Metastasising malignant lymphoma mimicking necrotising and hyperplastic gingivostomatitis

ARTICLE

CD30⁺ large cell anaplastic lymphoma has recently been described as a variant of malignant T cell lymphoma characterized by fulminant nodal and extranodal growth [1, 2]. Specific primary or secondary oral manifestations of T cell lymphoma are rare. Oral features are described as simultaneously necrotising and hyperproliferative infiltrates of the palate, tonsils, gingiva and buccal mucosa, clinically presenting with fever, pain and wasting [3, 4]. The loss of the mucosal barrier function, due to invading lymphoma mass and microbial overgrowth, and the acquired immunodeficiency status represent a risk of septicaemia originating in the mouth.

Aphthae are known as unspecific lesions in conjunction with immunological imbalance of various causes [5, 6]. Recurrent and persistent oral aphthae which become more necrotic and concurrent mucosal hyperplastic lesions may be indicators of this type of underlying malignant lymphoma, as outlined by the following case.

Case report

A 65 year-old woman presented with recurrent and later persistent painful oral ulcerations. Initially, they were isolated, lentil-sized and located on the lower muco-gingival border and the mucosal aspect of the lower lip. Single lesions healed within a few days. Over a period of 2 months, there was a balance of clearing and newly developing lesions so that some minor oral aphthoid ulcers were always present. At first presentation, painful mucosal lesions were present which were increasing in size and tending to merge. They were located on the middle and posterior third of the bony palate extending to the left buccal mucosa and the floor of the mouth. These ulcerations showed shiny, firmly attached fibrinous membranes, well delimited borders, and a bizarre shape (Fig. 1). They were surrounded by an erythematous inflammatory area. The lesions were of several different sizes. Histopathology revealed a non-specific necrosis, rich in fibrin and neutrophil granulocytes, consistent with unspecific oral aphthous ulceration.

Topical antimycotic treatment with amphotericin B and systemic anti-inflammatory and antiviral therapy with prednisolone and aciclovir, respectively, was started.
Thereafter, the lesions slowly healed.

Five weeks later, the woman was admitted again with distinctly foetid necroses of the oral mucosa and undulating septic fever. At this time, the entire oral mucous membrane was inflamed, oedematous and hyperaemic. An infiltrating, deeply and grossly ulcerating tumourous mucosal lesion with papillomatous areas as well as pseudomembranes was observed on the floor of the mouth. The necrotic ulcers extended to the mandibular gingiva and the buccal mucosa (Figs. 2 A and B). The remainder of the oral cavity showed some shiny aphthous ulcers of various size. There was no palpable lymphadenopathy. The general condition had markedly deteriorated due to septic fever bouts of up to 40° C.

Histopathological observation (Figs.3 A and B). Histology showed a marked necrosis with major reactive epidermal proliferation, but without specific pathognomonic alterations. There were only a few mitoses and focally increased dyskeratoses thought to be most probably reactive. Multiple sections gave the impression of a pseudocarcinomatous pattern. These changes were interpreted as reactive proliferating epithelia similar to necrotising sialometaplasia. Candida was not detected in PAS reaction. Malignant cells of epithelial or lymphocytic provenance were not detected.

Laboratory findings. Sedimentation rate 34/79; haemoglobin 4.9 mmol/l; haematocrit 0.23; ery 2.99; MCV 59fl; MCH 1.1fmol; leukocytes 4.9 Gpt/l; thrombocytes 556 Gpt/l; differential blood smear: polymorphs 0.67, lymphocytes 0.32, monocytes 0.01; CRP 99.1 mg/l; Iron 5.4 mol/l; transferrin 1.1 g/l; Ca 1.99 mmol/l; GGTP 3,643 nmol/l; AP 6.7 µmol/l*s; LDH 7.1 µmol/l*s (normal: < 6.5); total serum protein 48 g/l and albumin 29 g/l decreased, IgG 5.8 and IgM 0.3 markedly decreased. No paraproteins.

HTLV-1, HIV-1 and HIV-2 serology negative; HSV type I IgG antibodies: 1345/++; HSV type II IgG antibodies: 1,000/++ (reactivation?).

Immuno-phenotyping of circulating lymphocytes in the peripheral blood yielded the following data: lymphocytosis, but no B lymphocytes. Total T cells increased with doubling of CD8 cells, CD4 markedly reduced, CD30⁺. T lymphocytes exhibited CD8 markers. Almost all CD8⁺ cells carried HLA-DR antigen.

Interpretation: Suspicion of anaplastic large cell lymphoma, T cell type.

T cell function. Recall antigen testing (Multitest Mérieux) completely negative.

Blood culture. Staph. aureus found several times. Mycology: Candida albicans in saliva and stools++.

Oesophago-gastroscopy. Chronic active gastritis macroscopically and microscopically.

X-ray films, CT scan and MRI as well as sonography of head and neck: no signs of tumour infiltration and lymph node enlargement. Bone marrow biopsy without neoplastic infiltration.

Interpretation. Initially, after biopsy, laboratory, and all other examinations had virtually excluded autoimmune, neoplastic and internal systemic diseases, a tentative diagnosis of aphthous stomatitis of unknown aetiology with secondary Candida infection was reached. Due to thrombocytosis and a microcytic anaemia, an initial form of a myeloproliferative disorder was suggested. However, this could not be confirmed by bone marrow histopathology. The rapidly developing, deeply ulcerating and vegetating areas at first glance suggested a carcinoma or a lymphoma of the floor of the mouth. However, a diagnosis of an underlying malignant disease could not be reached histopathologically. Hence immuno-phenotyping of the blood cells indicated an anaplastic lymphoma of unknown site but haematogenous spread.

Treatment and follow-up. Despite combined broad-spectrum antibiotic therapy with flucloxacilline, gentamicin, metronidazole, and fluconazole, the ulcerous and hyperplastic oral lesions remained unchanged whereas a staphylococcal sepsis with cardio-pulmonary failure developed. The patient died 4 weeks later from acute gastro-intestinal bleeding.

Autopsy findings. Histopathology demonstrated infiltrates of polymorphous, large anaplastic lymphoma cells in the base of the hyperplastic oral lesion, in a submandibular lymph node, in a thrombus of the vena subclavia sinistra, in the oedematous pulp of the spleen and in the margins of both gastric ulcers (Figs.4 A and B). Immuno-histochemistry showed positive responses of the tumour cells for different T cell markers and CD30 antigen, MIB 1 revealed medium-grade proliferation. Cytokeratins were negative.

The ulcer on the anterior gastric wall was chronic and penetrating but still covered by the adjacent liver tissue. Acute gastric bleeding loss was the immediate cause of death.

Diagnosis. CD30⁺, large cell anaplastic T cell lymphoma.

Discussion

Except for recurrent benign oral aphthae, ulcerative oral (aphthous) lesions may reflect autoimmunological and neoplastic disorders or be secondary to inborn and acquired immune defects or to nutritional deficiencies.

Our patient first showed seemingly banal recurrent aphthous oral lesions that were initially interpreted as non-specific.Within a very short time, these developed into a fulminating necrotising and hyperplastic process on the floor of the mouth with secondary infection and a foetid odour.

Autopsy, which demonstrated lymphoma infiltrations into the floor of the mouth, submandibular lymph node, stomach, spleen, and thrombus of the subclavian vein, eventually confirmed the diagnosis of an extranodal large cell anaplastic CD30⁺ lymphoma already suspected from the immuno-phenotyping of peripheral mononuclear blood cells. The primary location of this extranodal lymphoma is not definitively clear, but it may have been the spleen or the gastric mucosa with haematogenous spread of lymphoma cells. The preferential localization in inflamed areas of the mouth and in a venous thrombus is of note. It could also be a concurrent nodal and oral CD30⁺ large cell lymphoma or a lymphoma with primary oral location.

Specific oral manifestations of T cell lymphomas are rare and were reported as ulcerous infiltrates of the palate, gums, tonsil and buccal mucosa. Aphthoid lesions devoid of tumour cells are regarded as non-specific markers of a more general immunological imbalance [3, 4, 6-9].

Anaplastic large cell lymphoma mainly affects young adults, mostly men in their second and third decades. It tends to develop as rapid nodal and extranodal growth with poor short-term response to intensive chemotherapy [1, 2, 10-13].

An exclusive cutaneous involvement has a more favourable prognosis [4, 12, 14]. Surgery and/or radiotherapy usually lead to complete remission. For these reasons, a correct diagnosis is essential. It is rendered difficult, how-ever, by the tendency of the lymphoma to simulate other inflammatory or neoplastic skin diseases, clinically and histopathologically [15].

Among the unusual clinical and histological types of cutaneous lymphomas, pseudoepitheliomatous hyperplasia has been poorly documented. This particular feature has occasionally been reported in cutaneous T cell lymphomas (CTCLs), especially in CD30⁺ anaplastic large cell lymphoma [16]. The clinical features of pseudoepitheliomatous hyperplasia mimicked a squamous cell carcinoma or keratoacanthoma. Courville et al. [17] evaluated in a group of 353 cases of cutaneous lymphomas the prevalence of this particular presentation as 28.5% of CD30⁺ cutaneous lymphomas and 2% of mycosis fungoides. They observed a relationship between the expression of EGFr (epidermal growth factor receptor) by the keratinocytes, and the thickening of the epidermis overlying the lymphomatous infiltrate. These results suggest that EGF and TGF alpha are secreted by lymphomatous T cells and may induce in some cases an epidermal hyperexpression of EGFr that is correlated with the presence of a pseudoepitheliomatous hyperplasia [17].

Secondary oral mucosal infiltration, seen terminally in this case of a presumed primarily extranodal malignant T cell lymphoma, is very rare and seems to be characterized by rapid necrotic ulceration [3, 4]. This causes considerable pain, interferes with food intake, leads to a foetid odour and decreased host defence against the invasion of pathogens [5, 6, 8]. The loss of topical barrier function due to the invading lymphoma mass, microbial overgrowth of transient, and even individual resident oral flora, and the acquired immunodeficiency status represent a risk of septicaemia originating from the mouth as an early lethal complication of oral lymphomas [5].

Our patient exhibited this serious spectrum of symptoms and developed a staphylococcal sepsis after an 8-week premonitory phase characterized by recurrent and later persistent and enlarging oral aphthae. This case report emphasises that oral malignant lymphoma may be the underlying cause of persistent aphthae and an extensive concurrent necrotising and hyperproliferative gingivostomatitis. The latter clinical appearance, even in conjunction with pseudoepitheliomatous (= pseudocarcinomatous) hyperplasia on the microscopic level may mimick an ulcerating squamous cell carcinoma.

It is difficult to establish whether the aphthoid lesions are premonitory signs of malignant lymphoma due to an immunological imbalance or a primary manifestation of the lymphoma itself.

Regressing oral aphthoid lesions may represent spontaneously regressing CD30⁺ lymphoma. Le Boit [18] even described the combination of pseudocarcinomatous epithelial hyperplasia and granulation tissue with neutrophil granulocytes in regressing large cell anaplastic non-Hodgkin lymphoma.

In brief, histology and immunohistology of deeply performed mucosal biopsy in addition with immuno-phenotypic blood cell analysis may enable early detection of an underlying primary or metastatic malignant lymphoma.

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