CASE REPORT
Eben L. Rosenthal, MD, Section Editor
PRIMARY LARYNGEAL LYMPHOMA: REPORT OF 3 CASES
AND REVIEW OF THE LITERATURE
Konstantinos Markou, MD, PhD,1 John Goudakos, MD, MSc,1 John Constantinidis, MD, PhD,1
Ioannis Kostopoulos, MD,2 Victor Vital, MD, PhD,1 Angelos Nikolaou, MD, PhD1
1
Department of Otorhinolaryngology—Head and Neck Surgery, ENT Department, AHEPA University Hospital,
Aristotle University of Thessaloniki, Thessaloniki, Greece. E-mail: [email protected]
2
Pathology Department, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
Accepted 7 January 2009
Published online 17 April 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.21104
Abstract: Background. Extranodal lymphomas limited to the
larynx are rare, accounting for less than 1% of all laryngeal neoplasms. The aim of this study was to report the experience of our
department in the management of these aggressive lesions, as
they require special diagnostic and therapeutic attention.
Methods. The case records of 3 patients with the diagnosis
of lymphoma involving the larynx were retrospectively reviewed.
Results. The histopathological diagnosis revealed 1 case of
marginal zone lymphoma mucosa-associated lymphoid tissue
type, 1 case of T-lymphoblastic lymphoma, and 1 case of a rare
coexistence of in situ squamous cell carcinoma with an isolated
intravascular (angioimmunoblastic) lymphoma of peripheral Tcell origin. Details of the presentation, diagnostic procedures,
treatment, and outcome of these patients were presented.
Conclusions. Primary laryngeal lymphoma is a rare entity.
Early symptoms are subtle and nonspecific, and confirmation
of the diagnosis is often difficult. Because of the rarity of this
tumor type, the optimal management remains controversial
and it seems that should be managed not as a distinct disease
entity but as an unusual presentation of non-Hodgkin lymC 2009
phoma, according to the recent treatment trends. V
Wiley Periodicals, Inc. Head Neck 32: 541–549, 2010
Keywords: primary; laryngeal; lymphoma; non-Hodgkin; NHL
Correspondence to: J. Goudakos
C 2009 Wiley Periodicals, Inc.
V
Primary Laryngeal Lymphomas
Squamous
cell carcinoma is the most common
malignant tumor of the larynx, with primary hemopoietic neoplasms representing less than 1%
of malignant laryngeal tumors. Among these hemopoietic neoplasms, lymphoma is the second
most common primary laryngeal tumor after
plasmatocytoma. Fewer than 100 cases of primary laryngeal lymphoma have been reported
in the global literature.1
The malignant lymphomas are divided in
Hodgkin disease and non-Hodgkin lymphomas
(NHL). Lymphomas primary to the larynx are
mainly NHL and are predominantly located in
the supraglottic region, as this area of the larynx
contains follicular lymphoid tissue.2 Among the
subtypes of the NHL, the diffuse large B-cell and
the mucosa-associated lymphoid tissue (MALT)type marginal zone B-cell lymphomas are the
most commonly found primary laryngeal hematopoietic neoplasms.1 Other types of lymphomas,
such as T- or natural killer (NK)-cell lymphomas,
are rarely reported.3–7 The presenting symptoms
and signs include dysphagia, dysphonia,
HEAD & NECK—DOI 10.1002/hed
April 2010
541
Table 1. Clinical data of cases.
Case
Sex/age
Location of
lymphoma
Symptomatology
1
2
3
M/67
M/53
M/32
Supraglottic
Vocal cord
Subglottic
Dyspnea, stridor, hoarseness
Hoarseness
Dyspnea, stridor
dyspnea, and cervical lymphadenopathy. The
indirect laryngoscopy usually reveals a polypoid
submucosal supraglottic mass, nonulcerated,
without these characteristics to be specific. The
diagnosis rests on histological examination of a
biopsy specimen.
Among 1034 cases of malignant tumors of the
larynx diagnosed and treated in first department
of Otorhinolaryngology of Aristotle University of
Thessaloniki during the last 12 years, there were
only 3 laryngeal lymphomas. The aim of this
study was to report the experience of our department in the management of these aggressive
lesions, as they require special diagnostic and
therapeutic attention.
CASE REPORTS
The review of the records of the 1034 cases with
laryngeal cancer revealed that 16 patients had a
non–squamous cell carcinoma, and 3 of these
patients had lymphoma involving the larynx.
The case records of these 3 patients were retrospectively analyzed. All cases were carefully
classified histologically according to the World
Health Organization Classification of Hematological Malignancies.8 The clinical stage at presentation is a major prognostic factor of primary
laryngeal NHL. Staging was based on Ann
Arbor clinical staging criteria.9 The modes of
presentation, diagnostic procedures, treatment,
and outcome of these cases were analyzed
(Tables 1 and 2).
Case 1. A 67-year-old man was admitted
urgently in our department because of severe
dyspnea and stridor. He had been suffering from
Duration of
symptoms
1y
1 mo
Histologic diagnosis
Marginal zone lymphoma MALT type
Angioimmunoblastic lymphoma þ in situ SCC
T-lymphoblastic lymphoma
mild dyspnea and progressive hoarseness for
the last year. The direct laryngoscopy (Figure 1)
and CT scan revealed an extensive exophytic
supraglottic mass, involving both the vocal cords
and causing severe deterioration of his airway
tract. He was immediately tracheostomized
under local anesthesia. The patient remained
tracheostomized during the treatment and was
decannulated after the remission of the mass,
4 months later.
Histological and immunohistochemical examination of the biopsy specimen taken showed a
marginal zone lymphoma MALT type (Figure 2).
The neoplastic lymphoid cells were positive for
CD20 (Figure 2c) and CD45RA, whereas they
were negative for the following antigens: CD3
(Figure 2d), CD5, CD23, CD10, and cyclin D1.
The clinical examination and the CT scan of
the neck, chest, abdomen, and pelvis revealed no
lymphadenopathy. The results of a bone scintiscan were also normal. The clinical stage was
evaluated as stage IE, according to the Ann Arbor
staging system. The treatment plan of the patient
consisted of a combination of chemotherapy,
including cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). Six courses of
combination chemotherapy were performed. Four
months after the initiation of therapy, both dyspnea and hoarseness were completely resolved.
The patient is disease free, both to tumor site and
lymph nodes, 4 years after the initial diagnosis.
Case 2. The second case was a very interesting
case of a 53-year-old man who was admitted
to our department with a major symptom of
progressive hoarseness, starting a year previously. Laryngoscopy revealed 2 nodular reddish
lesions on his right vocal cord. The histological
Table 2. Outcome data of cases.
Case
Clinical stage
Treatment
Status
Overall survival, mo
Relapse free, mo
1
2
3
IE
IE
IIE
Chemotherapy
Chemotherapy
Chemotherapy þ radiotherapy
Alive
Alive
Dead
48
60
26
48
60
24
542
Primary Laryngeal Lymphomas
HEAD & NECK—DOI 10.1002/hed
April 2010
FIGURE 1. Laryngoscopic image of extensive supraglottic
mass. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
(Figure 3A) and immunohistochemical (Figure
3B) examination of the biopsy specimens established the diagnosis of in situ squamous cell carcinoma (SCC) coexisting with an isolated
intravascular (angioimmunoblastic) lymphoma
of peripheral T-cell origin. Numerous vascular
spaces showing dilated lumens were observed
subepithelially, containing tufty aggregates of
neoplastic cells within the vascular lumens (Figure 3A). The tumor cells were positive for CD45,
CD45RO (Figure 3B), HLA-DR, and CD68, as
well as for vimentin.
The chest radiograph and CT scan that followed the diagnosis did not show any other
affected sites or metastasis. Physical examination did not reveal lymphadenopathy. The histological examination of the bone marrow biopsy
showed no evidence of malignancy. The treatment strategy for the management of the lymphoma included chemotherapy regimen (CHOP)
in 6 sessions, while the patient also received fractional radiation for the coexisting in situ SCC. He
received 200 keV of X-rays per session, for 35 sessions, 7000 keV in total. The above dose was high
but was considered essential for the control of the
2 carcinomas. After the termination of radiotherapy, the hoarseness of patient remained,
although it improved over his initial condition.
He is relapse free to date, 8 years after the initial
diagnosis.
Primary Laryngeal Lymphomas
Case 3. The third patient was a 32-year-old
man who admitted to our hospital for severe
stridor and episodes of dyspnea for about
10 days. The patient also reported difficulty in
swallowing and signs of distress for the same
time period. The indirect laryngoscopy revealed
a big submucosal tumor of the subglottic region
confirmed by CT scan findings (Figure 4A).
The biopsy of the tumor and the subsequent
histological examination (Figure 5) revealed a Tlymphoblastic lymphoma. The neoplastic lymphoid cells were of medium size with round nuclei
and evident nucleoli. Immunohistochemistry
showed the following immunophenotypes: CD7þ
(Figure 5b), Tdtþ (Figure 4c), CD99þ, CD10,
CD34, CD20 (Figure 4d), CD3, CD5,
CD56, CD4, and CD8.
The CT scan of the chest, abdomen, and pelvis
showed involvement of the lymph nodes of the
superior mediastinum. The clinical stage was
evaluated as stage IIE, according to the Ann
Arbor staging system. The patient was treated
with combination chemotherapy and radiotherapy.
First, the initiation of chemotherapy, a regimen of
bleo-CHOP (bleomycin, cyclophosphamide, doxorubicin, vincristine and prednisolone), contributed to
rapid regression of the subglottic tumor and the
mediastinum involvement, as it was shown in a CT
scan (Figure 4B). The patient’s dyspnea was completely resolved, without need for a tracheostomy.
The treatment plan was completed with a series of
radiotherapy courses, 20 for the subglottic region
(4000 cGy) and 20 for the mediastinum involvement (3600 cGy). The patient remained disease
free for almost 2 years, but a generalized relapse of
the lymphoma was the cause of his death, 26
months after the initial diagnosis.
DISCUSSION
Malignant lymphomas are neoplastic transformations of lymphoid tissue. NHL and Hodgkin
disease are the 2 major variants. Lymphomas
usually present lymphadenopathy at the initial
diagnosis. Extranodal involvement occurs in
approximately 25% of cases.10–13 In most of these
cases, lymphomas are seen in locations that normally contain lymphoid tissue. However, extranodal lymphomas may also arise in normal
nonlymphoid tissues such as the thyroid. In
the head and neck region, the vast majority
of extranodal lymphomas are NHLs, with
Waldeyer’s ring being the most common site of
involvement.14–17 Extranodal NHLs limited to
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543
FIGURE 2. (A) Hematoxylin-eosin (H&E) stain 100. Laryngeal mucosa with diffuse lymphocytic infiltrate. (B) Hematoxylin-eosin
(H&E) stain 40. Lymphoepithelial lesions. (C) Immunohistochemistry 100. Neoplastic lymphoid cells positive for CD20. (D) Immunohistochemistry 100. Lymphomatous cells negative for CD3 (many positive reactive T-cells). [Color figure can be viewed in the online
issue, which is available at www.interscience.wiley.com.]
the larynx are rare, accounting for less than 1%
of all laryngeal neoplasms.10 The incidence of primary laryngeal lymphoma in our cohort of
patients was 0.3%. The most common site of development of primary laryngeal lymphomas is
the supraglottic region, as it contains lymphoid
collections in lamina propria and in ventricles.
The age of onset for laryngeal lymphomas
varies between 4 and 81 years, with the mean
age of occurrence to be the seventh decade.10,18
The mean age of our patients was 50 years. Data
from previous studies are contradictory regarding
the preponderance of laryngeal NHLs in men or
women,10,18,19 whereas our patients were all male.
The usual initial symptomatology of patients
with primary laryngeal NHL includes hoarseness, cough, dysphagia, a feeling of ‘‘a foreign
body sensation,’’ stridor or systemic signs, such
FIGURE 3. (A) Hematoxylin-eosin (H&E) stain 400. Aggregates of neoplastic cells in dilated vascular lumens. (B) Immunohistochemistry 400. Tufty aggregates of lymphomatous cells positive for CD45RO. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
544
Primary Laryngeal Lymphomas
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April 2010
FIGURE 4. (A) CT scan: axial plane. Large submucosal tumor of the subglottic region. (B) CT scan: axial plane. Regression of the
subglottic tumor after the chemotherapy.
as weight loss and fever. The similarity in clinical
symptomatology between laryngeal lymphoma
and SCC is obvious. In this study, 2 patients were
initially seen with dyspnea and stridor and the
other was initially seen with progressive hoarseness. Systemic signs were present in 1 patient.
Duration of the symptoms varied from 10 days to
1 year.
The primary laryngeal lymphomas constitute
a diagnostic challenge because they are characterized by absence of clinical and gross differential criteria, compared with SCC. Based on a
FIGURE 5. (A) Hematoxylin-eosin (H&E) stain 400. Lymphomatous cells with round nuclei and indistinct nucleoli. (B) Immunohistochemistry 400. Neoplastic lymphoid cells positive for CD7. (C) Immunohistochemistry 400. Neoplastic lymphoid cells positive for
Tdt. (D) Immunohistochemistry 400. Neoplastic lymphoid cells negative for CD20. [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
Primary Laryngeal Lymphomas
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April 2010
545
systematic survey of published cases of laryngeal
lymphomas, Horny et al1,20 stated that most of
them are initially seen as nonulcerated smooth or
polypoid masses in the epiglottis and the arytenoepiglottic folds. Reviewing the majority of
English-language reported cases of primary
lymphomas in the larynx from 1996 to 2008, 47%
of them are located in supraglottic region, 25%
are in the glottic area, and the rest are either
subglottic or transglottic (Table 3). Regarding the
initial macroscopic characteristics of the cases of
Table 3, 20 of 36 cases (55%) were described
either as smooth or submucosal masses, whereas
in only 2 cases (5.5%) were ulcerated lesions
reported.
However, in our series of patients, only 1 was
seen with a mass in the supraglottic region. Laryngeal lymphomas in other locations, such as
vocal cords or subglottis, are occasionally
detected, presenting with hoarseness as its main
symptom. In 1 case of our series, we noticed synchronous occurrence in the right vocal cord of larynx of intravascular lymphoma and in situ SCC.
As far as we know, the above concurrent coexistence of these tumors is the first report in the
medical literature. Imaging techniques, such as
CT scan and MRI, may be helpful for assessment
of any laryngeal neoplasm,19,41 although histopathological examination is essential for the final
diagnosis. Especially for T/NK-cell lymphomas,
multiple deep biopsies are needed over a long period of time, as in early-stage disease, the dispersed atypical lymphoid cells and the
remarkable diversity of cellular infiltration do
not enable to distinguish safely the neoplastic
from inflammatory cells.5,40
Table 3. Characteristics of the English-language reported cases of laryngeal lymphomas from 1996 to 2008.
No. of
cases
Author, Journal, Year
21
Smith et al, Am J Otolaryngol, 1996
Kato et al, JLO, 199718
1
3
Ansell et al, Laryngoscope, 199710
6
Simo et al, JLO, 199822
Marianowski et al, Arch Otolaryngol, 19983
Bree et al, Eur Arch Otorhinolar, 199823
Cheng et al, Otolaryngol Head Neck Surg,
199924
Ohta et al, JLO, 200125
Cavalot et al, JLO, 200126
Mok et al, Head Neck, 20015
1
1
1
1
Fung et al, Ann Diagn Pathol, 200227
Nayak et al, ORL, 200328
Caletti et al, Gastroenterology, 200329
Palenzuela et al, Int J Pediatr
Otorhinolaryngol, 200330
King et al, AJNR, 200419
Roca et al, South Med J, 200531
Andratsche et al, In Vivo, 200532
Kania et al, Head Neck, 200533
Agada et al, JLO, 200534
Patiar et al, JLO, 200535
Word et al, Ear Nose Throat J, 200636
Steffen et al, In Vivo, 200737
Korst, Ann Thorac Surg, 200738
Tardio et al, Eur Arch Otorhinolar, 200839
Monobe et al, Head Neck, 200840
1
1
3
Subsite
Supraglottic
Supraglottic (2),
Glottic
Glottis (3),
Supraglottic (2),
Subglottic
Glottic
Supraglottic
Supraglottic
Supraglottic
Histopathology
Treatment
Status Outcome
T-cell
RT
T-cell, B-cell (2) RT (2), Chemo
Death
*
12 mo
*
B-cell (6)
RT-Chemo
†
B-cell
T-cell
MALT
B-cell
RT
Chemo-RT
RT
RT
Death
Death
DSF
DSF
8 mo
10 mo
24 mo
12 mo
†
B-cell
B-cell
T-cell, T/NK (2)
SG-RT
DSF
Chemo
DSF
Chemo-RT, Chemo (2) Death
36 mo
16 mo
1
1
1
1
Supraglottic
Glottic
Supraglottic (2),
Subglottic
Supraglottic
Supraglottic
Glottic
Transglottic
MALT
B-cell
MALT
B-cell
RT
Chemo
drug
Chemo-RT
DSF
DSF
DSF
Death
30 mo
13 mo
46 mo
2 mo
3
1
1
1
1
1
1
1
1
1
1
Transglottic (3)
Transglottic
Subglottic
Glottic
Supraglottic
Supraglottic
Glottic
Subglottic
Subglottic
Supraglottic
Supraglottic
T/NK (3)
B-cell
MALT
MALT
B-cell
B-cell
B-cell
MALT
MALT
T/NK
T/NK
–
RT
Chemo-RT
SG
Chemo
Chemo
Chemo
Chemo
SG
Chemo
Chemo
DSF
DSF
DSF
DSF
DSF
DSF
DSF
DSF
Death
Death
§
‡
§
12 mo
–
24 mo
6 mo
nr
36 mo
15 mo
4 mo
6 mo
1.5 mo
Abbreviations: RT, radiotherapy; Chemo, chemotherapy; SG, surgery; DSF, disease-free survival.
*Two patients are DSF (39 and 35 months), and 1 patient died after 36 months.
†
Median survival 67 months.
‡
All pateints died 32, 8, and 2 months after the initial diagnosis.
§
Two patients are DSF 36 and 11 months, respectively; 1 patient died after 2 months; and 1 patient was lost to follow-up.
546
Primary Laryngeal Lymphomas
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Comparison of the histological findings of the
previous reports of laryngeal lymphomas is difficult because of heterogeneous pathological classification schemes that have been used. An
accurate diagnosis requires immunohistochemical examination of paraffin-embedded or frozen
biopsy material. Various antibodies are used to
predict the lymphoid nature of the cells and provide more specific information about the classification of B-cell or T-cell lineage subsets. B-cell
lymphomas are reported to be more common
than T-cell lymphomas (ratio of 6:1).1,11,18 Pooling the published cases of laryngeal lymphomas,
in the last 12 years, almost 70% of them derived
from B-cell subset (Table 3). T/NK-cell and
MALT lymphomas, which are recently described,
are distinct clinicopathologic entities of laryngeal NHLs. According to our review, in 7 cases
(19%), a T/NK lymphoma was reported and in
another 7 cases (19%), the histopathological
examination revealed a MALT type of this neoplasia (Table 3). T/NK lymphomas show strong
tendency to the nasal and nasopharyngeal
region. MALT lymphomas belong to the category
of the extranodal marginal zone B-cell lymphomas and usually arise in the stomach. The
detection of a MALT lymphoma in larynx is
very rare, and less than 15 cases have been
reported since its first description by Diebold et
al40,42 In our department, the 2 cases had T-cell
type origin, and the rest B-cell (MALT type).
Radiation therapy and chemotherapy are the
most common therapeutic strategies advocated
worldwide for the treatment of the primary
laryngeal lymphomas (Table 3). Radiotherapy
has been advocated as the most appropriate
treatment. A great body of literature indicates
that lymphoma localized in the larynx is one of
the most radiosensitive tumors, and generally,
moderate-dose therapy (30–50 cGy) is needed
for their control.11,12,18,43–46 The above-reported
good response of laryngeal lymphomas to radiotherapy must be interpreted with caution
because the results are mainly based on lowgrade B-cell lymphomas and long-term follow-up
is limited. More recent bibliographic reports
have suggested combined-modality treatment
(radiotherapy plus chemotherapy)46,47 or chemotherapy alone,47,48 especially for recurrent or
disseminated cases. Surgery may be essential as
a salvage modality of lymphomas that present
with laryngeal obstruction or massive hemorrhage. However, it should be noted that the surgical excision has been recently proposed as the
Primary Laryngeal Lymphomas
initial treatment strategy for the MALT
laryngeal lymphomas.33 In our study, the primary
treatment modality of laryngeal lymphomas was
chemotherapy with a supplement of radiotherapy.
Nowadays, the extensive cellular phenotypic
characterization of tumor biopsy, using flow
cytometry and karyotypic analysis, is becoming a
new challenge in clinical oncology to create
patient-specific treatments. Flow cytometry is a
useful technique in the diagnosis and subclassification of lymphomas as well as in the determination of prognostic indicators of this neoplasia and
should be adopted by the pathologists and surgeons. Nayak et al28 reported the first case of
laryngeal lymphoma with extensive characterization of its tumor, leading to the application of a
specific immunotherapeutic treatment.
Reviewing the available literature, common
clinical features in the previously described cases
of laryngeal NHLs have been revealed. First, laryngeal lymphomas tend to remain localized for a
long period of time, without progress of symptoms. However, patients with acute airway
obstruction may be presented as the case 1 of this
study, and in this case, the treatment options, to
establish a secure airway, are tracheostomy, excision, or orotracheal intubation with tumor
debulking. For the slow-growing laryngeal lymphomas, debulking tumor by the Carbone dioxide
laser before the definitive therapy of laryngeal
neoplasia seems a safe and effective method,
providing certain benefits, such as the avoidance
of tracheostomy or laryngectomy, the accurate
histopathological diagnosis and the briefing
and informed consent of patient.49,50 Second,
dissemination often occurs to other extranodal
sites such as the upper respiratory tract, stomach, orbit, or skin, with a long disease-free interval. Third, radiotherapy and/or chemotherapy
are considered effective for both primary and
disseminated tumors, and long-term survival
can be achieved.11
In conclusion, although primary laryngeal
lymphoma is rare, it should be considered in the
differential diagnosis of a mass in the neck
region, especially in the supraglottic area. The
review of the literature reveals that the small
number of patients with primary laryngeal carcinoma that are included in studies does not
allow establishing the ideal treatment. It seems
that primary laryngeal lymphoma is an unusual
presentation for NHL rather than a separate
disease entity and should be managed according
to the recent treatment trends for NHLs.
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547
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