Clinical Case Report Medicine ®

OPEN

Simultaneous Hodgkin lymphoma and BRAFV600E-

positive papillary thyroid carcinoma
A case report
∗
Shu Liu, PhDa, Yanru Zhao, MDa, Miaojing Li, MDb, Jieying Xi, MDb, Bingyin Shi, MDa, Huachao Zhu, MDb,

Abstract
Rationale: Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. However, the simultaneous occurrence
of PTC and Hodgkin Lymphoma (HL) was rarely reported.
Patient concerns: We present a case of simultaneous BRAFV600E-positive PTC and HL in a 17-year-old female.
Diagnosis: She was referred to our clinic with a painless lump in her left neck. A highly suspicious thyroid nodule and multiple
enlarged lymph nodes in the neck were found by ultrasonography examination. The suspicious nodule was diagnosed as PTC by fine
needle aspiration cytology.
Interventions: A total thyroidectomy with bilateral lymph node dissection was performed and the microscopic examination
revealed a 2-cm PTC with BRAFV600E mutation and HL (mixed cellularity) in the bilateral lymph nodes. PTC was postoperatively
considered as T1bN0M0. Levothyroxine (125 mg/d) was administered to the patient for thyrotropin suppression therapy. Then the
patient was referred to the Department of Hematology to receive 4 cycles of ABVD followed by 30 Gy involved-site radiotherapy and
radioactive iodine (RAI) therapy for thyroid cancer.
Outcomes: After two cycles of ABVD, multiple enlarged lymph nodes showed a significant response to the chemotherapy in the
patient.
V600E
Lessons: Simultaneous HL and BRAF -positive PTC is extremely rare. Biopsy of the suspicious lymph nodes should be
performed to confirm malignancy metastasizing from PTC or other lesions. Similarly, in HL patients with suspicious thyroid nodule,
ultrasound-guided fine needle aspiration of thyroid nodule should be performed to exclude thyroid malignancy.
Abbreviations: FDG-PET = [18F]fluorodeoxyglucose positron emission tomography, ABVD = doxorubicin/bleomycin/
18

vinblastine/dacarbazine, CT = computed tomography, EORTC = the European Organization for Research and Treatment of Cancer,
ESMO = European Society for Medical Oncology, FNAC = fine needle aspiration cytology, HL = Hodgkin lymphoma, LYSA =
Lymphoma Study Association, PTC = papillary thyroid cancer, RAI = radioactive iodine, TERT = telomerase reverse transcriptase,
TSH = thyrotropin.
Keywords: BRAF mutation, Hodgkin lymphoma, papillary thyroid cancer, treatment

1. Introduction disease.[1] Prognosis is excellent, with 20-year survival surpassing

90% when appropriate therapy is undertaken.[2] Hodgkin
Papillary thyroid cancer (PTC) represents more than 90% of all
lymphoma (HL) accounts for approximately 10% of cases of
thyroid cancer cases and it is the most indolent form of the
newly diagnosed lymphoma in the United States.[3] HL is most
frequently diagnosed in the group ages 20–34 years.[3] Multiple
Editor: N/A. studies have reported an increased risk for thyroid cancer as
This work was supported by Foundation of the First Affiliated Hospital of Xi’an
secondary neoplasms after treatment for HL patients.[4–7]
Jiaotong University (No. 2016QN-17) and the Key Research and Development However, the synchronous PTC and HL is very rare. We found
Program of Shaanxi Province (No. 2017SF-185). only two reports in the English literature reporting simultaneous
Conflicts of interest: The authors declare that they have no conflicts of interest. PTC and HL.[8]
a
Department of Endocrinology, b Department of Hematology, The First Affiliated Herein, we present a case of simultaneous BRAFV600E-positive
Hospital of Xi’an Jiaotong University, Xi’an 710061, PR China. PTC and HL in a teenager.
∗
Correspondence: Huachao Zhu, Department of Hematology, The First Affiliated
Hospital of Xi’an Jiaotong University, Xi’an 710061, PR China
(e-mail: zhuhuachao@163.com). 2. Case presentation
Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc. A 17-year-old teenager, who complained about a painless lump in
This is an open access article distributed under the terms of the Creative her left neck for one week, was admitted to our clinic. The lump
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-
ND), where it is permissible to download and share the work provided it is
was approximately the size of 3  5 cm. During this period, the
properly cited. The work cannot be changed in any way or used commercially patient did not have fever, drenching night sweats, or weight loss.
without permission from the journal. After the physical examination, a 2  2 cm thyroid nodule was
Medicine (2019) 98:3(e14180) incidentally palpated in the left lobe. Then the patient underwent
Received: 6 August 2018 / Received in final form: 17 December 2018 / ultrasonography examination revealing a highly suspicious
Accepted: 25 December 2018 nodule with a size of 2.24  2.0  3.25 cm in the left thyroid
http://dx.doi.org/10.1097/MD.0000000000014180 lobe. In addition, the ultrasound presented enlarged lymph nodes

1
Liu et al. Medicine (2019) 98:3 Medicine

Figure 1. FNA and histological slides of papillary thyroid cancer. (A) Hematoxylin and eosin staining of FNA (magnification of main image, 200; magnification of the
smaller image, 400), illustrating the papillary structures and intranuclear cytoplasmic pseudoinclusions (arrow). (B) Representative histological images of
hematoxylin-eosin staining of sections from papillary thyroid cancer. FNA = fine needle aspiration.

in bilateral neck and supraclavicular regions, and their maximum 3. Discussion

size was 5.03  2.46 cm. The suspicious nodule was aspirated and Regional lymph node metastases are present at the time of
PTC was diagnosed by fine needle aspiration cytology (FNAC) diagnosis in a majority of patients with PTC, approximately in
(Fig. 1A). The patient was referred to the Department of 20%–50% of patients.[10] The most common site of nodal
Otorhinolaryngology Head and Neck Surgery. After admission, metastases is in the central neck (level VI). Lymph nodes in the
we performed a contrast-enhanced computed tomography, lateral neck, anterior mediastinum and rarely in level I may also
which revealed a low-density shadow lesion in the left thyroid be involved by thyroid cancer.[10] whereas supradiaphragmatic
lobe and multiple enlarged lymph nodes, even a few fusions of painless lymphadenopathy, including mediastinal involvement,
enlarged lymph nodes in the neck, supraclavicular fossa, and or left neck nodal enlargement, or right neck nodal enlargement,
mediastinum. The patient was preoperatively diagnosed as PTC is also a common mode of presentation of HL.[3] In this patient,
and cervical lymph node metastasis. A total thyroidectomy with there were multiple enlargement lymph nodes in the bilateral
cervical lymph nodes dissection was performed at June 19, 2018. neck, supraclavicular fossa, and mediastinum, and even a few
The microscopic examination of thyroid gland indicated PTC fusions of enlarged lymph nodes. FNA of the suspicious lymph
with a size of 2  1  1 cm and extracapsular invasion in the left nodes should be performed for cytology and washout for Tg
lobe and goiter in the right lobe. Surprisingly, the cervical lymph measurement to confirm malignancy metastasizing from PTC or
nodes were engaged by classical HL (mixed cellularity type) by other lesions. Involvement of multiple supradiaphragmatic nodal
histological and immunohistochemical analysis (Fig. 2). The areas, specifically with the presentation of a fusion of enlarged
BRAFV600E mutation and TERT promoter mutation were also lymph nodes or B symptoms, may remind us of the possibility of
postoperatively analyzed. The PTC was only BRAFV600E lymphoma, and core needle biopsy or even excisional biopsy of
mutated. The patient refused to take 18FDG-PET scanning. involved lymph node instead of FNA is preferred to establish a
Sixteen days later, we performed a whole body CT, which definitive diagnosis. Similarly, in HL patients with suspicious
revealed multiple enlarged lymph nodes in the neck, submandib- thyroid nodule, ultrasound-guided FNA of thyroid nodule should
ular, and mediastinum. No apparent sign of organ metastasis or be performed to exclude thyroid malignancy.
bone marrow involvement was observed. According to the Ann Multiple primary cancers are defined as the occurrence of two
Arbor classification and the European Organization for Research or more primary cancers in the same patient, either simulta-
and Treatment of Cancer (EORTC)/Lymphoma Study Associa- neously or sequentially.[11] The synchronous occurrence of PTC
tion (LYSA), this patient was subsequently diagnosed with Stage and lymphoma is extremely rare. We found only 2 cases reporting
IIA HL (mixed cellularity type) and was further allocated to simultaneous PTC and non-Hodgkin lymphoma and 2 cases with
intermediate stage due to the elevated ESR (57 mm/h).[9] simultaneous PTC and HL.[12–15] Pianovski in 2004[14] reported
According to 2015 ATA guidelines, PTC was postoperatively HL was presented as a rapidly enlarging supraclavicular nodule
considered as T1bN0M0, and Levothyroxine (125 mg/d) was 30 days after a total thyroidectomy in a teenager and Rizkallah
administered for thyrotropin suppression therapy. After multi- et al[15] in 2014 reported a case of HL presenting as typical B
disciplinary discussion, the patient was referred to the depart- symptoms incidentally diagnosed with PTC by mediastinoscopy
ment of Hematology to receive 4 cycles of ABVD followed by 30 in a young man. Both of them had no molecular analysis of PTC
Gy involved-site radiotherapy according to 2018 ESMO Clinical and were little different from our case; the occurrence of PTC an
Practice Guidelines and radioactive iodine (RAI) therapy for HL was presented as a suspicious thyroid nodule and enlarged
thyroid cancer. After two cycles of ABVD, multiple enlarged cervical lymphadenopathy.
lymph nodes showed a significant response to the chemotherapy. Synchronous multiple primary cancers are difficult to manage
The Institutional Ethics Committee of our hospital approved the because of lack of a standard approach. Surgery for thyroid cancer
publication of the case. The patient has provided informed is an important element of a multifaceted treatment approach, and
consent for publication of the case. RAI therapy was considered after total thyroidectomy to improve

2
Liu et al. Medicine (2019) 98:3 www.md-journal.com

Figure 2. Histological and immunohistochemical analysis of the lymph node of the patient. (A) Hematoxylin and eosin staining of the tumor tissue (magnification of
main image, 200; magnification of the smaller image, 400). Hodgkin and Reed-Sternberg cells were observed in a cellular background rich in lymphocytes,
histiocytes, and eosinophils. Tumor cells were (B) CD30-positive, (C) CD15-positive, and (D) TTF-1 negative. The smaller image shows the magnified image of
the area.

disease-free survival by destroying residual disease or persistent BRAFV600E mutation plays an important role in the develop-
disease in intermediate/high-risk level differentiated thyroid cancer ment of thyroid cancer.[16] In our case, BRAF mutation was
patients,[10] whereas chemotherapy and radiotherapy are the positive in PTC. The malignant cells in HL have its unique micro-
mainstays of HL treatment.[9] With current treatment advance- environment and are characterized by a highly altered genomic
ments, approximately 90% of all patients diagnosed with HL landscape.[17] Different molecular pathways may play a role in
achieved an excellent disease control.[3] The initial treatment of HL the transforming events in HRS cells. However, the potential
will be optimal when a patient was diagnosed with the HL and molecular link between thyroid cancer and HL is yet unknown.
PTC. First, PTC is a most indolent form of thyroid cancer[1]; Further studies are necessary to clarify the molecular mechanism
second, enlarged lymph nodes involved by HL will diminish or of synchronous occurrence of 2 malignancies.
disappear after HL treatment and thus will be helpful to
preoperatively make a better surgery strategy for PTC to improve 4. Conclusion
the completeness of surgery and decrease the injury and wound
Simultaneous HL and BRAFV600E-positive PTC is extremely rare,
complication of regional lymph node dissection. For our patients,
which may pose significant diagnostic and treatment challenges.
in fact, there was no need for the cervical lymph nodes dissection
To date, although there is no standardized approach, we suggest
because the lymph nodes will respond to chemoradiotherapy.
“lymphoma first approach,” and total thyroidectomy and RAI
Hence, we agreed that the “lymphoma first approach” was
therapy for thyroid cancer are necessary to improve the long-term
recommended for the synchronized condition.[8,12] In this patient,
survival of the synchronized condition. Further studies are still
we started the chemotherapy of HL after total thyroidectomy. It is
necessary to clarify the molecular mechanism of synchronous
noted that patients received HL treatment are at increased risk of
occurrence of 2 malignancies.
secondary neoplasms, specifically thyroid cancers.[4,7] Chemo-
radiotherapy has been proposed as a cause of this increased risk,
Author contributions
especially radiation exposure of the thyroid gland increases the risk
of a secondary thyroid malignancy at the younger ages. We suggest Conceptualization: Shu Liu, Jieying Xi, Bingyin Shi, Huachao
that a total thyroidectomy and RAI therapy are necessary to Zhu.
improve long-term survival of this synchronous condition. Data curation: Shu Liu.

3
Liu et al. Medicine (2019) 98:3 Medicine

Funding acquisition: Shu Liu. [9] Eichenauer DA, Aleman BMP, André M, et al. Hodgkin lymphoma:
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-
Investigation: Yanru Zhao, Miaojing Li, Bingyin Shi.
up. Ann Oncol 2018;29:iv19–29.
Writing – original draft: Shu Liu, Miaojing Li, Jieying Xi, Bingyin [10] Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid
Shi, Huachao Zhu. Association management guidelines for adult patients with thyroid
Writing – review & editing: Shu Liu, Huachao Zhu. nodules and differentiated thyroid cancer: the American Thyroid
Association Guidelines Task Force on Thyroid Nodules and Differenti-
ated Thyroid Cancer. Thyroid 2016;26:1–33.
References
[11] Park SL, Caberto CP, Lin Y, et al. Association of cancer susceptibility
[1] Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship variants with risk of multiple primary cancers: the population
statistics, 2012. CA Cancer J Clin 2012;62:220–41. architecture using genomics and epidemiology study. Cancer Epidemiol
[2] Davies L, Welch HG. Thyroid cancer survival in the United States: Biomarkers Prev 2014;23:2568–78.
observational data from 1973 to 2005. Arch Otolaryngol Head Neck [12] Popivanov GI, Bochev P, Hristoskova R, et al. Synchronous papillary
Surg 2010;136:440–4. thyroid cancer and non-Hodgkin lymphoma: case report. Medicine
[3] Shanbhag S, Ambinder RF. Hodgkin lymphoma: a review and update on (Baltimore) 2018;97:e9831.
recent progress. CA Cancer J Clin 2018;68:116–32. [13] Singh NJ, Tripathy N, Roy P, et al. Simultaneous triple primary head and
[4] Baras N, Dahm S, Haberland J, et al. Subsequent malignancies among neck malignancies: a rare case report. Head Neck Pathol 2016;10:
long-term survivors of Hodgkin lymphoma and non-Hodgkin lympho- 233–6.
ma: a pooled analysis of German cancer registry data (1990–2012). Br J [14] Acosta-Ortega J, Montalbán-Romero S, García-Solano J, et al.
Haematol 2017;177:226–42. Simultaneous medullary carcinoma of the thyroid gland and
[5] Gözdaşo glu S, Pamir A, Ünal E, et al. Secondary neoplasms in children Hodgkin’s lymphoma in bilateral lymph nodes of the neck: a potential
with Hodgkin’s lymphoma receiving C-MOPP and radiotherapy: pitfall in fine-needle aspiration cytology. Diagn Cytopathol 2004;31:
presentation of four cases. Turk J Haematol 2016;33:66–70. 255–8.
[6] Garaventa A, Haupt R, Panarello C, et al. Early occurrence of a [15] Rizkallah JJ, Jambart SS, Maalouli GD. Synchronous diagnosis of a
secondary thyroid carcinoma in a child treated for Hodgkin disease. Med Hodgkin lymphoma and a papillary carcinoma of the thyroid. Case Rep
Pediatr Oncol 2001;36:396–7. Intern Med 2014;1:235–7.
[7] Chowdhry AK, Fung C, Chowdhry VK, et al. A population-based study [16] Liu S, Gao A, Zhang B, et al. Assessment of molecular testing in fine-
of prognosis and survival in patients with second primary thyroid cancer needle aspiration biopsy samples: an experience in a Chinese population.
after Hodgkin lymphoma. Leuk Lymphoma 2018;59:1180–7. Exp Mol Pathol 2014;97:292–7.
[8] Dudeque Pianovski MA, de Lacerda Filho L. A teenager with [17] Cuceu C, Hempel WM, Sabatier L, et al. Chromosomal instability in
simultaneous Hodgkin disease and thyroid carcinoma. Med Pediatr Hodgkin lymphoma: an in-depth review and perspectives. Cancers
Oncol 2003;41:91–2. (Basel) 2018;10:91doi: 10.3390/cancers10040091.