Mycosis fungoides involving head and neck mucosal sites: Review of the literature

A 59-year-old Caucasian woman presented to the Cutaneous Lymphoma Clinic of the Department of Dermatology at our institution with a generalized pruritic erythematous rash and lesions consistent with tumors on her right upper extremity and chest. She had a 4-year history of a rash first localized to her palms that had spread to several cutaneous sites, notably the gluteal folds and inframammary areas. Although originally diagnosed as having pustular psoriasis, biopsies of the right upper extremity and right chest lesions were consistent with mycosis fungoides. Hematopathology did not reveal any disease in her blood and she was diagnosed with stage IIB (T3N0M0Bx) disease. Immunohistochemistry of the biopsy specimen revealed an infiltrate that was CD2+, CD3+, CD5+, CD4-/CD8-, CD7-, and CD56-, with TCR-beta F1+ phenotype. T-cell receptor gamma gene rearrangement was positive for a clonal T-cell population.

The patient initially underwent total skin electron-beam therapy to a total dose of 36 Gy delivered in 24 fractions of 1.5 Gy each using the 6-dual-field irradiation technique.² During this period, she reported symptoms of a dry and sore throat as well as odynophagia. Esophagogastroduodenoscopy by an outside gastroenterologist revealed signs of reflux, and she began taking Lansoprazole (Prevacid, Takeda Pharmaceuticals USA, Deerfield, Illinois) 30 mg twice daily, which offered short-lived mild relief. A barium swallow revealed an unremarkable esophagus. Upon further evaluation in the Department of Otolaryngology, areas of inflammation consistent with laryngeal and oropharyngeal candidiasis were identified, and she received treatment with oral fluconazole for 4 weeks. Although the candidiasis resolved at that time, the patient continued to complain of persistent symptoms that were worse after meals and at night. Re-examination of her throat showed an irritated appearance of the posterior soft palate, uvula, and anterior tonsillar pillars (Figure 1A). Flexible nasopharyngolaryngoscopy revealed irritated mucosa diffusely on the epiglottis and arytenoids bilaterally with a similar appearance along the left lateral pharyngeal wall. Biopsy specimens from the uvula and epiglottis revealed lesions consistent with her previously diagnosed mycosis fungoides including an identical TCR-gamma clone. Immunohistochemistry demonstrated an infiltrate positive for CD2, CD3, CD5, CD43 and weakly positive for beta-F1. Infiltrates were negative for CD56, CD30, and CD20. Positron emission tomography and computed tomography (PET/CT) scans showed no involvement of her viscera and mild fluorodeoxyglucose (FDG) uptake of an SUV of 2.3 in her axillary and inguinal lymph nodes. The oropharyngeal and laryngeal lesions were treated with 6-MV photons using an intensity-modulated radiation therapy (IMRT) technique. The initial planned dose was 30.6 Gy to be delivered in 17 fractions. However, she developed confluent fibrinous mucositis (grade III) and severe odynophagia, which required multiple breaks in treatment, significantly prolonging treatment duration. Ultimately, we terminated her treatment at a dose of 20.8 Gy. Two years after treatment completion, the patient has had no local recurrence of her mucosal lesions. She has subsequently undergone external-beam radiation therapy on multiple occasions for localized skin lesions. She continues to follow up with dermatology and radiation oncology.

A 69-year-old Caucasian man was diagnosed with cutaneous mycosis fungoides 10 years prior to his presentation to our institution. At the time he was seen in the Department of Dermatology, he noted a 2-month history of new leather-like lesions on his bilateral extensor elbow surfaces. He also had multiple exophytic nodules on his bilateral lower and upper extremities, in addition to plaques on his torso and all 4 extremities. The mycosis fungoides lesions on his scalp had been treated with radiation therapy 5 years earlier, with no recurrence at those sites. He had also received intermittent psoralen and ultraviolet A (PUVA) light therapy and methotrexate until 3 years prior to presentation. At consultation, he was taking bexarotene (Targretin, Valeant Pharmaceuticals International Inc., Laval, Quebec, Canada) 75 mg 3 times daily in addition to using triamcinolone 0.1% cream daily. A biopsy of one of the new lesions revealed marked pseudoepitheliomatous hyperplasia with dermal granulomatous inflammation. Culture of the lesions revealed staphylococcus aureus, and he began receiving daily intravenous vancomycin 1 gm for 30 days with minimal improvement. Another biopsy taken from the left forearm lesion demonstrated cutaneous T-cell lymphoma with pseudoepitheliomatous hyperplasia, a positive monoclonal T-cell rearrangement and a CD3+, CD4+, CD8+, and CD30- phenotype. PET/CT showed no metabolic disease at any site.

The patient was treated with total skin electron-beam therapy to a total dose of 36 Gy using the technique described above. Shielded areas, including the palms, soles and buttocks, received a boost of 8 Gy in 1 fraction. This was followed by 4 cycles of weekly pralatrexate 15 mg/m². Although this treatment initially appeared beneficial, several weeks later the patient presented with new lesions on his torso, extremities, and on the left tonsil and alveoli (Figure 1B). Biopsy of the left soft palate and left superior alveolar ridge again was consistent with mycosis fungoides. The oral lesions were treated with external-beam radiation therapy to a prescribed dose of 30.6 Gy in 17 fractions. However, the patient received only 10 fractions for a total dose of 18 Gy due to severe mucositis, which was not relieved by sucralfate, and eventually required hospitalization due to significant decreased oral intake and failure to thrive. His treatment was discontinued at this dose. Although the oral lesions responded well to the therapy, he eventually began a regimen of cyclophosphamide, hydroxyduanorubicin, etoposide, vincristine, and prednisone (CHEOP) chemotherapy and intrathecal methotrexate due to overall disease progression, including involvement of his bone marrow. Unfortunately, our patient succumbed to disseminated disease after receiving a single cycle of CHEOP.

We performed a PubMed search for articles in English containing the following key words: mycosis fungoides, cutaneous T-cell lymphoma, oral cutaneous T-cell lymphoma, oral mycosis fungoides, oropharyngeal mycosis fungoides, and treatment of oral mycosis fungoides. Articles describing patients with only cutaneous manifestations of mycosis fungoides were excluded. Only reports of cases of head and neck mucosal mycosis fungoides were included for analysis. Additional cases were identified by reviewing and evaluating the references in articles retrieved from our PubMed search.

Our literature search uncovered 57 previously reported patients with biopsy-proven mycosis fungoides manifestations in the head and neck mucosal areas,^1,3-44 with the first case reported in 1891. We report 2 additional cases treated in our institution. The age of these 59 patients ranged from 12 to 86 years (median 65 years, mean 60.4 years). Of these, 38 were men (64%) and 19 were women (32%) (Table 1). We were unable to verify the gender of 2 patients (3%).^7,13

Since many case reports provide only the age of the original diagnosis, we estimated the exact age of a given patient at the time of head and neck mucosal manifestations using the time frame given in the reports.

All but 6 patients were previously diagnosed with cutaneous mycosis fungoides prior to head and neck mucosal presentation. Based on the limited information from prior publications, we were able to estimate the duration from initial cutaneous presentation of mycosis fungoides to mucosal involvement in 30 of the 53 patients (this excludes the 6 patients who presented initially with oral/oropharyngeal disease). These periods ranged from 1 month to 21 years (Table 1). The mean time was 5.7 years, with a median time of 4 years.

Atypical lymphocytes exhibiting cerebriform and indented nuclei were described in most biopsy specimens. Pautrier microabscesses were also noted in some reports. When examining cellular markers, 12 patients were CD4+, a common finding in mycosis fungoides.^{1,33,34,36,38-42} Of these, 7 were CD4+/CD8-^{1,33,38,39,41,42} and 3 were CD4+/CD8+.^34,43,44 Three were CD4-/CD8+^1,33 and only 1 patient was CD4-/CD8- (case 1 of this report), a rarity.

Although head and neck mucosal mycosis fungoides was noted in a wide array of anatomical sites, the most common sites for disease presentation were the tongue (n = 25, 42%) and hard or soft palate (n = 18, 31%). Other sites of disease were (in descending order of frequency) gingiva, epiglottis, buccal mucosa, tonsils, and lips.

The treatment modalities of 36 patients were described. Of these, 26 patients received some form of radiation, including total skin electron-beam therapy and/or local field radiation therapy. Based on the information in the published reports, at least 18 patients received external-beam radiation therapy to their mucosal lesions. An additional 2 patients were prescribed radiation, but either declined or died before receiving radiation therapy. Prescribed doses to mucosal lesions included 65 Gy in 32 fractions, 36 Gy in 15 fractions, 30.6 Gy in 17 fractions, 27 Gy in 9 fractions, 24 Gy in 12 fractions, and 4 Gy in 1 fraction. We initially prescribed 30.6 Gy in 17 fractions to both of our patients; however, neither one could complete the entire treatment due to severe toxicities. Only 2 patients were reported to have undergone surgical tumor debulking.

Information regarding follow-up was available for 35 (59%) patients. Of these, 24 died; however, it should be noted that not all deaths were related to mycosis fungoides. The time from head and neck mucosal presentation to death in these patients ranged from 1 month to 8 years, with a mean of 1.7 years and a median of 1 year. Fourteen patients were alive at last known follow-up, which ranged from 1 month to 5 years. Of these, 7 had no evidence of oral or cutaneous disease at follow-up.

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma. Although it typically presents with cutaneous manifestations, the viscera and bloodstream may become involved. Rarely, mycosis fungoides is found in head and neck mucosal sites, generally in the context of previously diagnosed disease.¹

The most common area for disease manifestation in the oral cavity is the tongue, with 50% of reported patients having such lesions. The palate and gingiva are the next most common areas, followed by the buccal mucosa, lips and oropharynx.⁴³

Histological changes that may be seen on biopsy include Pautrier microabscesses and large, convoluted or indented nuclei. Immunostaining typically will show CD4+ and CD8- phenotypes. CD8+ cells are unusual; we report a patient with lesions found to be both CD4- and CD8- and another with CD4+ and CD8+ phenotype. In a single-center departmental review of 140 patients presenting with mycosis fungoides, 18 were found to have CD4- and CD8- staining.⁴⁵

Treatment of oral manifestations is typically external-beam radiation therapy prescribed at doses ranging from 30-40 Gy in 15-17 fractions (ie, 1.6 to 2.5 Gy per fractions).⁴³ Postorino et al, however, reported successfully treating a patient with a combination of weekly alemtuzumab 15 mg, a monoclonal CD52 antibody, once per week and 6 monthly cycles of CHOEP. Although that patient relapsed after 6 months, further treatment of alemtuzumab and gemcitabine stabilized the disease with maintenance photopheresis.⁴⁴

Our patients both experienced severe mucositis during their treatment regimens. Reynolds et al similarly reported a patient with mucosal irritation after receiving 3000 rads to the entire oral cavity; this resolved with conservative therapy.²⁵ Other publications in our review did not report these or other similar treatment side effects. It is, however, important to consider these toxicities during treatment planning and to recognize them as possible impediments to treatment completion.

Predominantly a cancer of the skin, mycosis fungoides presenting in the oral cavity and oropharyngeal mucosa is uncommon. A review of the previously reported 57 cases and 2 new cases at our institution shows that head and neck mycosis fungoides is a rare and late manifestation of the disease and carries a poor prognosis. External-beam radiation therapy is the most common treatment modality. Toxicities can include severe mucositis and can delay or prevent full treatment regimens.