Adult T-cell Leukemia/Lymphoma (ATL) in the Nasal and Paranasal Cavity: Four Cases Report

Abstract

Adult T-cell leukemia/lymphoma (ATL) is a form of leukemia caused by the human T-cell leukemia virus type I (HTLV-1). Otolaryngologists often diagnose ATL based on cervical lymphadenopathy or Waldeyer ring lesions. However, there are few reports of ATL occurring in the nasal and paranasal cavity. Here, we report four such cases of ATL. Case 1: An 82-year-old man diagnosed with acute-type ATL with a tumor in the nasal cavity underwent 5 courses of THP-COP, but died after 36 months due to ATL. Case 2: A 62-year-old woman diagnosed with lymphoma-type ATL with a tumor in the frontal sinus was treated with 5 courses of VCAP-AMP-VECP, and has survived for more than 10 years. Case 3: A 64-year-old man diagnosed with lymphoma-type ATL with a tumor in the maxillary sinus underwent 8 courses of VCAP-AMP-VECP and 2 courses of mogamulizumab, but died after 34 months due to ATL. Case 4: A 52-year-old woman diagnosed with lymphoma-type ATL with tumors in both ethmoid sinuses received 2 courses of CHOP, 2 courses of DeVIC, radiotherapy (32 Gy) and 2 courses of mogamulizumab, but died after 9 months due to ATL.

Introduction

Adult T-cell leukemia/lymphoma (ATL) is a form of leukemia with symptoms that arise due to infection with the human T-cell leukemia virus type I (HTLV-1) [1]. ATL has an extremely poor prognosis. There are an estimated 5 to 20 million HTLV-1-infected individuals worldwide, and these persons have a lifetime risk of developing ATL of 3–5%, with high HTLV-1 proviral loads shown to be an independent risk factor [2]. However, there have been few reports of ATL occurring in the nasal and paranasal cavity. Here, we report four such cases of ATL and we discuss these cases in the context of the available literature.

Case Presentation

Patient Background

Data were analyzed for 1083 patients with a histologically confirmed diagnosis of head and neck cancer (confirmed using multiple modalities) at Kagoshima University Hospital between April 2011 and March 2020. There were 165 cases of malignant lymphoma, including 19 of ATL. Except for the four cases in this study and a past case report [3], most cases of ATL were diagnosed by biopsy from cervical lymph nodes. All patients were Asian.

Case 1

An 82-year-old man presented to our ENT service with a two-month history of neck swelling. The patient had been diagnosed with indolent ATL one year ago and followed up at another hospital. An endoscopic examination revealed a red tumorous lesion in the nasal cavity (Fig. 1A). Pre-treatment blood test data are shown in Table 1. Endoscopic biopsy was also performed. Computed tomography (CT) showed a mass region in the same region (Fig. 1B). Histological analysis showed variant cells that stained positively for CD3, CD4, CD5 and CD25, but were negative for CD8, CD20 and CD79a. Collectively, these findings led to diagnosis of acute-type ATL. The patient was treated with 5 courses of THP-COP (50 mg/m² pirarubicin, 750 mg/m² cyclophosphamide, 1.4 mg/m² vincristine on day 1, and 100 mg/body prednisolone on days 1–5) at another hospital, but died due to ATL 36 months after visiting our department.

Fig. 1.

Case 1. (A) Endoscopic examination showed a red tumorous lesion (a⇒) in the nasal cavity. (B) Computed tomography (CT) showed a mass region in the same region (b⇒). No bone destruction was observed

Table 1.

Pre-treatment blood test data for cases 1–4

Item		Case 1	Case 2	Case 3	Case 4
Age (years)		82	62	64	52
Sex		Male	Female	Male	Female
Site		Nasal Cavity	Frontal Sinus	Maxillary Sinus	Ethmoid Sinus
Blood test	Standard	Pre-treatment
WBC	3.3–8.6 × 103 /µL	7.41	8.46	9.47	8.81
Lymphoid cells	25–45%	38.5	9	25	13.8
Number of lymphoid cells	1000–4800 /µL	2852	761	2367	1215
Abnormal lymphocytes	Negative	5%	(-)	(-)	(-)
RBC	4.35–5.55 × 106 /µL	4.09	4.31	4.29	6.2
Hb	13.7–16.8 g/dL	11.7	12.2	12.5	14.8
Plt	158–348 × 103 /µL	155	115	324	268
AST	13–30 IU/L	96	15	18	12
ALT	10–42 IU/L	159	8	18	20
LDH	124–222 U/L	190	182	187	190
Total protein	6.6–8.1 g/dL	6.8	8	7.9	7
BUN	8.0–20.0 mg/dL	29.7	7.9	8.1	11.5
Cr	0.65–1.07 mg/dL	1.67	0.51	0.57	0.61
Na	138–145 mEq/L	137	142	142	135
K	3.6–4.8 mEq/L	4.5	3.9	3.3	4.3
Cl	101–108 mEq/L	105	106	103	95
Ca	8.7–10.3 mg/dL	9	9.6	9.2	9.8
CRP	< 0.14 mg/dL	2.58	0.59	3.52	0.58
IL-2R	127–582 U/ml	12,514	947	1199	914
Anti-HTLV-1 antibody	Negative	Positive	Positive	Positive	Positive
Other examination		Monoclonal integration of HTLV-1 proviral DNA detectable by Southern blotting	Monoclonal integration of HTLV-1 proviral DNA detectable by Southern blotting	Abnormal lymphocytes in bone marrow are CD3(+), CD4(+), CD7(-), CCR4(+)	Monoclonal integration of HTLV-1 proviral DNA detectable by Southern blotting
Diagnosis		Acute-type ATL	Lymphoma-type ATL	Lymphoma-type ATL	Lymphoma-type ATL
Therapy		THP-COP	VCAP-AMP-VECP	VCAP-AMP-VECP, mogamulizumab	CHOP and DeVIC, radiotherapy, mogamulizumab
Prognosis		Death due to cancer	Alive for > 10 years	Death due to cancer	Death due to cancer

THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisone)

THP-COP regimen (50 mg/m² pirarubicin, 750 mg/m² cyclophosphamide, 1.4 mg/m² vincristine on day 1, and 100 mg/body prednisolone on days 1-5)

Case 2

A 62-year-old woman presented to our ENT service with a one-month history of swelling between the eyebrows (Fig. 2A) without neck lymphadenopathy. Pre-treatment blood test data are shown in Table 1. An endoscopic examination did not show a tumorous lesion in the nasal cavity. Enhanced CT and magnetic resonance imaging (MRI) showed an inversional region in the frontal sinus (Fig. 2B, C). Positron emission tomography/computed tomography (PET/CT) showed accumulation in the frontal sinus with a standardized uptake value (SUV) of 5.3 (Fig. 2D). A biopsy was performed using a nasal endoscope under general anesthesia. Histological analysis showed variant cells that stained positively for CD3 and CD4, but were negative for CD8, CD20, CD56 and CD79a. A blood test was positive for anti-HTLV-1 antibody. These findings led to diagnosis of lymphoma-type ATL. The patient underwent 5 courses of VCAP-AMP-VECP (VCAP: 1 mg/m² vincristine, 350 mg/m² cyclophosphamide, 40 mg/m² doxorubicin and 40 mg/m² prednisone on day 1; AMP: 30 mg/m² doxorubicin, 60 mg/m² ranimustine and 40 mg/m² prednisone on day 8; VECP: 2.4 mg/m² vindesine, 100 mg/m² etoposide, 250 mg/m² carboplatin and 40 mg/m² prednisone on day 15) at another hospital. She has been alive for more than 10 years after visiting our department.

Fig. 2.

Case 2. (A) The patient had swollen eyebrows (a⇒). (B, C) An inversional region in the frontal sinus was found on enhanced CT (b⇒) and MRI (c⇒). (D) PET/CT showed accumulation (SUV 5.3) in the frontal sinus (d⇒)

Case 3

A 64-year-old man presented to our ENT service with a one-month history of right cheek swelling (Fig. 3A) without neck lymphadenopathy. An elevated lesion was observed in the oral vestibule, and mouth opening was restricted. Pre-treatment blood test data are shown in Table 1. An endoscopic examination did not detect a tumorous lesion in the nasal cavity. Enhanced CT and MRI showed an inversional region in the right maxillary sinus (Fig. 3B,C), and PET/CT showed accumulation in the right maxillary sinus (SUV 66.2) (Fig. 3D). An open biopsy was performed from the oral vestibule under local anesthesia. Histological analysis showed variant cells that stained positively for CD3, CD4, CD25 and CD30, but were negative for CD8, CD20 and CD79a. A blood test was positive for anti-HTLV-1 antibody. These findings indicated a diagnosis of lymphoma-type ATL. The patient received 8 courses of VCAP-AMP-VECP (VCAP: 1 mg/m² vincristine, 350 mg/m² cyclophosphamide, 40 mg/m² doxorubicin and 40 mg/m² prednisone on day 1; AMP: 30 mg/m² doxorubicin, 60 mg/m² ranimustine and 40 mg/m² prednisone on day 8; VECP: 2.4 mg/m² vindesine, 100 mg/m² etoposide, 250 mg/m² carboplatin and 40 mg/m² prednisone on day 15) in another hospital, and was also treated with 2 courses of mogamulizumab (1 mg/kg). However, he died 34 months after visiting our department.

Fig. 3.

Case 3. (A) The patient had a swollen cheek (a⇒). (B, C) An inversional region in the right maxillary sinus was found on enhanced CT (b⇒) and MRI (c⇒). (D) PET/CT showed accumulation (SUV 66.2) in the right maxillary sinus (d⇒)

Case 4

A 52-year-old woman presented to our ENT service with a one-month history of right eye pain (Fig. 4A) without neck lymphadenopathy. Pre-treatment blood data are shown in Table 1. An endoscopic examination revealed a red tumorous lesion in the right middle turbinate (Fig. 4B). Enhanced CT showed an inversional region in both ethmoid sinuses (Fig. 4C). PET/CT showed accumulation in the right ethmoid sinus (SUV 28.4) and the left ethmoid sinus (SUV 18.0) (Fig. 4D). A biopsy was performed using a nasal endoscope under local anesthesia. Histological analysis showed variant cells that stained positively for CD3, CD4 and CCR4, but were negative for CD8, CD20, CD25, CD30 and CD79a. A blood test was positive for anti-HTLV-1 antibody. These findings led to diagnosis of lymphoma-type ATL. The patient was treated with 2 courses of CHOP (750 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, 1.4 mg/m² vincristine on day 1, and 100 mg/body prednisone on days 1–5), 2 courses of DeVIC (40 mg/m² dexamethasone on days 1–3, 100 mg/m² etoposide on days 1–3, 300 mg/m² uromitexan on days 1–3, 1500 mg/m² ifosfamide on days 1–3, 300 mg/m² carboplatin on day 1), and radiotherapy (32 Gy) at another hospital, and also received 2 courses of mogamulizumab (1 mg/kg). However, she died 9 months after visiting our department.

Fig. 4.

Case 4. (A) The patient had no swelling of the eyebrows, but had severe right eye pain. (B) An endoscopic examination revealed a red tumorous lesion in the right middle turbinate (b⇒). (C) Enhanced CT showed an inversional region in both ethmoid sinuses (c⇒). (D) PET/CT showed accumulation in the right ethmoid sinus (SUV 28.4) (d⇒) and in the left ethmoid sinus (SUV 18.0)

Discussion

ATL is a form of leukemia caused by HTLV-1 infection. Clinically, ATL is classified into four types: acute, lymphomatous, chronic, and smoldering. The first two of these variants are classified as aggressive, and the latter two are classified as indolent. HTLV-1 is endemic to southwestern Japan [4], and Kagoshima Prefecture, where our facility is located in the southwestern part of Japan, is an area with a high rate of HTLV-1 carriers. However, HTLV-1 carriers are now distributed beyond the endemic southwestern region of Japan, and are found throughout the country, particularly in the greater Tokyo metropolitan area [4].

Patients with ATL exhibit diverse clinical features such as generalized lymphadenopathy, hepatosplenomegaly, neuritis, skin lesions, leukocytosis with increased abnormal lymphocytes with cerebriform or flower-like nuclei or increased neutrophils, hypercalcemia, and frequent complication with opportunistic infections due to Pneumocystis jirovecii, Candida, Cytomegalovirus, and Strongyloides stercoralis [2]. Otolaryngologists often diagnose ATL based on cervical lymphadenopathy or Waldeyer ring lesions. However, there have been few reports of ATL in the nasal and paranasal cavity [5–9]. At our hospital, we have previously experienced one case of ATL occurring in the sphenoid sinus [3].

ATL cells characteristically express CD3, CD4, CD25, CCR4, and FOXP3 on their surface, and monoclonal integration of HTLV-1 proviral DNA is detectable by Southern blotting. Recently, CCR4 expression has been examined as a basis for mogamulizumab dosing decisions [2]. Differential diagnosis of ATL includes other mature T-cell neoplasms such as T-cell prolymphocytic leukemia, Sézary syndrome, peripheral T-cell lymphoma and occasionally healthy carriers of the virus or Hodgkin disease [10].

Initially, ATL was not assumed for the four cases in this report. Case 1 showed the appearance of abnormal lymphocytes and a high IL-2R level, but in Cases 2 to 4 there were no abnormalities in blood tests. However, these three cases had bone destruction, and thus, squamous cell carcinoma was suspected. For this reason, all collected specimens were fixed in formalin and were not submitted for flow cytometry. Additional biopsy was considered in some cases, but the treatment schedule was prioritized due to rapid disease progression.

There is still no successful treatment for ATL. THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisone) is sometimes used for elderly patients with T-cell lymphoma in Japan [11]. The longer 3-year overall survival (OS) and higher CR rate with VCAP-AMP-VECP compared with biweekly CHOP suggests that VCAP-AMP-VECP might be a more effective regimen at the expense of greater toxicities, and this provides the basis for future studies for treatment of ATL. However, a sub-analysis of patients aged 56 years and older showed no superiority of VCAP-AMP-VECP therapy for OS [12].

Mogamulizumab (Poteligeo®) is a defucosylated, humanized monoclonal antibody targeting CC chemokine receptor 4 (CCR4). Mogamulizumab was approved in Japan for treatment of relapsed or refractory ATL in 2012 and is the first Potelligent® antibody to receive marketing approval worldwide [13, 14]. After 2013, cases 3 and 4 were examined for CCR4 expression and treated with mogamulizumab, but this was not effective in these cases.

Conclusion

The four cases reported here show the difficulty of diagnosis of ATL in initial examination of nasal and paranasal cavity tumors by otolaryngologists based on clinical symptoms and laboratory findings. ATL is usually suspected only after a histopathological examination. In such cases, diagnosis may require flow cytometry using histopathological specimens and HTLV-1 antibody measurement, together with consultation with pathologists and hematologists.

Funding

None.

Declarations

Disclosure Statement

The authors have no conflicts of interest to declare. No funding was received for the work in this study.

Conflict of Interest

None.