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NK/T cell lymphoma with inverted papilloma: A rare coexistence

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Natural killer/T-cell (NK/T) lymphomas are an infrequent tumour type of NK and NK-T cells commonly occurring in the upper aero-digestive tract. Most reported cases in the literature are random solitary cases of NK/T-cell lymphoma. A 35-year-old male farmer from Sikkim reported to our institution with NK/T-cell lymphoma (nasal type) with coexistent inverted papilloma of the nose. This case is being reported due to the unique and unusual simultaneous occurrence of these two tumour entities.
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[AMJ 2014, 7, 8, 318322]
NK/T cell lymphoma with inverted papilloma: A rare coexistence
Asitava Deb Roy, Isha Preet Tuli, Deepti Joshi
Sikkim Manipal Institute of Medical Sciences, Gangtok, Sikkim, India
318
CASE STUDY
Please cite this paper as: Deb Roy A, Tuli IP, Joshi D. NK/T
cell lymphoma with inverted papilloma: A rare coexistence.
AMJ 2014, 7, 8, 318322.
http//dx.doi.org/10.4066/AMJ.2014.2025
Corresponding Author:
Asitava Deb Roy
Ashray, Anandanagar Lane 3,
Adabari, Guwahati 781012,
Assam, India
Email: asitavadr@gmail.com
ABSTRACT
Natural killer/T-cell (NK/T) lymphomas are an infrequent
tumour type of NK and NK-T cells commonly occurring in
the upper aero-digestive tract. Most reported cases in the
literature are random solitary cases of NK/T-cell lymphoma.
A 35-year-old male farmer from Sikkim reported to our
institution with NK/T-cell lymphoma (nasal type) with
coexistent inverted papilloma of the nose. This case is being
reported due to the unique and unusual simultaneous
occurrence of these two tumour entities.
Key Words
NK/T-cell lymphoma, inverted papilloma, nasal, tumour co-
existence
Implications for Practice:
1. What is known about this subject?
NK/T-cell lymphoma is a rare tumour, but has been
reported in various parts of the world. However, its
coexistence with a benign pathology-like inverted papilloma
has rarely been reported.
2. What new information is offered in this case study?
This case is unusual with respect to its clinical presentation.
The patient had two different yet co-existing
nasopharyngeal pathologies, one benign and the other
malignant. Despite an extensive literature search, no case of
simultaneous occurrence of inverted papilloma with T-cell
lymphoma could be found.
3. What are the implications for research, policy, or
practice?
Although rare, physicians should be careful in considering
the presence of two pathologies of different nature and
prognosis. Clinically suspicious cases may be subjected to
frozen section biopsy during surgery to rule out malignancy.
Our report emphasises the need for awareness about such
coexisting pathologies and proper communication between
clinicians and pathologists.
Background
Natural killer/T-cell (NK/T) lymphomas represent a group of
rare tumours of NK and NK-T cells, frequently seen in Asian,
and Central and South American populations.1 The nasal-
type NK/T-cell lymphoma is the most common and best
characterised variant. This tumour shows a predilection for
the upper aero-digestive tract, accounting for the historic
terms lethal midline granuloma and midline reticulosis.
Most reported cases in the literature are random solitary
cases of NK/T-cell lymphoma. Its simultaneous occurrence
with other aero-digestive tumours has not been
described.2,3 We present a rare coexistence of NK/T-cell
lymphoma (nasal type) with inverted papilloma of the nose
in a 35-year-old male farmer from Sikkim.
Case details
A previously healthy 35-year-old male farmer from South
Sikkim, India, presented in December 2012 to the
Otorhinolaryngology Department with a one-year history of
nasal obstruction and two-month history of blood tinged
nasal discharge, which had not resolved despite several
courses of antibiotics. The nasal obstruction was of insidious
onset, initially right-sided and intermittent, but it gradually
progressed to become persistent, bilateral, and complete.
The nasal discharge was thin, pale, watery, not foul
smelling, and moderate in amount. There was occasional
blood tingeing of the discharge, particularly after sneezing.
[AMJ 2014, 7, 8, 318322]
319
He also had foreign body sensation in the throat two
months prior to presentation, along with a dull pain while
swallowing solid food and a hyponasal voice. He gave no
history of any night sweats, fever, cough, hawking, facial
pain, frank epistaxis, dyspnea, otalgia, addiction,
tuberculosis, or diabetes.
Physical examination revealed a large multi-lobulated,
polypoidal, pale mass completely filling the right nasal
cavity. On probing it was soft, neither bleeding nor sensitive
to touch, and the probe could be passed all around the
mass. On nasal endoscopy, the anterior rhinoscopy findings
were confirmed. The mass was seen arising from the right
middle meatus with thick mucopurulent discharge,
extending anteriorly till the anterior end of the inferior
turbinate and posteriorly to the choana. Middle turbinate
was pushed medially. Left-sided nasal mucosa was pale with
mucoid discharge. Septum was deviated towards the left.
Oral cavity examination showed multiple slough covered
punched out ulcerations over a thickened, eroded uvula
(Figure 1) and left side of soft palate with thick, post-nasal
discharge. Gag reflex was present. Nasopharyngeal
examination showed a mass arising from the upper surface
soft palate extending into the choana with a thickened
ulcerative mucosa of the nasopharyngeal surface of soft
palate and onto the left lateral wall of the nasopharynx.
Fossae of Rosenmuller on both sides were not involved.
There was no external nasal or facial deformity or cervical
lymphadenopathy.
Figure 1: Clinical picture showing the nasopharyngeal mass
extending to the soft palate
A contrast-enhanced computed tomography (CECT) (Figure
2) of the nose and paranasal sinuses with axial and coronal
sections sinuses showed soft tissue density in the right
maxillary (medial portion) and ethmoid sinuses and nasal
cavity, suggestive of right sinonasal polyposis along with a
soft tissue density in the nasopharynx towards the left side
measuring about 19 mm x 17 mm. There was no significant
contrast enhancement or any bony erosion. Nasal
endoscopy with biopsy was done. Two separate samples
were taken from the right cavity and the left nasopharynx
for histopathological examination.
Figure 2: CECT image showing the right-sided nasal mass
Histopathology of the nasopharyngeal mass revealed
ulcerated tissue, densely populated by atypical lymphoid
cells (Figure 3) with large areas of necrosis. The cells were
small to medium sized with irregularly folded and angulated
nuclei, dense chromatin, and inconspicuous nucleoli.
Occasional large cells with clear cytoplasm were noted.
Distortion and destruction of mucosal glands and vessels by
these cells were seen. Immunohistochemistry for CD56
showed positive membranous staining in these cells (Figure
4). Histopathology of the right nasal mass showed features
of inverted papilloma (Figure 5). The final diagnosis was
NK/T-cell lymphoma with inverted papilloma.
The right nasal mass was debulked and the patient was
started on chemotherapy with follow-up and has been
referred outside the state for radiotherapy. No recurrence
was noted at the last follow-up at 10 months.
[AMJ 2014, 7, 8, 318322]
320
Figure 3: Histopathology showing sheets of atypical
lymphoid cells with irregular angulated nuclei (H and E,
400X)
Figure 4: Immunohistochemistry showing CD 56 positivity
in the neoplastic cells (400X)
Figure 5: Histopathology of the associated inverted
papilloma (H and E, 100X)
Discussion
Nasal-type NK/T-cell lymphoma is an uncommon neoplasm
accounting for 28 per cent of non-Hodgkin lymphomas in
Asia, where this entity shows its highest prevalence. In
Europe and North America, nasal-type NK/T-cell lymphoma
represents fewer than 2 per cent of non-Hodgkin
lymphomas.1 Previously known as lethal midline granuloma,
this neoplasm is said to be causally associated with Epstein
Barr virus (EBV).1,2
It is characterised as a very aggressive disease, with local
destroying activity, and refractoriness to treatment. The
tumour bulk can be responsible, at presentation, for
respiratory obstruction and/or periorbitary oedema.
Infiltrating lesions show a destroying activity against soft
and bony oropharyngeal and nasal structures, as was seen
in our patient with uvular necrosis. It can spread to the
central nervous system, cutis, and testis, and be responsible
for hemophagocytosis in bone marrow.4 Tumour behaviour
is aggressive with a reported median overall survival ranging
from 13 to 38 months.1
On histopathology, an angiocentric/angiodestructive growth
pattern with fibrinoid changes in the blood vessels with
frequent coagulative necrosis as a consequence of vascular
occlusion is observed.4 In most cases, the lymphoma is
composed of neoplastic lymphocytes ranging from small
cytologically bland cells, which may create a diagnostic
dilemma, to large cells that are frankly malignant. Most
cases show a morphologic spectrum with intermediate-
sized and large cells predominating with irregular nuclei,
[AMJ 2014, 7, 8, 318322]
321
granular chromatin and mitotic figures.1,4 Neoplastic cells
are usually admixed with an inflammatory infiltrate
containing small lymphocytes, histiocytes, neutrophils, and
eosinophils.1 When inadequate biopsies yield only
inflammatory infiltrate, a false-negative diagnosis becomes
inevitable. Hence, it is important to sample adequate
representative areas of the lesion to avoid a false-negative
diagnosis.
Neoplastic cells are surface CD3−, cytoplasmic CD3ε+,
CD56+, cytotoxic-molecule positive, Epstein-Barr virus
positive, with germline T-cell receptor gene.1,2,4 The lesion
on the right side in our patient showed all the above
features of atypical small- to medium-sized lymphocytes
with immunohistochemistry positive for CD 56, confirming
our diagnosis of NK/T-cell lymphoma.
Inverted papillomas, by contrast, are uncommon, benign
sinonasal tumours that are locally aggressive with a
significant malignant potential. Nasal obstruction or
perception of a nasal mass is the most common presenting
symptom. Almost equally the papillomas may be endophytic
(inverted) or exophytic (fungiform), and a few may have
mixed patterns.5
The concurrent or sequential malignancies associated with
inverted papilloma are mostly squamous cell carcinomas;
the median rate of malignant association reported being
approximately 9 per cent.6 Despite an extensive literature
search, no case of simultaneous occurrence with T-cell
lymphoma as seen in our case could be found. The presence
of Epstein Barr virus had been reported in both NK/T-cell
lymphomas1,2,4 and inverted papillomas,7 but subsequent
studies have refuted any association between Inverted
papilloma and Epstein Barr virus.8,9
For localised NK/T-cell lymphomas, radiotherapy together
with chemotherapy is the standard approach. In
disseminated disease, systemic chemotherapy remains the
mainstay of treatment.2,4 Endoscopic surgical techniques
and a more conservative approach is reserved for less
widespread and more medially located inverted papillomas,
while in tumours extending more peripherally from the
lateral nasal wall or with concomitant malignancy a more
aggressive approach to the papilloma, even an external, en
bloc resection is preferred.6
In our patient, both the papilloma and the lymphoma were
localised, and therefore a conservative approach was
chosen. Though aggressive treatment of Schneiderian
papillomas with concurrent squamous cell carcinoma is
advocated,6 no such guidelines were available for its
treatment with other varieties of concurrent malignancies,
causing a therapeutic dilemma. The patient is doing well on
this treatment and there has been no evidence of any
recurrence of either pathology on the six-month follow-up.
Another important factor to be considered is the delayed
diagnosis of the diseases, as happened in this case, where
the patient had symptoms of nasal discharge from one year
before presentation to the specialist. Presentation to a
family doctor with nasal congestion is not uncommon. Such
patients are often treated for chronic sinusitis as symptoms
include nasal stuffiness, post-nasal drip, facial fullness, and
malaise for a period of 12 weeks or longer. The treatment
comprises an adequate, preferably culture-directed
antibiotic trial for three to four weeks and supportive
treatment. Diagnostic work-up must include a diagnostic
nasal endoscopy. CT scanning is the imaging standard and
best done after antibiotic therapy. Serious underlying
conditions, such as tumours and immunodeficiency states
are always considered in the work-up. Benign as well as
malignant tumours of the sinonasal cavities, nasopharynx,
and skull base must be considered in the differential.10 This
patient had a history of the said symptoms for more than a
year. Any history of longstanding nasal obstruction,
particularly lasting more than 12 weeks, even after an
antibiotic trial of three weeks must be referred to an
otolaryngologist. The blood-tinged nasal discharge
necessitated immediate referral as many benign and
malignant tumours may cause epistaxis.10 Ideally, the
patient should have been referred to a specialist within
three weeks of treatment, as his condition did not resolve. A
nasal endoscopy and CT scan would have detected both the
tumours quickly and treatment could have been instituted
immediately. If this had not been done, the blood-tinged
nasal discharge should alert the healthcare provider. Thus,
the patient had an avoidable diagnostic delay of at least two
months, if not 11 months from the initial presenting
complaint.
Family doctors should refer patients to specialist care if
cases of nasal congestion, especially those with blood-
tinged rhinorrhea, do not completely resolve within 12
weeks after onset In cases similar to that presented here.
General practitioners must also ensure that once patients
have been treated for the more aggressive condition of the
two (NK/T-cell lymphoma) that surgery for the second
pathology (inverted papilloma) is considered. Inverted
papillomas have a tendency to be locally malignant or
undergo malignant transformation to squamous cell
carcinoma, which can be prevented by their complete
removal.5,6
[AMJ 2014, 7, 8, 318322]
322
Conclusion
Inverted papillomas are known to be associated with hidden
or apparent squamous cell carcinoma, not with nasal-type
NK/T-cell lymphomas. Still, the presence of one type of
tumour does not obviate the occurrence of another entity.
This may pose diagnostic and therapeutic challenges, as was
present in our case. A thorough and detailed examination of
any sinonasal mass supplemented with histopathology and
immunohistochemistry is vital for appropriate planning of
treatment. Further, the association of Epstein Barr virus
with inverted papillomas needs to be re-investigated, to
support the likely co-existence of both the entities.
References
1. Schwartz EJ, Molina-Kirsch H, Zhao S, Marinelli RJ,
Warnke RA, Natkunam Y. Immunohistochemical
characterization of nasal-type extranodal NK/T-cell
lymphoma using a tissue microarray: an analysis of 84
cases. Am J Clin Pathol. 2008;130(3):34351.
2. Tse E, Kwong Y-L. How I treat NK/T-cell lymphomas.
Blood. 2013;121(25):49975005.
3. Li YX, Liu QF, Fang H, Qi SN, Wang H, Wang WH, Song
YW, Lu J, Jin J, Wang SL, Liu YP, Lu N, Liu XF, Yu ZH.
Variable clinical presentations of nasal and Waldeyer
ring natural killer/T-cell lymphoma. Clin Cancer Res
2009;15(8):290512.
4. Pagano L, Gallamini A, Trapè G, Fianchi L, Mattei D,
Todeschini G, Spadea A, Cinieri S, Iannitto E, Martelli M,
Nosari A, Bona ED, Tosti ME, Petti MC, Falcucci P,
Montanaro M, Pulsoni A, Larocca LM, Leone G;
Intergruppo Italiano Linfomi. Intergruppo Italiano
Linfomi. NK/T-cell lymphomas ‘nasal type’: an Italian
multicentric retrospective survey. Ann Oncol
2006;17(5):794800.
5. Christensen WN, Smith RRL. Schneiderian papillomas: A
clinicopathologic study of 67 cases. Hum Pathol
1986;17(4):393400.
6. Krouse JH. Development of a Staging System for
Inverted Papilloma. Laryngoscope 2000;110:96568.
7. Macdonald MR, Le KT, Freeman J, Hui MF, Cheung RK,
Dosch HM. A majority of inverted sinonasal papillomas
carries Epstein Barr virus genomes. Cancer
1995;75:230712.
8. Gaffey MJ, Frierson HF, Weiss LM, Barber CM, Baber
GB, Stoler MH. Human papillomavirus and Epstein-Barr
virus in sinonasal Schneiderian papillomas. An in situ
hybridization and polymerase chain reaction study. Am
J Clin Pathol. 1996;106(4):47582.
9. Dunn ST, Clark GD, Cannon TC, Min KW. Survey of
sinonasal inverted papillomata for Epstein-Barr virus.
Head Neck 1997;19(2):98106.
10. Brook I, Hinthon DR. Chronic Sinusitis. [updated 2014
April 7; cited 2014 July 11]. Available from:
http://emedicine.medscape.com/article/232791
PEER REVIEW
Not commissioned. Externally peer reviewed.
CONFLICTS OF INTEREST
The authors declare that they have no competing interests.
ETHICS COMMITTEE APPROVAL
Not taken, as it is a single case report.
PATIENT CONSENT
The authors, Deb Roy A, Tuli IP, and Joshi D declare that:
1. They have obtained written, informed consent for
the publication of the details relating to the
patient(s) in this report.
2. All possible steps have been taken to safeguard the
identity of the patient(s).
3. This submission is compliant with the requirements
of local research ethics committees.
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The relationship between sinonasal inverted papilloma (IP) and various strains of human papilloma virus (HPV) has been examined previously. Yet there is little consensus regarding the incidence or role of HPV in IP. The possible role of Epstein-Barr virus (EBV), which, like HPV, is a DNA virus linked to human lymphoid and epithelial malignancies, was investigated. The polymerase chain reaction (PCR) was used to detect EBV genomic sequences in surgical specimens of IP, in benign nasal polyps, and various control tissues. The IP specimens were similarly examined for the presence of HPV types 6, 11, 16, and 18. EBV DNA was found in 13 of 20 IP specimens (65%) and none of the 10 control tissues. Nine of the 20 specimens contained HPV DNA, and 5 of 20 specimens contained both EBV and HPV. These results imply a previously unsuspected role for Epstein-Barr virus in the pathogenesis of sinonasal inverted papilloma.
Article
Using the polymerase chain reaction (PCR), it has been recently reported that the Epstein-Barr virus (EBV) is present in the majority of Schneiderian sinonasal papillomas (SNP) of the inverted type and may play a role in the pathogenesis of these lesions. The reported prevalence rates of human papillomavirus (HPV) in different types of SNP is also controversial and in need of clarification. Twenty-eight SNP from 27 patients were histologically classified and evaluated for evidence of EBV using PCR and 2 different sensitive and specific in situ hybridization (ISH) procedures for EBER1. Similarly, two methods of ISH were also used for the detection of HPV, using biotinylated DNA probes sensitive for 14 different HPV types as well as more sensitive and specific radioactive RNA probes for HPV types 6, 11, and 16. Polymerase chain reaction was successful in 19 papillomas, including 12 of 19 inverted SNP, 1 of 1 inverted SNP with squamous cell carcinoma, 4 of 5 fungiform SNP, and 2 of 3 oncocytic lesions. Southern blot hybridization of PCR products showed the presence of EBV DNA in two lesions, including one inverted SNP and the single inverted SNP with squamous cell carcinoma. By both DNA- and RNA-mRNA ISH, positivity for EBER was detected in rare stomal lymphocytes but not the overlying epithelium in the inverted SNP with SCC. The remaining cases, including the other inverted SNP positive for EBV by PCR, were completely negative by both ISH techniques. Human papillomavirus was detected by ISH in 1 of 19 (5%) inverted, 1 of 1 (100%) inverted with squamous cancer, 5 of 5 (100%) fungiform, and 0 of 3 (0%) oncocytic SNP. Three SNP contained HPV 6 (all fungiform), three SNP labeled for HPV 11 (two fungiform and the inverted SNP with squamous cancer), and one inverted SNP contained HPV 16. Of the five fungiform SNP, four showed foci of koilocytosis. The results indicate that EBV is not present in sinonasal papillomas. The presence of EBV positive stromal lymphocytes in these lesions may account for a proportion of PCR-positive cases. Oncocytic SNP are unassociated with HPV, whereas inverted SNP contain HPV in a minority of cases. In contrast, fungiform SNP are consistently associated with HPV types 6 and 11 and usually show histologic evidence of viral infection.
Article
Several studies have indicated an etiologic role for viruses in the development of sinonasal inverted papillomata (IP). A recent report demonstrates a strong relationship (65%) between Epstein-Barr virus (EBV) and these lesions using polymerase chain reaction (PCR) analysis. The present study analyzes a series of paraffin-embedded tissues, comprising 25 surgically resected IPs and four fungiform papillomata (FP) for the presence of EBV using a sensitive in situ hybridization (ISH) assay and PCR. None of the specimens examined showed evidence of EBV infection by ISH, and only two papillomata (one sinonasal IP and one FP) gave positive reactions for EBV using PCR. These data challenge the previous report and suggest that EBV is not a significant etiopathologic factor to be considered in the development of sinonasal IP.
Article
Inverted papillomas of the nose and sinuses are uncommon neoplasms. In the past decade there has been a trend toward the use of endoscopic surgical techniques in the management of these tumors, in contrast to the extensive open procedures recommended previously. This trend has not been without controversy, given the association of inverted papillomas with malignancy. It has been difficult to compare surgical approaches to these neoplasms, because of the absence of a uniformly applied staging system representing the extent of disease. It was the purpose of this study to develop such a system that could be easily applied in outcomes research. This study involved an integrated literature review and a synthesis of findings from a number of studies. Previous and current clinical studies examining the treatment of inverted papilloma were reviewed. Findings were organized, and a staging system was framed based on this review. A simple, easily applied staging system was developed based on the extent of tumor involvement noted on endoscopic examination of the nasal cavity and computed tomography (CT) scan evaluation. Stage I disease is limited to the nasal cavity alone. Stage II disease is limited to the ethmoid sinuses and medial and superior portions of the maxillary sinuses. Stage III disease involves the lateral or inferior aspects of the maxillary sinuses or extension into the frontal or sphenoid sinuses. Stage IV disease involves tumor spread outside the confines of the nose and sinuses, as well as any malignancy.
  • I Brook
  • Dr Hinthon
Brook I, Hinthon DR. Chronic Sinusitis. [updated 2014