From Volume 38, Issue 7, September 2011 | Pages 472-476
A case of a 66-year-old man, who was referred to the Oral Medicine service with persistent oral ulceration and widespread cutaneous rash is presented. Laboratory investigations confirmed a diagnosis of epitheliotropic, CD8-positive, cytotoxic, T-cell lymphoma.
Lymphoma is the second most common malignant oral disease.1,2 Non-Hodgkin lymphoma is the fifth most common cancer in the UK.3 Lymphoma represents a group of haematological neoplasms with many defined classifications, essentially divided into Hodgkin and non-Hodgkin lymphoma of B or T lymphocyte origin. The disease is a malignant proliferation of lymphocytes, usually seen in lymph nodes with extra-nodal primary malignancies less common. The incidence of cutaneous lymphoma has been reported as increasing.1,4
A 66-year-old gentleman was referred to the Oral Medicine service by his general medical and dental practitioners simultaneously. In his referral, the GP outlined a history of persistent, worsening and confluent mouth ulcers. These had arisen at the same time as a widespread, macular and erythematous skin rash.
The patient had presented to both his general medical and dental practitioners three months earlier with left-sided angular cheilitis, which he associated with recent dental treatment. Swabs from this lesion showed a growth of Candida, which duly responded to treatment with fluconazole. However, by this time the patient was beginning to develop a cutaneous rash. This rash started with a large lesion on the thorax, which was red, asymptomatic and quickly faded. Thereafter many red, asymptomatic, macular and circular lesions spread across the rest of the patient's skin. It was thought that this solitary truncal lesion, preceding a more extensive rash, was a ‘herald lesion’. Accordingly, a provisional diagnosis of pityriasis rosea was made.
Pityriasis rosea is a common cutaneous condition that presents with discrete, scaly, ovoid plaques, notably preceded by a herald patch. Despite the dramatic appearance of pityriasis rosea, it is self-limiting and requires only symptomatic control of itching.5Pityriasis rosea does not, however, present intra-orally. In the intervening time the patient's rash progressed and he developed oral ulceration.
At his first visit to the Oral Medicine clinic, the patient complained of being unable to wear his dentures or eat solids owing to the ulcers affecting multiple intra-oral sites. His symptoms by this stage had spanned five months, despite treatment with Adcortyl in Orabase, Beclometasone spray and various skin ointments. The patient reported no systemic upset other than mild night sweats and weight loss, which he attributed to reduced food intake through his painful mouth. There were no symptoms affecting his eyes, nasal passages or genital tract.
Past medical history included osteoarthritis, GORD and borderline hyperglycaemia. The patient was a single, 66-year-old, retired agricultural worker who had given up smoking 15 years previously and imbibed very little alcohol.
On clinical examination no cervical lymphadenopathy was detected. A widespread macular rash was evident across the patient's face, with angular cheilitis on the left side (Figure 1), arms and trunk (Figure 2). One lesion on the left forearm appeared to be more papular with a central punctum and a ‘target lesion’ appearance. Target lesions are characteristic of erythema multiforme. Intra-orally, sloughing ulceration was seen across multiple intra-oral sites (Figure 3), including the palate (Figure 4), which did not have an aphthoid appearance.
Given this history and clinical presentation, our differential diagnosis included:
Haematological investigations requested included syphilis serology, Borrelia serology, antinuclear antibodies and circulating skin antibodies. Two incisional biopsies of ulcerated buccal mucosa were performed: one sample was preserved in formalin for conventional histopathological examination, while the other was sent fresh for direct immunofluorescence.
The results of haematological investigations were within normal ranges. Direct immunofluorescence proved to be negative for IgG, IgA, IgM and C3. Histopathological examination revealed a large shallow ulcer with acute inflammatory exudate and a base of organizing inflamed granulation tissue. The epithelium adjacent to the ulcer and the underlying corium were extensively infiltrated with lymphocytes, some of which displayed irregular nuclear outlines (Figure 5). This histology could have supported many of the possibilities in our differential diagnoses. Immunohistochemical analysis found that the infiltrative lymphocytic cells were almost all T-cells of CD8 phenotype (Figure 6). This phenotype is rarely seen in cutaneous T-cell lymphoma.6 A high rate of labelling was also seen with the proliferation marker Ki-67.
Following review by the East of Scotland Lymphoma Pathology Review Group, a diagnosis of epitheliotropic CD8-positive cytotoxic T-cell lymphoma was made. This diagnosis was further supported by a cutaneous biopsy. This rare CD8 phenotype was only first described as a distinct disease entity in 1999 by Berti et al.7
This patient was referred to our haematology colleagues for further investigation, including bone marrow biopsy, CT and management via the haematology multidisciplinary team. He was commenced on combination chemotherapy, which has been shown to have a higher complete response rate than other therapies in cases of cutaneous lymphoma.6
Lymphoma is a malignancy characterized by the excessive production of B or T lymphocytes. Lymphoid malignancies are generally classified as leukaemia, if they primarily involve the blood and bone marrow, and lymphoma if they present in the lymphatic system or other organs.
First described by Thomas Hodgkin in 1832, the term ‘lymphoma’ now encompasses a wide heterogeneous group of pathologies. Non-Hodgkin lymphoma presents more commonly than Hodgkin lymphoma and, with an incidence of 12 in 100 000, is the fifth commonest cancer in the UK.3 Histologically, Hodgkin lymphoma is characterized by the presence of occasional Reed-Sternberg cells, which have paired nuclei, not seen in non-Hodgkin lymphoma.
Hodgkin lymphoma is most common among Caucasian males, with a primary peak incidence between ages 15 and 34 years, with a second peak later in life. This is unlike other malignancies whose incidence increases with progressing age.3 Most cases of non-Hodgkin lymphoma arise within the lymphatic tissue, ie lymph nodes, bone marrow or spleen, although other body systems may be involved. The gastrointestinal tract, including the oral cavity, is the most common site of a primary extra-nodal lymphoma, with the skin the second most common.
These pathologies have been classified by the World Health Organization8 and are divided into four groups, according to the type of lymphocytes involved and their state of maturity. Individual prognosis depends on the classification of the disease, for example small lymphocytic lymphomas are indolent while Burkitt's lymphoma is more aggressive. As in any neoplastic disease, the individual case must be correctly and accurately staged in order that the appropriate treatment might be arranged. The Ann Arbor staging system9,10 provides the basis for anatomical staging of both Hodgkin and non-Hodgkin lymphoma and serves a similar purpose as the TNM system does for solid tumours (Table 1). There are four stages which relate to the anatomical sites involved. Stages are modified by extra-nodal disease or the presence of fever, night sweats or weight loss.
| Stage Features | |
| I | Involvement of a single lymph node region or lymphoid structure (eg spleen, thymus, Waldeyer's ring). |
| II | Involvement of two or more lymph node regions on the same side of the diaphragm. |
| III | Involvement of lymph regions or structures on both sides of the diaphragm. IV Involvement of extra-nodal site(s) beyond that designated E. |
| For all Stages | |
| A | No symptoms. |
| B | Fever (>38°C), drenching sweats, weight loss (10% body weight over 6 months). |
| For Stages I to III | |
| E | Involvement of a single, extra-nodal site contiguous or proximal to known nodal site. |
The five-year survival rate is based upon certain prognostic factors, reduced prognosis being conferred by:
The aetiology of lymphoma is uncertain but, in common with other malignancies, DNA changes result in abnormal cell division and apoptosis. Viral aetiology has been suggested; in particular Epstein Barr virus is associated with Hodgkin lymphoma, some T-cell lymphomas and some lymphomas associated with immunosuppression. Mucosa Associated Lymphoid Tissue (MALT), lymphoma affecting the salivary glands, thyroid or stomach, is thought to be linked with the chronic immune stimulation of connective tissue diseases, such as Sjögren's and Hashimoto's disease. Patients with Sjögren's syndrome have a 5% lifetime chance of developing lymphoma.12 Unlike other malignancies, no apparent link with tobacco smoke, alcohol or ionizing radiation has been found. Links with pesticides and viral infection are currently under investigation.
After squamous cell carcinoma, non-Hodgkin lymphoma is the second most common intra-oral malignancy.1,3 The incidence of cutaneous lymphoma has been quoted as 0.4 per 100,000 per year.7 This incidence, however, has seen a substantial increase in recent times,4 possibly due in part to the AIDS epidemic.1 Owing to the rising incidence, it is more likely that the general dentist may encounter hitherto undiagnosed symptoms and signs associated with lymphoma (Table 2). In addition, an increased number of oral complications arising from lymphoma and its treatment will need consideration.
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Presentations
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In particular, patients with lymphoma are more susceptible to infection due to altered immunity as a result of lymphocyte abnormality, and from decreased numbers of neutrophils following chemotherapy. Dental screening and treatment should be arranged, ideally, before the commencement of chemo- or radiotherapy to prevent later osteoradionecrosis, odontogenic and mucosal infection, or other complications.
Xerostomia affects many lymphoma patients and may have a number of aetiologies. In addition to the effects of radiotherapy, xerostomia may be brought about by chemotherapy, opiate analgesics, sedatives and anti-depressants. The effects of reduced salivary flow on caries risk and mucosal infection are well known. General dentists are well placed to provide appropriate prevention with fluoride preparations and artificial saliva.
Oral mucositis, which has its own WHO classification system,13 is an inflammation principally of the non-keratinized oral mucosa, ranging in severity and resulting from the effects of cytotoxic chemotherapy or local irradiation. The consequences of mucositis are pain, inability to tolerate food, deterioration of oral health and ulceration, which provides a route for opportunistic infection in an already immunocompromised patient. Local irritants such as sharp teeth, calculus, defective restorations, and poor prostheses may aggravate mucositis. The literature does not support one single treatment of mucositis; however, benzydiamine hydrochloride mouthwash and chlorhexidine mouthwash are frequently employed.
Thrombocytopenia is defined as having a platelet count below 100 x109 g/L and may affect lymphoma patients because of chemotherapy, autoimmune causes or bone marrow suppression by irradiation or malignant disease. This may manifest as mucosal petechiae, haematoma or spontaneous gingival bleeding, especially if periodontal disease is present. Affected patients should avoid aspirin and use a soft toothbrush. Consideration needs to be given to possible thrombocytopenia when planning invasive procedures.12
Aplastic anaemia is a serious complication in lymphoma which carries a poor prognosis, with a 50% mortality rate in six months. Symptoms are the same as for any other form of anaemia with an additional abnormal susceptibility to infection and bleeding tendencies from associated leukopenia and thrombocytopenia. Treatment may involve bone marrow transplantation.
The role of the dentist in regard to oncology patients, particularly those with lymphoma, must include screening for undiagnosed disease, providing often radical dental treatment prior to chemo- or radiotherapy and maintaining appropriate dental and periodontal health. In addition, dentists should be able to recognize and manage the oral side-effects of cancer treatment, including mucositis, infection and bleeding.
