Introduction
Langerhans cell histiocytosis (LCH) is a rare neoplastic disease of dendritic cells with indefinite etiology and pathogenesis.1 The incidence rate of the disease is 4.0–5.4 per 1 million individuals, and the mortality rate is about 3% in adults.2,3 LCH is often encountered in pediatric patients and can be observed as single-organ involvement or multisystemic disease. The disease affects almost every organ in the body, including bone, skin, lung, lymph nodes, hypothalamopituitary axis, liver, spleen, and other sites.2,4 Thyroid involvement in LCH is rare and usually seen in adults.5 When it occurs in children, it is often accompanied by multisystemic involvement.6,7 Because of its rarity, LCH with involvement of the thyroid gland can cause delays in diagnosis and misdiagnosis.
Case Report
A 10-year-old boy was admitted to our clinic who had enlarged neck masses for 3 months. The patient had dyspnea, especially in sleep, and moderate dysphagia with solid foods. He had no fever, hoarseness, nausea, vomiting, or palpitations. Physical examination revealed a 5-cm non-tender mass over the anterior right neck and soft and matted cervical lymph nodes greater than 2 cm (Figure 1). Other system examinations were normal. The patient had no known illness and did not have a family history of thyroid disease and malignancy. Laboratory investigation showed that serum thyroid stimulating hormone was 11.8 mU/L (normal range, 0.4–4.2), free thyroxine was 5.53 pmol/L (normal range, 11.4–22.6), free triiodothyronine was 2.87 pmol/L (normal range, 3–6.7), serum thyroglobulin (Tg) was 393.6 ng/mL (normal range, 0–50), and anti-Tg and anti–thyroid peroxidase were negative. There was no abnormality in complete blood count or kidney and liver function tests. Erythrocyte sedimentation rate, lactate dehydrogenase, and urine analysis were normal. Ultrasonography (USG) of the neck revealed a 5.2 × 3 cm irregularly edged nodule with microcalcifications in the right lobe of the thyroid gland and hilus-erased lymphadenopathies greater than 2 cm in the right lateral neck (Figure 2). USG-guided fine-needle aspiration biopsy (FNAB) was performed on the thyroid nodule. The biopsy was reported as anaplastic epithelial tumor and/or histiocytosis: atypical lymphoid proliferation with no definitive discrimination. Afterward, the patient was investigated for systemic involvement. Computed tomography (CT) of the thorax demonstrated fine-walled bullae up to 6 cm in both lungs with a mid-to-upper lung zone predominance, no interstitial involvement, bilateral pneumothorax, and mediastinal lymphadenopathies up to 2.5 cm. There were no pathological findings on abdominal USG and CT. No evidence of disease involvement was found in the bone survey.
Figure 1.
Physical examination. Anterior neck masses due to the thyroid and cervical lymph node involvement.
Figure 2. a, b.
Neck ultrasonography. (a) Lymph nodes greater than 2 cm in the right lateral neck. (b) A 5.2 × 3 cm massive thyroid nodule with irregular borders covering a large part of the right lobe.
Considering the presence of compression symptoms, right lobectomy of the thyroid gland and excisional lymph node biopsy were performed. Pathology findings showed proliferation of Langerhans cells with nuclear grooves in a background of dispersed eosinophils. Immunohistochemical staining for CD1a and S100 were positive, and LCH was diagnosed. The BRAF V600E mutation was not detected by direct DNA sequencing.
The patient subsequently underwent chemotherapy, including vinblastine. Induction therapy was a dose of 6 mg/m2 every 7 days in combination with prednisone for 6 weeks, and maintenance was a dose of 6 mg/m2 every 3 weeks in combination with prednisone for 12 months. At follow-up 1 year later, there was no relapse in the thyroid gland. The largest of the lung bullae was smaller than 3 cm, and the total number of bullae decreased. Pneumothorax and pleural effusion were not observed. The size of cervical and mediastinal lymph nodes decreased.
Because the patient was under the age of 18, informed consent was obtained from the parents regarding use of the data and materials to be published.
Discussion
The most common organ involvement in LCH is bones (80% of cases). It causes asymmetric osteolytic lesions in the bones and often affects the skull.8 Skin involvement is seen in approximately 33% of cases.4 The most common endocrinological abnormality in LCH is central diabetes insipidus.9 In approximately half of patients with LCH involving the thyroid, hypothalamopituitary abnormalities are observed, and usually these patients had central diabetes insipidus.10 In our case, no findings suggesting central diabetes insipidus were found.
Thyroid involvement in LCH usually manifests itself with nodular or diffuse enlargement of the gland (Table 1). Because of its rarity, it can be misinterpreted as benign goiters, undifferentiated carcinoma/anaplastic carcinoma, or lymphoma.6 It has also been shown that LCH of the thyroid accompanies primary thyroid malignancies at the same time.11
Table 1.
LCH Cases Presented with Thyroid Gland Involvement Published in the English Literature in the Last 5 Years
| Year | Author | Age, years | G | Site | TSH, μIU/mL | fT4, pmol/L | fT3, pmol/L | Anti-TPO | Anti-Tg | BRAF mutations | Other thyroid pathology | her organ Otinvolvement | Treatment | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2016 | Kuhn et al. (15) | 73 | F | Left | 9.08 | NR | NR | NR | NR | BRAF V600E (+) | Autoimmune thyroiditis | None | Total thyroidectomy | Alive |
| 2016 | AlZahrani et al. (16) | 27 | F | Bilateral | 0.01 | 13.7 | 3.1 | NR | NR | NR | PTC | Pituitary gland, lymph node, liver, spleen | Total thyroidectomy, RAI, prednisone, chemotherapy (NR) | Alive |
| 2017 | Wu et al. (17) | 40 | M | Bilateral | NR | NR | NR | NR | NR | NR | PTC | Lymph node, lung, liver, hypothalamus, palate | Right lobectomy, methotrexate, AraC | Alive |
| 2019 | Al Hamad et al. (18) | 36 | F | Bilateral | NR | NR | NR | NR | NR | BRAF V600E (+) in PTC and V600K (+) in LCH | PTC | Lymph node, skin | Total thyroidectomy, etoposide, prednisone | Alive |
| 2019 | Yokoyama et al. (8) | 3 | F | Bilateral | 20.17 | NR | NR | NR | NR | NR | None | Lung | Induction with AraC, VCR, and PSL (progression). Second course with ADR, VCR, CPM, PSL, and CyA | Alive |
| 2019 | He et al. (9) | 3.5 | M | Bilateral | 87.8 | 10.36 | 2.92 | Neg | Neg | BRAF V600E (−) | None | Lymph node, lung, liver, spleen, skin | PSL, JLSG-96 induction regimen, vemurafenib | Alive |
| 2019 | Zaidi et al. (19) | 31 | M | Right | NR | NR | NR | NR | NR | BRAF V600E (+) in PTC and/or LCH | PTC | Pituitary gland | Hemithyroidectomy, RAI, LCH-DAL HX-83 protocol | Alive |
| 2020 | Nacef et al. (20) | 37 | F | Right | NR | NR | NR | NR | NR | NR | None | Pituitary gland, bone, lymph node, lung | Total thyroidectomy, vinblastine, prednisone | Alive |
| 2020 | Ozisik et al. (11) | 45 | M | Bilateral | 4.47 | 9.39 | NR | NR | NR | BRAF V600E (+) in PTC and LCH | PTC | Pituitary gland, lymph node, gingiva | Total thyroidectomy, RAI | Alive |
| 2020 | Ozisik et al. (11) | 58 | M | Left | 0.37 | NR | NR | NR | NR | NR | PTC | None | Total thyroidectomy | |
| 2020 | Current case | 10 | M | Right | 11.8 | 5.53 | 2.87 | Neg | Neg | BRAF V600E (−) | None | Lymph node, Lung | Right lobectomy, prednisone, vinblastine | Alive |
Abbreviations: ADR, doxorubicin; AraC, cytarabine; CPM, cyclophosphamide; CyA, cyclosporine A; F, female; fT3, free triiodothyronine; fT4, free thyroxine; G, gender; JLSG-96, Japan LCH study group-96; LCH, Langerhans cell histiocytosis; LCH-DAL HX-83, LCH Deutsche Arbeitsgemeinschaft für Leukaemieforschung Histocytosis X-83; M, male; Neg, negative; NR, not reported; PSL, prednisolone; PTC, papillary thyroid cancer; RAI, radioactive iodine treatment; Tg, thyroglobulin; TPO, thyroid peroxidase; TSH, thyroid stimulating hormone; VCR, vincristine.
Different thyroid hormone conditions can be seen in patients with thyroid LCH. Most often, euthyroid and hypothyroid statuses are detected, but subclinical hypothyroidism and subclinical hyperthyroidism are also seen. In addition, anti-Tg and antimicrosomal antibodies rarely can be determined in cases of LCH involving the thyroid.3
USG and FNAB are the first methods used in the investigation of thyromegaly.5 Although FNAB of the thyroid is useful to establish a diagnosis, it can be confused with poorly differentiated or undifferentiated carcinoma.7,12 When FNAB is insufficient in diagnosis, the patient should be evaluated in terms of trucut/core biopsy. Fluorine-18-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) is not a common method in the diagnosis of thyroid LCH, but some reports have shown that it can be useful in diagnosis, staging, and evaluation of treatment. 18F-FDG PET/CT can also provide benefits in investigating other organ involvements.13 Because histopathological features may interfere with other diseases, CD1a and S100 positivity should be seen for a definite diagnosis.5,14 In some publications, it is stated that CD207 (Langerin) immunohistochemical staining will also help in the accurate diagnosis of LCH.14 When primary thyroid LCH is diagnosed, it is recommended to perform some tests, such as thoracic CT, bone scintigraphy, and abdominal USG, to determine the presence of multisystem involvement.3,6
There are no specific guidelines for the management of patients with LCH in the thyroid. Although isolated thyroid LCH can only be treated with thyroidectomy, systemic treatment is preferred in cases with multisystemic involvement.4,5 For disseminated aggressive disease, various chemotherapeutic agents can be used, including glucocorticoids, vinblastine, etoposide, methotrexate, doxorubicin, and cyclophosphamide. Because of the frequency of occurrences, a majority of adults underwent surgery alone; however, the majority of children underwent the combination of surgery and chemotherapy for thyroid LCH treatment.3,7
Consequently, although thyroid LCH is rarely seen, it should be kept in mind in patients with goiter. In some patients, multisystemic involvement may be overlooked and cause delays in diagnosis and treatment. In patients who cannot be diagnosed by FNAB and have compression symptoms, surgery may be useful in definitive diagnosis and treatment.
Footnotes
Peer-review: Externally peer-reviewed.
Author Contributions: Concept - R.I., A.A.; Design - R.I., A.A.; Supervision - A.A.; Resources - A.A.; Materials - A.A., A.A., I.H.; Data Collection and/or Processing - R.I., A.A., A.A., I.H.; Analysis and/or Interpretation - R.I., A.A., A.A.; Literature Search - R.I.; Writing Manuscript - R.I.; Critical Review - A.A.
Conflict of Interest: The authors declare that there are not any conflict of interest.
Financial Disclosure: The authors declare that this study has received no financial support.
References
- 1.Haroche J, Cohen-Aubart F, Rollins BJ, et al. Histiocytoses: emerging neoplasia behind inflammation. Lancet Oncol. 2017;18(2):e113–125. doi: 10.1016/S1470-2045(17)30031-1. [DOI] [PubMed] [Google Scholar]
- 2.Emile JF, Abla O, Fraitag S, et al. Review Article Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127(22):2672–2681. doi: 10.1182/blood-2016-01-690636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Patten DK, Wani Z, Tolley N. Solitary langerhans histiocytosis of the thyroid gland: a case report and literature review. Head Neck Pathol. 2012;6(2):279–289. doi: 10.1007/s12105-011-0321-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Attakkil A, Thorawade V, Jagade M, Kar R, Paxparelka RK. Isolated langerhans histiocytosis in thyroid: thyroidectomy or chemotherapy? J Clin Diagnostic Res. 2015;9(9):XD01–XD03. doi: 10.7860/JCDR/2015/12313.6466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lollar K, Farrag TY, Cao D, Niparko J, Tufano RP. Langerhans cell histiocytosis of the thyroid gland. Am J Otolaryngol. 2008;29(3):201–204. doi: 10.1016/j.amjoto.2007.05.004. [DOI] [PubMed] [Google Scholar]
- 6.Tajik P, Nazari S, Javaherizadeh H. Langerhans cell histiocytosis with thyroid involvement in a 3 year-old child – a case report. Pol Przegl Chir. 2012;84(8):411–414. doi: 10.2478/v10035-012-0069-1. [DOI] [PubMed] [Google Scholar]
- 7.Lin CH, Lin WC, Chiang IP, Ho YJ, Peng TC, Wu KH. Langerhans cell histiocytosis with thyroid and lung involvement in a child: a case report. J Pediatr Hematol Oncol. 2010;32(4):309–11. doi: 10.1097/MPH.0b013e3181c4de1a. [DOI] [PubMed] [Google Scholar]
- 8.Yokoyama S, Nakaoka T, Fukao D, et al. Pulmonary Langerhans cell histiocytosis with thyroid involvement manifesting as recurrent bilateral pneumothorax and tension bullae in a 3-year-old child. Int J Surg Case Rep. 2019;60:239–243. doi: 10.1016/j.ijscr.2019.06.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.He Y, Xie J, Zhang H, Wang J, Su X, Liu D. Delayed diagnosis of langerhans cell histiocytosis presenting with thyroid involvement and respiratory failure: a pediatric case report. J Pediatr Hematol Oncol. 2020;42(8):e810–e812. doi: 10.1097/MPH.0000000000001625. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Xia CX, Li R, Wang ZH, et al. A rare cause of goiter: langerhans cell histiocytosis of the thyroid. Endocr J. 2012;59(1):47–54. doi: 10.1507/endocrj.EJ11-0243. [DOI] [PubMed] [Google Scholar]
- 11.Ozisik H, Yurekli BS, Demir D, et al. Langerhans cell histiocytosis of the thyroid together with papillary thyroid carcinoma. Hormones (Athens) 2020;19(2):253–259. doi: 10.1007/s42000-020-00181-2. [DOI] [PubMed] [Google Scholar]
- 12.Sangtian J, Riangwiwat T, Triamchaisri S, Kanoksil W, Sriphrapradang C. Fine-needle aspiration biopsy of langerhans cell histiocytosis of thyroid gland. J Clin Endocrinol Metab. 2015;100(1):15–16. doi: 10.1210/jc.2014-2859. [DOI] [PubMed] [Google Scholar]
- 13.Long Q, Shaoyan W, Hui W. 18F-fluorodeoxyglucose positron emission tomography/computed tomography for primary thyroid langerhans histiocytosis: a case report and literature review. Indian J Nucl Med. 2015;30(4):328–330. doi: 10.4103/0972-3919.159688. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wohlschlaeger J, Ebert S, Sheu SY, Schmid KW, Totsch M. Immunocytochemical investigation of Langerin (CD207) is a valuable adjunct in the cytological diagnosis of Langerhans cell histiocytosis of the thyroid. Pathol Res Pract. 2009;205(6):433–436. doi: 10.1016/j.prp.2008.12.012. [DOI] [PubMed] [Google Scholar]
- 15.Kuhn E, Ragazzi M, Zini M, Giordano D, Nicoli D, Piana S. Critical pitfalls in the use of braf mutation as a diagnostic tool in thyroid nodules: a case report. Endocr Pathol. 2016;27(3):220–223. doi: 10.1007/s12022-016-9414-y. [DOI] [PubMed] [Google Scholar]
- 16.AlZahrani R, Algarni M, Alhakami H, et al. Thyroid Langerhans cell histiocytosis and papillary thyroid carcinoma. Gland Surg. 2016;5(5):537–540. doi: 10.21037/gs.2016.09.03. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Wu X, Chen S, Zhang LY, Luo YP, Jiang Y, Feng RE. Langerhans cell histiocytosis of the thyroid complicated by papillary thyroid carcinoma: A case report and brief literature review. Medicine (Baltimore) 2017;96(35):e7954. doi: 10.1097/MD.0000000000007954. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Al Hamad MA, Albisher HM, Al Saeed WR, Almumtin AT, Allabbad FM, Shawarby MA. BRAF gene mutations in synchronous papillary thyroid carcinoma and Langerhans cell histiocytosis co-existing in the thyroid gland: a case report and literature review. BMC Cancer. 2019;19(1):170. doi: 10.1186/s12885-019-5372-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Zaidi A, Gautam U, Srinivasan R, Bal A, Prakash G, Sood A. Challenging diagnosis of two neoplasms, Langerhans cell histiocytosis and papillary thyroid carcinoma, from fine needle aspiration of the thyroid by cell-block immunocytochemistry and molecular testing for BRAF V600E mutation. Cytopathology. 2020;31(6):598–601. doi: 10.1111/cyt.12816. [DOI] [PubMed] [Google Scholar]
- 20.Nacef IB, Mekni S, Mhedhebi C, et al. Langerhans Cell Histiocytosis of the Thyroid Leading to the Diagnosis of a Disseminated Form. Case Rep Endocrinol. 2020;2020:6284764. doi: 10.1155/2020/6284764. [DOI] [PMC free article] [PubMed] [Google Scholar]