A 58-year-old man presented with a 5-month history of swallowing discomfort. A nasopharyngeal lesion was biopsied under nasopharyngoscopy, and nasopharyngeal carcinoma (NPC) was confirmed by histopathologic examination. The patient was subsequently referred to the Department of Stomatology of Sun Yat-sen Memorial Hospital on 19 April 2018 for further diagnosis and treatment. He reported no spontaneous pain or tenderness in the oropharynx or nasal cavity. He also had no numbness, bleeding, fever, or weight loss. The patient had been smoking an average of two cigarettes per day for 40 years. He had no history of alcohol abuse and no known family history of NPC.
Physical examination revealed facial symmetry, a soft neck, and smooth movement. Two enlarged lymph nodes with a diameter of 1.0 and 1.5 cm, respectively, were palpated at the posterior lower pole of the bilateral parotid glands, and the nodes had a medium to hard texture and clear boundaries. Two other enlarged lymph nodes with a diameter of 3.0 and 2.0 cm, respectively, were palpable on both sides of the jaw; these nodes exhibited moderate mobility and no tenderness or adhesion to surrounding tissues. Moreover, an enlarged lymph node with a diameter of 1.0 cm was palpated under the chin. Blood examination revealed a white blood cell (WBC) count of 6.48 × 109/L (reference range, 3.50–9.50 × 109/L). Red cell count, hemoglobin concentration, platelet count, lymphocyte proportion and count, the serum concentration of alanine aminotransferase, aspartate aminotransferase, total protein, albumin, unsaturated iron binding capacity, carbohydrate antigen 72–4, carbohydrate antigen 125, carbohydrate antigen 19–9, alpha-fetoprotein, and carcinoembryonic antigen were showed in Table1. Lactate dehydrogenase (LDH) concentration was 141 U/L (reference range, 108–252 U/L). Blood tests for syphilis, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus were also negative.
Table 1
Variable
|
Reference Range, Adults
|
On Initial Evaluation
|
After the First Chemotherapy
|
After the Second Chemotherapy
|
Red cell count (1012/L)
|
4.30–5.80
|
5.75
|
5.46
|
5.82
|
Hemoglobin ( g/L)
|
130–175
|
125
|
118
|
124
|
Platelet count (109/L)
|
125–350
|
253
|
257
|
292
|
Lymphocyte proportion (%)
|
20–50
|
32.3
|
31.2
|
32.6
|
Lymphocyte count (109/L)
|
1.1–3.2
|
2.09
|
1.74
|
1.7
|
Alanine aminotransferase (U/L)
|
9–50
|
17
|
15
|
11
|
Aspartate aminotransferase (U/L)
|
15–40
|
16
|
14
|
15
|
Glucose(mmol/L)
|
3.9–5.6
|
4.7
|
4.3
|
4.6
|
Total cholesterol(mmol/L)
|
2.90-6.00
|
4.15
|
2.66
|
4.60
|
Triglyceride (mmol/L)
|
0.31–2.30
|
0.75
|
1.29
|
1.26
|
High density lipoprotein(mmol/L)
|
0.80–1.96
|
0.97
|
0.70
|
1.01
|
Low density lipoprotein(mmol/L)
|
1.30–3.60
|
2.64
|
1.53
|
2.86
|
Prealbumin (g/L)
|
0.18–0.40
|
0.30
|
0.25
|
0.30
|
Total protein (g/L)
|
65.0–85.0
|
67.4
|
67.5
|
67.1
|
Albumin(g/L)
|
40.0–55.0
|
39.3
|
36.9
|
37.2
|
Globulin(g/L)
|
20.0–40.0
|
28.1
|
30.6
|
29.9
|
Albumin/globulin ratio
|
1.2–2.4
|
1.4
|
1.2
|
1.2
|
Serum iron(µmol/L)
|
7.0–32.0
|
26.7
|
9.1
|
11.9
|
Total iron binding force(µmol/L)
|
45.0–75.0
|
50.2
|
59.0
|
50.8
|
Unsaturated iron bonding force(µmol/L)
|
31.0–51.0
|
23.5
|
49.9
|
38.9
|
Transferrin(g/L)
|
1.90–3.80
|
2.34
|
2.25
|
2.16
|
Carcinoembryonic antigen (ng/ml)
|
≤ 5
|
3.3
|
|
|
Alpha-fetoprotein (ng/ml)
|
≤ 25
|
2.06
|
|
|
Carbohydrate antigen 72 − 4 (U/ml)
|
≤ 7
|
1.4
|
|
|
Carbohydrate antigen 125 (U/ml)
|
≤ 35
|
6.3
|
|
|
Carbohydrate antigen 19 − 9 (U/ml)
|
≤ 34
|
4.3
|
|
|
Magnetic resonance imaging (MRI) of the neck and maxillofacial region showed lesions in the nasopharynx, oropharynx, and tonsils as well as multiple enlarged lymph nodes in the parotid gland, retroauricular and cervical regions (Fig. 1), necessitating differential diagnosis between lymphoma and NPC. Sagittal T1WI with contrast showed thickening with obvious enhancement as well as enhancement of the nasopharynx and pharyngeal tonsils. Diffusion-weighted imaging showed limited diffusion in the nasopharyngeal lesion area, pharyngeal ring, tonsil lesions, and bilateral cervical lymph nodes. According to the MRI findings, our first impression was a synchronous, double primary tumor in which NPC and lymphoma co-exist.
Pathology consultation findings showed two nasopharyngeal mucosal tissue specimens measuring 0.5 × 0.4 × 0.3 cm and 0.6 × 0.6 × 0.4 cm, respectively, had an abnormal structure (Fig. 2). Numerous atypical lymphocytes were distributed in a nodular pattern. Beside of the atypical lymphoid tissue, multiple focal atypical epithelial cell nests were also observed. The atypical epithelial cells contained large tumor cells with a syncytial appearance, round to oval vesicular nuclei, and large central nucleoli. The nuclei were chromatin-rich rather than vesicular, and the neoplastic cells generally had scant amphophilic or eosinophilic cytoplasm. On immunohistochemical staining, these atypical large cell nests were positive for cytokeratin (CK), CK5/6, p63, cyclin D1, and B-cell lymphoma 2 (Bcl-2) and negative for cluster of differentiation 3 (CD3), CD20, CD19, CD5, CD10, and Bcl-6. The MIB-1 labeling index was approximately 80%. In situ hybridization showed positivity for Epstein–Barr virus (EBV)-encoded small RNAs (EBERs). Thus, the lesion was diagnosed as nasopharyngeal carcinoma (NPC), non-keratinizing squamous cell carcinoma, undifferentiated subtype. The morphology of the tumor with atypical lymphocytes showed monomorphic lymphoid proliferation with a vaguely nodular, diffuse mantle zone composed of small to medium lymphoid cells with slightly or markedly irregular nuclear contours. The nuclei of the atypical lymphocytes contained dispersed chromatin but inconspicuous nucleoli. In immunohistochemical staining, these atypical lymphocytes were positive for CD19, CD20, CD5, cyclin D1, and Bcl-2 and negative for CD10, Bcl-6, CD3, CD30, CK, CK5/6, and p63. The MIB-1 labeling index was approximately 15%. In situ hybridization showed that the atypical lymphocytes were negative for EBERs. Fluorescence in situ hybridization of the atypical lymphocytes revealed IgH/CCND1 gene translocation. An IgH gene rearrangement study showed that the B-cell rearrangement was positive (polymerase chain reaction + fragment analysis). Therefore, the lesion of atypical lymphocytes was diagnosed as mantle cell lymphoma (MCL), classical subtype.
Radiographs of the chest showed no evidence of metastasis in the lung. Positron emission tomography–computed tomography (PET-CT) showed that the nasopharynx, oropharynx, and tonsils were diffusely and moderately enlarged, with multiple metabolically active lymph nodes of varying sizes throughout the body (Fig. 3). In addition, multiple small metabolically active nodules were present under the skin of the left neck, right shoulder, and left chest as well as within the deltoid muscle of both upper limbs. Active metabolism of the bilateral inguinal lymph nodes was also observed. The collision tumor of NPC and lymphoma in the nasopharynx was thus considered. Multiple lymph nodes throughout the body were infiltrated by lymphoma. The liver was enlarged, but the spleen was not, and no abnormal metabolism of the liver or spleen was observed. There was no metastasis to the bone marrow as confirmed by a bone marrow biopsy.
The combination of MRI, PET-CT, and histopathology led to the diagnosis of a nasopharyngeal collision tumor of NPC and primary MCL. The NPC was staged as T1N0M0 according to the American Joint Committee on Cancer Tumor-Node-Metastasis staging system [4]. The MCL was stage III according to the revised staging system for malignant lymphoma based on the Lugano classification [5–6]. The patient’s Eastern Cooperative Oncology Group performance status (ECOG PS) was 2 [7]. The MCL International Prognostic Index (MIPI) score was calculated as follows: MIPI score = (0.03535 × age [years]) + 0.6978 (if ECOG PS > 1) + (1.367 × log10[LDH/ULN]) + (0.9393 × log10[WBC count]) + (0.02142 × Ki-67 [%]) [8], where ULN is the upper limit of normal. The patient’s MIPI score was 3.49, which indicated that the patient was at low risk in terms of his survival prognosis.
The patient received two courses of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by head and neck radiotherapy for 30 days (PGTVnx 70 Gy/30 Fr, PGTVnd-L 68 Gy/30 Fr, PGTVnd-R 68 Gy/30 Fr, PTV-1 60 Gy/30 Fr, and PTV-2 54 Gy/30 Fr). After radiotherapy, the patient's swallowing was normal and the lesion was disappearance on MRI. Follow-up physical examination, laboratory test, and imaging for over five years showed no recurrence. At the time of this writing, the patient had survived for 62 months without disease progression and was still undergoing follow-up.