphoma/chronic lymphocytic leukemia (Kemp et al., 2008). Of the different subtypes of NHL, EMBZ-MALT is generally among the least frequent types, accounting for only 2.1–8.2% of cases (Ryu et al., 2009), but among oral NHL it is the second or third in frequency, with DLBCL consistently being the dominant subtype (Kemp et al., 2008). In contrast, among the cases of NHL of the lips reported in the literature, as well as in the present new series, over 80% of cases were EMBZ-MALT, with only single cases of DLBCL, CD30 positive large cell lymphoma, plasmablastic, NK-T and mantle cell lymphomas. Mucosa associated lymphoid tissue (MALT) is not present in normal minor salivary glands, nor is it recognized in the lip mucosa or skin. Chronic inflammation or autoimmune diseases, such as SS may lead to the formation of acquired MALT, and give rise to EMBZ-MALT in some cases (Kolokotronis et al., 2005). However, in contrary to the expectation that EMBZ-MALT of the lips would develop from acquired MALT tissue, in both the literature and the present series, of a total of 24 cases only 9 (37.5%) occurred in association with SS and a single case with IgG4 disease, but still the majority involved the minor salivary glands. Thus, the potential origin remains enigmatic, and the cause
There is only sparse information regarding clinical presentation, diagnosis, disease course and outcome in cases of lymphoma of the lips. Therefore, the objective of the present study is to present clinical and pathological features of a new case series and to review the literature. 2. Materials and methods
The new case series includes 7 female patients, age 59–92 years, mean 75 (Table 1). The clinical presentation in all cases was of submucosal, non-ulcerated firm masses, described as slowly progressing (Fig. 1). The majority (7, 85.71%) were asymptomatic, only one patient (anaplastic CD30+ large cell lymphoma) presented partial lip paresthesia. None presented systemic signs and symptoms (such as fever, night-sweats or weight loss). The lesions involved the lower lip in 5 cases and upper lip in two, all but one were isolated to the lip. The pre-biopsy clinical differential diagnosis was mucocele or benign salivary gland tumor in all but one case. Only a single case (14.2%) developed in association with SS, with no other autoimmune or other recognizable contributing factor in the remaining cases. Seven cases (85.71%) were typed as EMZB-MALT (Figs. 2 and 3), and one as anaplastic CD30 positive large cell lymphoma (Fig. 4). EMBZ-MALT cases stained diffusely positive for CD20, with a subpopulation positive for CD3 and CD43. Bcl-2 and CD23 were focally positive only in remnants of germinal centers. CD5, Bcl-6, cyclinD1 and CD10 were negative, and Ki67 was lower in the tumor cells than within the remnants of germinal centers. The case of large DLBCL CD30 lymphoma showed a diffuse population of large lymphoid cells, effacing the structure of the salivary gland. The large cells were diffusely positive for CD20 and CD30, with only a small fraction of cells positive for CD3, Bcl-6 and CD10. In all 7 cases, surgical excision of the masses was performed. Additional treatment modalities were reported in two cases: chemotherapy and local radiotherapy in one case, and chemotherapy with CD20 monoclonal antibody (Mabthera) in one case. Recurrent disease was documented in only one case with EMZBMALT that presented as a local recurrence, which had been locally resected and the patient remained free of disease for 5 additional years. 3.2. Analysis of the new case series and cases from the literature The literature search yielded 14 articles reporting 16 cases of NHL of the lips. Combined with the 7 new cases the analysis included 23 cases. The patients included 12 males and 11 females, age 7–82 years. Four of these occurred in 7–14 years old children, mean 10.1 years; 18 were adults, 27–82 years old, mean 61.1 years, with an overall mean age of 51.8 years. The majority 16 (69.56%) of cases involved the lower lip, upper lip in 4 (17.39%), both lips in 2 (8.69%) cases and the commissure area (where both lips are joint) in 1 (4.34%). In 14 (60.87%) cases the disease was isolated to the lips, and in 8 (34.78%) it was multifocal. 2
LL LL& submandibular gland LL&UL LL LL, Palate, base of tongue, vocal cords LL UL
F/9 M/82 M/27 F/60 F/64
M/43 F/33
F/58 F/7 F/62
F/53 F/51 F/55
M/57
Moayedi et al. (2012) Nicola et al. (2009)
Park et al. (2013) Ryu et al. (2009) Shwetha et al. (2014)
Van Mello et al. (2005)
Villa et al. (2010)
3
LL LL UL LL LL
F/59 F/87 F/82 F/82 F/66
F/79
F/71
Present Case 6
Present Case 7
Mass, 1 cm
NA Firm mobile mass, 2 cm Firm mass, 0.5 cm. Mass, 1 cm, Mobile, firm mass, 0.5 cm Mass, 3 cm, paresthesia
Mass, 1.1 cm
Ulcer
Painless mass, 1 cm Multiple nodules 2 masses, 6 and 8 cm No mucosal abnormality Multifocal and recurrent masses Mass Swelling with ulceration, 4 cm Diffuse swelling Mass,1.5 cm 2 Non-tender masses 1and 1.3 cm No mucosal abnormality No mucosal abnormality No mucosal abnormality
Mass, 1 cm
Clinical presentation
No
No
Yes/ Previous NHL No Yes No No
No
No
Yes Yes Yes
No Yes Yes
No Yes/ Hashimoto
No No / IgG4 disease No Yes No
No
SS / other autoimmune or hematologic condition
EMZB-MALT - extranodal marginal zone B cell lymphoma of Mucosa associated Lymphoid Tissue. DLBC - diffuse large B cell lymphoma. Hep - hepatitis. HP - Helicobacter Pylori. FOD - free of disease. FU - follow up. NA - not available. NHL - non-Hodgkin lymphoma. PB – plasmablastic lymphoma. PCR – polymerase chain reaction. SG - salivary glands. SS - Sjogren's syndrome.
UL first presentation and later involved LL
LL and vestibule
UL
M/14
Zambrano et al. (2006) Present Case 1 Present Case 2 Present Case 3 Present Case 4 Present Case5
Commissure
LL LL LL
LL LL LL&UL
LL
M/11
Bombeccari et al. (2011) Crandley et al. (2011) Hayashi et al. (2015) Kawasaki et al. (2014) Keszler et al. (2013) Kojima et al. (2006)
Location Lower lip = LL Upper lip = UL
Gender /age (yrs)
Source
Table 1 Summary of clinical and pathological data, cases from literature and new case series combined.
EMBZ- MALT
DLBC CD30+
EMZB- MALT, PCR(+) EMBZ- MALT EMBZ- MALT EMBZ- MALT EMBZ- MALT EMBZ- MALT
NK-T cell lymphoma EMZB- MALT EMZB- MALT Isolated to lip EMZB- MALT Suspected EMZBMALT EMZB- MALT CD 30 (+) T-cell
PB lymphoma EMZB MALT
EMZB- MALT Mantle cell EMZB- MALT EMZB- MALT EMZB- MALT
EMZB- MALT
Type of NHL
No/Isolated to lips
Yes/Isolated to lip
No/Cutaneous only, Isolated to lip No/Cutaneous only, Isolated to lip Yes/Isolated to lip Yes/Isolated to lip Yes/Isolated to lip Yes/Isolated to lip Yes/Isolated to lip
Yes/Not isolated Yes/NA Yes/Previous NHL of groin
No/Multifocal cutaneous Yes/Isolated to lip Yes/Isolated to lip
Yes/Isolated to lip Yes/Multifocal Yes/Isolated to lips Yes/Isolated to lip Yes/Multifocal only in upper aerodigestive tract No/Multifocal Yes/Isolated to lip
Yes/Isolated to lip
Involvement of SG/other organ involvement
Chemotherapy and radiotherapy, survived 9yrs; died of unrelated reasons Surgical resection, no FU available
Chemotherapy and Mabthera; 11yrs FOD Surgical resection, FOD 1yr Surgical resection, no FU Surgical resection, FOD 2yrs Surgical resection, no FU available
No information
Negative for viruses
No information
No information Habitual chewing, HP, Hep B,C; HIV(-) No information
HIV(+) HP(+)
Habitual chewing, HP(-) Colon carcinoma HP, Hep B,C; HIV(-) HP(+) No information
Habitual chewing, HP(-)
Additional information
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Fig. 1. Similar clinical presentation in three cases, showing non-ulcerated submucosal masses of the lower lip. In the right panel, there is a scar visible from a previous resection, with recurrent lesion in the same area.
Fig. 2. A: EMBZ-MALT lymphoma: At low magnification, a dense cellular infiltrate can be observed, with no remnants of normal salivary gland tissue (scale bar 500 μ). A small myoepithelial island can be observed (square frame) A cytokeratin stain aids in recognizing the myoepithelial proliferation, infiltrated by small lymphoid cells B: EMBZ-MALT lymphoma: Left panel shows diffuse proliferation of mostly medium-sized cells with small irregular nuclei (centrocyte-like), as well as cells with well-defined borders and abundant pale cytoplasm (monocytoid). Invasion of blood vessel walls by the tumor cells can be observed. Right panel shows mostly small and regular cells, resembling small mature lymphocytes. A thin capsule defines the borders of the mass. (scale bars 100 μ).
Fig. 3. a EMBZ-MALT lymphoma: CD20 is strongly and diffusely expressed, with a subset of T-cells expressing CD3. Aberrant co-expression of CD43 by CD20 positive small B cells is present. CD23 is positive in the remnants of germinal center but negative in the malignant lymphoid infiltrate (scale bars 500 μ). b EMBZ-MALT: BCL-6 is only positive in remnants of germinal centers, but negative in the rest of the infiltrate, while Bcl-2 demonstrates non-germinal center staining. Ki67 shows higher index in the germinal center area than in the tumor population (scale bars 500 μ).
female predominance. In general, they have an indolent prolonged course, and only a minority may disseminate to other locations, usually after prolonged disease free intervals (Ryu et al., 2009; Lopez-Jornet and Bermigo-Fenoll, 2005). Most of the NHL of the lips fall within these general characteristics, although a subgroup (4 cases) have been reported in children, thus, age distribution seems to have 2 peaks, one
for onset of malignant transition in this particular environment is yet unknown. The present analysis suggests that the lips seem to have a unique pattern of NHL, which deserves separate recognition and further investigation. Most cases of EMBZ-MALT occur in adults, over the age of 60, with a
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Fig. 4. a DLBC-CD30 positive lymphoma: A dense infiltrate of large atypical, pale lymphoid cells with vesicular nuclei is demonstrated. CK7 stain (inset) helps to identify small epithelial islands, remnants of the salivary glands, which could not be visualized in the hematoxylin and eosin stained slides (scale bar X100). b DLBC-CD30 positive lymphoma: Strong membranous CD30 staining in the majority of cells supports the diagnosis. (scale bar 100 μ).
variants. Expression of CD30 in DLBCL is reported to correlate with better survival and prognosis (Sotomayor et al., 2014). In the literature and the present series combined, only 2 (8.7%) of cases were CD30 positive DLBCL, thus it is a rare event among lymphomas of the lips, in contrast to other organs. Although no conclusions can be drawn from single cases, the CD30 positive case from the present series seemed to fall into the pattern characterized by a relatively less-aggressive behavior as described in CD30 positive DLBCL in other locations, since the patient survived for 9 years post-diagnosis and died of unrelated causes. In recent years, a large amount of information has come through, regarding specific genetic changes for many types of lymphoma. Testing for these characteristic markers may help in diagnosis, although they are not required for every case, and a thorough review of these is beyond the scope of this study. Cytogenetic testing has not been performed in the new cases presented or in the majority of cases reviewed from the literature. In general, translocations observed in EMZB-MALT lymphomas such as t(14;18) (IGH-MALT1) and t(11;18) (API2-MALT1) are uncommon in those lymphomas in the head and neck area (Streubel et al., 2004), therefore the diagnosis is mainly based on the morphology and immunophenotype of the neoplastic lymphocytes.
around age 10 and a second peak around age 60. All EMBZ-MALT of the lips seem to have a prolonged and indolent disease course, and should be treated in a conservative manner. The histologic characteristics of salivary glands EMZB-MALT lymphoma include proliferation of marginal zone B cells around the ductal epithelium, the formation of solid sheets of marginal zone B cells, and prominent lympho-epithelial lesions (Ryu et al., 2009). The cytological characteristics in EMZB-MALT are variable: small to medium-sized cells with small irregular nuclei (centrocyte-like) are common, but in other cases abundant pale cytoplasm with well-defined cell borders (monocytoid) may be encountered, as well as cells resembling small mature lymphocytes. Occasionally, larger cells, which resemble centroblasts or immunoblasts, as well as plasma cells, may be observed (Bacon et al., 2007). EMBZ-MALT lymphoma at many sites (including salivary glands) is associated with the presence of lympho-epithelial islands, which become infiltrated by aggregates of neoplastic lymphoid cells. These features are helpful in the diagnosis, with cytokeratin stains aiding in their recognition. In addition, a diffuse dense infiltrate of CD20 positive cells, associated with destruction of the normal parenchyma of the glands are features supporting lymphoma. Immunohistochemistry is a very important tool in the diagnosis of lymphoma. Unfortunately, a specific immunohistochemical marker for EMZB-MALT lymphoma does not yet exist, thus, the diagnosis relies on recognition of the morphological characteristics and the combined phenotypic results of immunostainings (Bacon et al., 2007). The neoplastic cells stain positive for CD20 and IgM, and negative for IgD, CD5, CD10, Bcl-6 and cyclin D1. There may be an admixed population of CD3 positive reactive T cells. Immunoglobulin light-chain restriction may also be demonstrated, especially in plasma cells. If present, light-chain restriction is helpful in the exclusion of reactive changes. Another feature observed in around 50% of cases is aberrant co-expression of CD43 by CD20 positive small B cells. If present, this phenotype can serve as a strong indication for lymphoma (Bacon et al., 2007). The pattern of negative immunoreactivity for stains mentioned above also serves to rule-out other types of small B-cell lymphoma, such as follicular lymphoma, which is usually Bcl-6 and CD10 positive (Bacon et al., 2007). CD 23 and Bcl-6 would be negative in EMZBMALT, but may be helpful in identifying any residual germinal centers, which stain positive for both these markers, but are negative in the transformed neoplastic cells in EMZB-MALT lymphoma. Proliferation index, evaluated by staining with Ki67 (MIB-1) is usually high in the reactive follicles, and lower in the neoplastic cell population (Bacon et al., 2007). This finding correlates well with the indolent nature of this type of lymphoma Diffuse large B-cell lymphoma (DLBCL) is in general the most common and one of most heterogeneous types of NHL. DLBCL is subclassified by morphology, pattern of immunophenotype and molecular analysis, into distinct subtypes/entities in the current World Health Organization classification (Hu et al., 2013). Centroblastic, immunoblastic, and anaplastic are the most common morphological
5. Conclusions The lips seem to have a unique pattern of NHL, which deserves separate recognition and further investigation. It is predominated by EMZB-MALT lymphoma, rarely other NHL types, and more than half develop without a background of chronic inflammation such as in SS. Although the number of reported cases is rather small, the prognosis seems to be good. Lesions typically present as asymptomatic slowly progressing, usually non-ulcerated submucosal masses (either with or without a history of SS). Lymphoma should be included in the differential diagnosis, even in the absence of systemic signs and symptoms, as most of the lip lymphomas present without constituent symptoms. References Bacon, C.M., Du, M.Q., Dogan, A., 2007. Mucosa-associated lymphoid tissue (MALT) lymphoma: a practical guide for pathologists. J. Clin. Pathol. 60, 361–372. Berrebi, D., Lescoeur, B., Faye, A., Faure, C., Vilmer, E., Peuchmaur, M., 1998. MALT lymphoma of labial minor salivary gland in an immunocompetent child with a gastric Helicobacter pylori infection. J. Pediatr. 133, 290–292. Bombeccari, G.P., Guzzi, G., Ruffoni, D., Gianatti, A., Mariani, U., Spadari, F., 2011. Mucosa –associated lymphatic tissue lymphoma of the lower lip in a child. J. Pediatr. Surg. 46, 2414–2416. Crandley, K.N., Aguiar, M.A., Lowe, E.J., 2011. MALT lymphoma of the lip. Pediatr. Blood.Cancer. 56, 683–684. Hayashi, Y., Moriyama, M., Maehara, T., Goto, Y., Kawano, S., Ohta, M., Tanaka, A., Furukawa, S., Hayashida, J.N., Kiyoshima, T., Shimizu, M., Chikui, T., Nakamura, S., 2015. A case of mantle cell lymphoma presenting as IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz’s disease. World J. Surg. Oncol. 13, 225. Hu, S., Xu-Monette, Z.Y., Balasubramanyam, A., Manyam, G.C., Visco, C., Tzankov, A., Liu, W.M., Miranda, R.N., Zhang, L., Montes-Moreno, S., Dybkær, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., his, E.D., Choi, W.W., Han van Krieken, J., Huang, Q., Huh, J., Ai, W., Ponzoni, M., Ferreri, A.J., Zhao, X., Winter, J.N., Zhang,
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