Clinical pathologic conference case: An older woman with a painless, deep, and indurated ulcer on her mandibular alveolar mucosa
Sharon J. Akrish, DDS,a,b,cAdi Rachmiel, DMD,a,cImad Abu El-Naaj, DMD,dand Ofer Ben-Izhak, MDb,c (Oral Surg Oral Med Oral Pathol Oral Radiol 2020;129:3 7)
A 79-year-old female presented to her oral surgeon with a 3£ 2 cm indurated ulcerated mass on her man- dibular left alveolar mucosa and a palpable enlarged submandibular lymph node, which were present for 2 weeks (Figure 1). Four years earlier, the patient had been diagnosed with diffuse large B-cell lymphoma of the germinal center type, involving the liver and spleen. At that time, treatment consisted of 6 cycles of (R-CHOP) chemotherapy. The patient was in remission at the time of presentation.
CLINICAL DIFFERENTIAL DIAGNOSIS
In the oral cavity, a clinically asymptomatic and indu- rated deep ulcer, especially with an enlarged cervical lymph node, is highly suspicious for a malignancy of either hematolymphatic origin (lymphoma) or epithe- lial origin (squamous cell carcinoma). Other clinical entities that present with a similar clinical appearance include traumatic ulcerative granuloma with eosino- philia (TUGSE), deep fungal infection, and post-trans- plant lymphoproliferative disorder (PTLD). TUGSE is a chronic, benign, self-limiting lesion of the oral mucosa with an unclear pathogenesis. Although it may appear at any intraoral site, the most common location is the tongue. Treatment is local and following a biopsy procedure, spontaneous resolution is seen. Within the oral cavity, deep fungal infections that present as an indurated, deep ulcer include histoplasmosis and mucormycosis. Intraoral cases are relatively rare and usually appear with the disseminated form of the dis- ease, primarily in immunocompromised patients. A differentiating feature from the current case presented
is that most cases are symptomatic, painful lesions.
PTLD is a lymphoid proliferation or lymphoma that develops in immunocompromised patients after they receive a solid organ or bone marrow allograft. Evi- dence shows that the majority of PTLD are caused by an Epstein-Barr virus (EBV) infection. About 20% to 30% of PTLD cases occur in the head and neck region.
Within the oral cavity, the common location is the tongue, palate, and gingiva.
MICROSCOPIC AND RADIOGRAPHIC FEATURES (FIGURES 2 5)
An excisional biopsy was conducted, and the tissue specimen was sent to the pathology department. The tissue sections showed ulcerated mucosa with poly- morphous, dense, mixed inflammatory infiltrate, a few apoptotic cells, and scattered large pleomorphic blasts reminiscent of Reed-Sternberg cells. The atypical B-lymphocytes were found at the base of the ulcer, without deep extension, and stained positive for CD30 and latent membrane protein-1 (LMP-1) of EBV, par- tially expressed CD20 and PAX-5, and were negative for CD79a, BCL-6, and cytokeratin. EBV positivity was also identified by using EBV-encoded RNA-1 in situ hybridization. Numerous CD3-positive small T lymphocytes and CD68-positive histiocytes sur- rounded the atypical B lymphocytes. Ki-67 showed brisk cell proliferation of the atypical B cells. The tis- sue specimen was also sent for polymerase chain reac- tion (PCR) analysis, which is a standard tool for distinguishing polyclonal B-cell populations from monoclonal B-cell populations. PCR analysis revealed monoclonal IgH rearrangement.
Radiographic features (Figure 6)
Panoramic radiography did not show intraosseous changes or infiltration, although the CT scan revealed an enlarged submandibular lymph node.
DIAGNOSIS AND MANAGEMENT
On the basis of the microscopic and immunopheno- typic features, together with the lack of deep extension of the atypical B lymphocytes, a diagnosis of
aDepartment of Oral and Maxillofacial Surgery, Rambam Medical Center, Bat Galim, Haifa, Israel.
bDepartment of Pathology, Rambam Medical Center, Bat Galim, Haifa, Israel.
cTechnion School of Medicine, Bat Galim, Haifa, Israel.
dDepartment of Oral and Maxillofacial Surgery, Baruch Padeh Medi- cal Center, Faculty of Medicine, Bar Ilan University, Galilee, Israel.
Received for publication Feb 5, 2018; returned for revision May 24, 2018; accepted for publication May 30, 2018.
Ó 2018 Elsevier Inc. All rights reserved.
2212-4403/$-see front matter
EBV-positive mucocutaneous ulcer (EBV-MUC) was rendered. As the patient is currently not taking immu- nosuppressive medications, it is suspected that her advanced age is the contributing factor in the develop- ment of EBV-MUC.
Following the biopsy procedure, no further treatment was rendered. Six months later, there was nearly com- plete resolution of the lesion with a small area of resid- ual leukoplakia and scar tissue. There was no evidence of a recurrence or lymph node enlargement (Figure 7);
therefore, it was decided to continue monitoring the patient on frequent recall appointments and spare her any further surgeries at this time.
EBV-MUC is a distinctive, localized, and self-limiting type of EBV lymphoproliferative disorder. It is found in patients with various causes of immunosuppression, which include advanced age, AIDS, immunosuppres- sive medications, and transplantatioin.1
Microscopic differential diagnosis
Distinguishing EBV-MUC from the more aggressive and systemic PTLD is essential because of the different treatment regimens. Unlike PTLD, EBV-MUC mani- fests as isolated mucosal lesions. In addition, EBV- MUC does not present with increased whole blood EBV DNA, even though tissue specimens positively express EBV-encoded RNA and LMP-1.2
TUGSE, a reactive lesion of unknown etiology, shares many of the microscopic features found in EBV-MUC.3 TUGSE presents microscopically as an ulcerated lesion that contains a polymorphic inflamma- tory infiltrate rich in T cells and atypical B cells, as well as numerous eosinophils found deep within the connective tissue infiltrating between the skeletal mus- cle fibers. Like EBV-MUC, Hirshberg et al. published a study that described CD30+ atypical B cells in 25%
of their TUGSE cases.3
Distinguishing EBV-MUC from a B-cell lymphoma microscopically is challenging, especially in patients with a history of lymphoma. Furthermore, as was Fig. 1. Clinical photograph from the left maxillary alveolar
mucosa with an indurated, deep ulcer.
Fig. 2. Epstein-Barr virus positive mucocutaneous ulcer (EBV-MUC). A, Low-power view showing an ulcerated frag- ment of loose fibrous connective tissue with an intense inflammatory reaction without deep extension. (hematoxylin and eosin [H&E], original magnification£ 40). B, Higher- power view of the polymorphous, dense, mixed inflammatory infiltrate (H&E, original magnification£ 100).
Fig. 3. Epstein-Barr virus positive mucocutaneous ulcer (EBV-MUC). High-power view of the inflammatory infiltrate with large atypical B lymphocytes and some large pleomor- phic lymphoid blasts reminiscent of Reed-Sternberg cells (short black arrows), binucleated plasma cells (long black arrow), and numerous scattered eosinophils (black arrow- head). (hematoxylin and eosin [H&E], original magnifica- tion£ 200)
shown in the current case, PCR for IgH rearrangement may show a monoclonal proliferation of EBV-infected B lymphocytes, as with a lymphoid malignancy.1How- ever, in EBV-MUC, the atypical B cells are limited to
the base of the ulcer, with minimal extension into the deep connective tissue. In addition, immunohistochem- ical stains, such as CD3 and CD68, will reveal numer- ous histiocytes and reactive T cells that surround the atypical B cells. T-cell/histiocyte-rich B-cell lympho- mas, which are rare variants of B-cell lymphoma, may be microscopically indistinguishable from EBV-MUC, but no intraoral cases have yet been published.4 In addition, unlike some cases of EBV-MUC, T-cell/his- tiocyte-rich B-cell lymphomas do not express CD30.5
Intraoral EBV-MUC, although a common location for EBV-MUC, is relatively rare. Other cases have been described in the oropharynx, skin, and gastroin- testinal tract.6
A PubMed search of all intraoral cases published in the English language literature from 2012 to 2017, in addition to the current case, revealed 10 single or small series case reports with a total of 20 patients2,6-13 (Table I).
Clinicopathologic analysis revealed that the tongue (n = 7) and the palate (n = 5) were the most common intraoral locations followed by the gingiva (n = 4) and the labial mucosa (n = 1). Clinically, the majority were asymptomatic, deep, and indurated mucosal ulcers.
Fig. 4. Immunohistochemical stains of LMP-1 (A) and CD30 (B)showing strong staining of the lesional cells, limited to the base of the ulcer without deep extension (original magni- fication£ 100).
Fig. 5. Strongly and diffusely positive immunohistochemical stains of Epstein-Barr virus positive mucocutaneous ulcer (EBV- MUC). A, CD3-T-cell marker (original magnification£ 100). B, CD68-histiocyte cells marker (original magnification £ 40). C, Ki67-proliferation marker (original magnification£ 100).
Fig. 6. Panoramic radiograph confirming that the lesion is limited to the soft tissue without intraosseous extension.
Only a minority of patients experienced tenderness, pain, or trismus. The precise source of immunosuppres- sion can be divided into “medication related” (60%) and
“age related” immunosuppression (35%). One case was unknown. Mycophenolate (33%) and methotrexate (33%) were the most common immunosuppressive drugs that contributed to EBV-MUC.2,6,8,11 Azathio- prine, cyclosporine-A, and antiretroviral medications6,10 were mentioned in 1 case each. Eight patients were being treated for a systemic disease (rheumatoid arthri- tis, sarcoidosis, and HIV infection),6,8,10,11 and 2 were being treated for a malignancy (breast cancer and
lymphoma).7,13Only 3 patients from a single case report were organ transplant recipients (15%).2Conservative treatment was the treatment of choice in all cases, with many resolving spontaneously after cessation of the immune-inducing medications. No transformation to a malignancy or recurrence was reported.
EBV is a member of the herpesvirus family, and sali- vary contact is the mode of EBV transmission. It has been reported that over 90% of the adult population has been exposed to EBV, and once infected, the per- son becomes a lifelong carrier.14Initially, EBV enters through the squamous epithelium of the oropharynx, where it causes an acute infection and then enters a latent stage.15The virus may persist in memory B cells, and therefore, reactivation may occur wherever B cells reside.16In healthy individuals, an EBV-specific cyto- toxic T-lymphocyte (CTL) response to latent viral pro- teins act to prevent the expansion of these activated B cells. In the immunocompromised patient, CTL is often suppressed, and there is a compromised ability for anti- body feedback inhibition of the lymphoid prolifera- tion.17 When combined with a system overload of EBV, an EBV-associated lymphoproliferative disease or a lymphoid malignancy may result. Chronic stimula- tion of EBV on epithelial cells may allow the oncovirus to acquire the capacity to activate intracellular signal- ing that control B-cell proliferation, a process that appears to be partially responsible for the lymphoid malignancies often found in immunocompromised patients.18 EBV has been implicated as the causative
Table I. Twenty patients presenting with intraoral EBV-MUC
Cases Age/gender Location Source of immunosuppression
Akrish S et al., 2017 76/f Man gingiva Old age none
Satou et al., 2017 52/f Tongue DLBCL PBSCT
Chen B et al., 2017 58/f Man gingiva RA MTX
Dojcinov S et al., 2010 80/f Palate Old age none
84/f Tongue Old age None
64/f Tongue Old age none
68/f Tongue Old age none
80/m Tongue RA MTX
42/m Max gingiva Sarcoidosis & MG AZA
48/f Tongue SLE CYA
60/f Labial mucosa RA MTX
Roberts T et al., 2016 49/f Palate & Gingiva n/a n/a
Bunn B et al., 2015 54/m Palate HIV Antiretroviral
36/f Palate HIV n/a
Kenemitsu M et al., 2015 45/m Max gingiva SLE MYC
Maghales M et al., 2015 81/f Palate Old age none
Hart M et al., 2014 33/m Tongue Kidney transplant MYC
63/f Gingiva Kidney transplant MYC
18/m Buc muc and Tonsil Heart transplant MYC
Attard A et al., 2012 81/f Tongue Breast cancer MTX
AZA, azathioprine; Buc muc, buccal mucosa; CYA, cyclosporine-A; DLBCL, diffuse large B-cell lymphoma; EBV-MUC, Epstein-Barr virus posi- tive mucocutaneous ulcer; Man, mandible; Max, maxilla; MG, myasthenia gravis; MTX, methotrexate; MYC, mycophenolate; PBSCT, peripheral blood stem cell transplantation; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.
Fig. 7. Clinical photograph from the left alveolar mucosa 6 months after the biopsy procedure showing nearly complete healing of the ulcer.
factor in several other reactive and neoplastic intraoral lesions. Reactive lesions include hairy leukoplakia, a white patch found on the lateral tongue in immuno- compromised patients, primarily patients with HIV infection; acute sialadenitis, where EBV is one of the causative agents19; and viral lymphadenitis (mononu- cleosis).20 EBV as an etiologic factor in Sj€ogren dis- ease is still being debated.21Intraoral EBV-associated neoplastic lesions are rare and include lymphoepithe- lial carcinoma of the salivary gland (undifferentiated carcinoma),22 nasopharyngeal carcinoma,23 endemic Burkitt lymphoma,24 and extranodal natural killer-/T- cell lymphoma, nasal type.25
The clinicopathologic features of EBV-MUC, espe- cially when presenting with a monoclonal IgH rear- rangement, may strongly resemble a hematologic malignancy. Recognizing the subtle microscopic and immunohistochemical features of EBV-MUC may allow for an accurate diagnosis and prevent excessive treatments. EBV-MUC has a self-limiting, indolent clinical course, and although the management guide- lines have yet to be ascertained, conservative therapy seems to be the treatment of choice.4In fact, as in our reported case as well as in others, the lesion often resolves spontaneously once the underlying immuno- suppression is corrected.
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Reprint requests: Sharon J. Akrish, Yahalom 2 Caesarea, 38900 Israel