Intraoral CD30+ T-Cell Lymphoproliferative Disorder with Lymphomatoid Papulosis Type C Features Mimics Lymphoma Histopathologically and Immunohistochemically

Abstract

Background

Previous studies have shown that at least a of intraoral eosinophilic ulcer is best classified as a CD30 + T-cell lymphoproliferative disorder (LPD), with histopathology reminiscent of lymphomatoid papulosis (LyP) of the skin. Microscopically, a mixed population of inflammatory cells, often including eosinophils and varying numbers of atypical lymphoid cells, frequently expressing CD30, is typical for LyP, whose clinicopathological spectrum includes type A, B, C, D, E, and LyP with DUSP22/IRF4 rearrangement. To date, about 27 intraoral LyP cases have been reported. Of them, 7 cases were diagnosed as LyP type C, which is frequently confused with anaplastic large cell lymphoma (ALCL) on histopathology.

Methods

A 60-year-old male was referred for a one-month history of a tongue ulcer.

Results

Microscopy showed numerous subepithelial atypical large lymphoid cells, which expressed CD4 (with partial loss of CD3, CD5, and CD7), CD8 (few cells), CD30 (about 50%, in non-diffuse pattern with size variability), TIA-1, and Ki-67 (85%), without staining for CD56, ALK, LMP1, and EBER1/2, concerning for a diagnosis of ALCL. However, after three weeks, the lesion completely healed.

Conclusion

We present here a rare case of intraoral CD30+ T-cell LPD that we believe is the oral counterpart of cutaneous LyP type C.

Introduction

Self-resolving or waxing and waning CD30 + T-cell lymphoproliferative diseases are well-recognized in the skin; such proliferations of the oral cavity are rare and present an important diagnostic challenge [1–3]. If incorrectly identified, a misdiagnosis of high-grade lymphoma may have significant therapeutic and prognostic implications. The eosinophilic ulcer or traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) of the oral mucosa is, in many cases, felt best categorized as such and deserves attention in the head and neck pathology literature, especially since some cases show numerous large atypical mononuclear cells and few or scarce infiltrating eosinophils [1, 2]. Relevantly, Ficarra et al. (1997) suggested that a TUGSE subset represents a CD30 + T-cell lymphoproliferative disorder (LPD) [4], with subsequent studies showing T-cell clonality within TUGSE [1, 2] with histopathology very reminiscent of cutaneous lymphomatoid papulosis (LyP) [2, 5, 6].

To date, about 27 intraoral LyP cases have been reported [3, 7, 8]. Of them, 7 cases were diagnosed as LyP type C, the type most similar in appearance to anaplastic large cell lymphoma (ALCL) [3, 7, 8].

Case Report

A 60-year-old Brazilian man presented with a tongue ulcer which developed 4 weeks before consultation. The patient’s medical history was noncontributory, and he denied trauma, surgery, or use of medication. Involvement of other mucosal surfaces and skin was excluded on extraoral examination. Clinically, a large ulcer on the right lateral border of the tongue was observed (Fig. 1A). The patient reported pain and difficulty eating. The clinical differential diagnoses included traumatic ulcer, eosinophilic ulcer, infectious disease, and squamous cell carcinoma. HIV, syphilis, and hepatitis B and C serologic tests were negative. Incisional biopsy was performed and microscopic examination revealed a dense subepithelial lymphoid infiltrate, without epitheliotropism, composed of numerous medium-sized to large atypical cells, showing irregular nuclear contours and conspicuous nucleoli, admixed with many fewer small lymphocytes (Fig. 2A-C). Immunohistochemistry showed that the atypical lymphoid cells were immunoreactive for CD4 (with partial loss of CD3, CD5, and CD7), CD8 (few cells), CD30 (about 50%, in non-diffuse pattern with size variability), and TIA-1. Ki-67 stained the majority (85%) of atypical cells. CD20, PAX5, CD56, ALK, LMP1, and in situ hybridization to Epstein–Barr virus–encoded RNA (EBER1/2) were negative (Fig. 2D-Q). These findings were suspicious for ALCL. However, clinicopathological correlation, especially considering the significant improvement of the lesion after topical corticosteroid (clobetasol propionate 0.05% oral solution) administered for 2 weeks, favored a CD30 + T-cell LPD with features of LyP type C. After 1 additional week, there was complete resolution (Fig. 1B). Currently, with 1 year of follow-up, the patient is well, without relapse.

Fig. 1.

Clinical photograph showing a large ulcer on the right lateral border of the tongue (A). After 3 weeks of follow-up, the lesion completely healed (B)

Fig. 2.

Microscopic, immunohistochemical and in situ hybridization (ISH) studies. Large areas showing a compact lymphoid proliferation beneath the epithelium composed of numerous medium-sized to large atypical cells (H&E stain; A, x4; B, x10; C, x40). Immunohistochemical analysis revealed that the atypical lymphoid cells were positive for CD3 (D), CD4 (E), CD5 (F), and CD7 (G). Notice partial loss of CD3, CD5, and CD7 expression. CD8 stained only few lymphoid cells (H). CD20 (I) and PAX5 (J) were negative. CD30 highlighted about half of atypical lymphoid cells, in non-diffuse pattern with size variability (K), while CD15 was negative (L), with TIA-1 showing positivity in a similar proportion to CD30 (M). ALK (N), CD56 (O), and LMP1 (P, including EBER/12 by ISH [not shown]), were negative. Ki-67 highlighted most (85%) atypical lymphoid cells (Q) (D-Q, x10, inset x40)

Discussion

According to the World Health Organization (WHO) classification [9], CD30 + T-cell LPDs present with a wide clinicopathological spectrum and include primary systemic and cutaneous diseases. CD30 + T-cell LPDs include true lymphomas such as ALK-positive ALCL and ALK-negative ALCL, while primary cutaneous CD30 + T-cell LPDs are classified into primary cutaneous ALCL and LyP [7, 9, 10]. In addition, benign atypical intralymphatic CD30 + LPD, infectious diseases, and non-infectious inflammatory processes (pityriasis lichenoid and varioliformis acuta, atopic dermatitis, drug-induced reactions, and insect bites) containing CD30 + atypical lymphoid cells should also be included in the differential diagnosis [7, 11, 12].

The authors present here a rare case of intraoral CD30 + T-cell LPD that is felt to represent the oral counterpart of cutaneous LyP type C, as previously reported [3]. Clinically, LyP presents as papulonecrotic eruptions, small nodules, and ulcerations in different stages of evolution, often showing self-healing. Although rare in children, LyP can afflict patients of any age [13]. The clinicopathological spectrum of LyP includes type A, B, C, D, and E, and LyP with DUSP22/IRF4 rearrangement on chromosome 6p25.3 [3, 7, 13]. LyP type A represents > 80% of all LyP cases, and typically shows scattered CD4+/CD30 + Reed–Sternberg–like cells within the background of other inflammatory cells. LyP type B (< 5%) shows intraepidermal/intraepithelial infiltrates of CD4 + small/medium-sized atypical lymphoid cells, with variable expression of CD30, simulating early-stage mycosis fungoides. In LyP type C (10%), a dense infiltrate of sheets of CD4+/CD30 + pleomorphic cells are present in the dermis/lamina propria-submucosa. LyP type D (< 5%) and LyP type E (< 5%) exhibit a predominant epidermotropic and angiocentric/angiodestructive infiltrate of CD8+/CD30 + small/medium-sized atypical lymphoid cells, respectively. LyP with DUSP22/IRF4 rearrangement shows an epidermotropic and dermal infiltrate of CD30 atypical lymphoid cells [7, 8, 13].

LyP type C may be indistinguishable from ALCL on histopathology and clinicopathologic correlation is essential [3, 9, 13]. Most patients with primary cutaneous ALCL present with solitary or localized skin plaques, nodules, or tumors, following a progressive or aggressive course. Relevantly, this disease may have primary mucosal involvement or, rarely, concomitant mucosal and cutaneous involvement. ALCL is defined phenotypically by CD30 expression of at least 75% of large lymphoid cells, which are uniformly positive for CD4 and cytotoxic markers (TIA-1, granzyme B, and perforin), with variable loss of CD2, CD3, CD5, and CD7 antigens. Radiation therapy and multi-agent chemotherapy can be therapeutic approaches [6, 12, 13]. In the current case, the lesion resolved after 3 weeks, CD30 was expressed in about 50% of large atypical cells in non-diffuse pattern with size variability, without obvious loss of CD5 and CD7 antigens, the former in particular favoring LyP type C. To date, about 35 ALCL cases affecting the oral cavity have been reported [14, 15]. Most cases occurred in male patients (n = 23), with a mean age of 53 years. The gingiva/alveolar ridge was preferentially affected (n = 14), followed by hard palate (n = 6), tongue (n = 5), and lip (n = 4) [14, 15].

Intraoral LyP is rare. To date, including the current case, 28 cases have been reported. Of them, 18 were women and 10 were men, with a mean age of 48 years (range, 19–85 years). The tongue was commonly affected (n = 16), followed by lips (n = 5), buccal mucosa (n = 4), palate (n = 2) vestibular fornix (n = 1). Eight patients (28%) presented with cutaneous involvement before oral lesions, and 20 (71%) reported relapse. Eight of 28 cases were diagnosed as LyP type C. Of them, 6 were women and 2 were men, with mean age of 53 years (range, 38–71 years), affecting the tongue (n = 4), lip (n = 2), tongue/lip (n = 1), and tongue/buccal mucosa (n = 1). No case had skin involvement. For 4 patients no treatment was used, 3 cases were treated with dexamethasone, and 1 case was treated with chemotherapy [3, 7].

Funding

Jorge Esquiche León have received research Grants (2016/11419-0; 2022/07479-9 and 2022/12760-9) from State of São Paulo Research Foundation (FAPESP) and research Grant (304241/2021-0) from National Council for Scientific and Technological Development (CNPq).

Data Availability

The data underlying this study are available in the article.

Code Availability

Not applicable.

Declarations

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent for Publication

Consent for publication was obtained for every individual person’s data included in the study.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Conflict of Interest

The authors declare that they have no conflict of interest.