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  Table of Contents  
Year : 2022  |  Volume : 59  |  Issue : 1  |  Page : 115-118

Langerhans cell histiocytosis of thyroid: Case report with review of literature

Department of Surgical Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission04-Jun-2020
Date of Decision18-Jun-2020
Date of Acceptance30-Dec-2020
Date of Web Publication19-May-2022

Correspondence Address:
Munita Bal
Professor and Pathologist, Department of Pathology, Tata Memorial Center, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_608_20

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 » Abstract 

Langerhans cell histiocytosis (LCH) is a rare monoclonal disease of antigen presenting cells. Involvement of thyroid gland by LCH is exceedingly rare. Herein, we present a case of LCH involving the thyroid in a 38-year-old woman. Our patient presented clinically as a case of primary thyroid neoplasm. Presence of elongated, epithelioid neoplastic cells with grooved nuclei along with presence of background eosinophils were seen on fine-needle aspiration cytology (FNAC) and histopathology. Positive staining for CD1a and S100 immunohistochemistry confirmed the diagnosis of LCH. Patient was given combination chemotherapy and has responded well to the same without any complaints for last 6 months. With this report, our goal is to expand awareness of this rare tumor in the thyroid. Consideration at the time of FNAC and its correct diagnosis on subsequent excision is imperative for patient management.

Keywords: Cytology, histopathology, immunohistochemistry, Langerhans cell histiocytosis, thyroid

How to cite this article:
Yadav SC, Bal M, Patil A. Langerhans cell histiocytosis of thyroid: Case report with review of literature. Indian J Cancer 2022;59:115-8

How to cite this URL:
Yadav SC, Bal M, Patil A. Langerhans cell histiocytosis of thyroid: Case report with review of literature. Indian J Cancer [serial online] 2022 [cited 2022 Jul 7];59:115-8. Available from:

 » Introduction Top

Langerhans cell histiocytosis (LCH) is a rare malignancy caused by monoclonal proliferation of bone marrow-derived Langerhans cells accounting for an incidence of about 4.0–5.4 in 1,000,000 individuals annually.[1] The World Health Organization has grouped the clinical presentations of LCH into three overlapping clinical syndromes: (1) unifocal disease (solitary eosinophilic granuloma) involving a single anatomic site, (2) multifocal disease with unisystem involvement, and (3) multifocal disease with multisystem involvement (Letterer–Siwe syndrome).[2]

Typically, LCH has a proclivity for bones, skin, lungs, and the pituitary. The involvement of the thyroid gland is exceptionally rare,[3] wherein it can present a considerable diagnostic challenge. Herein, we present a case of LCH of the thyroid gland along with an updated review of the literature to add to the existing sparse information on this rare occurrence.

 » Case History Top

A 38-year-old woman, known case of hypothyroidism under treatment, presented with a midline neck swelling above the sternoclavicular joint for 18 months. Clinical examination revealed an anterior neck swelling of 5 × 4 cm with retrosternal extension. Her thyroid function tests were normal. However, her baseline serum prolactin levels were very high (2996.7 nanograms/milliliter). Magnetic resonance imaging (MRI) brain showed thickened and enhancing pituitary stalk with nonvisualization of the posterior pituitary, suggestive of the involvement of the pituitary gland and thus explaining high prolactin levels. Positron emission tomography (PET) scans were done to look for any other lesions or metastasis elsewhere. PET scans [Figure 1]a revealed heterogeneously enhancing thyroidal soft tissue lesion encasing the trachea and larynx with erosion of the thyroid cartilage along with hypermetabolic cervical and mediastinal lymph nodes. The patient underwent ultrasound (USG)-guided fine needle aspiration cytology (FNAC) of the thyroid lesion and conventional Papanicolaou (Pap)-stained smears were prepared. Cytology smears were cellular and showed scattered and small clusters of elongated atypical cells with nuclear enlargement and nuclear grooves [Figure 1]b, [Figure 1]c. Cytomorphology was suggestive of a neoplasm; however, for further characterization of the lesion, histological diagnosis was advised. Biopsy from the thyroid lesion, showed diffuse sheets of neoplastic cells with histiocytoid morphology, convoluted nuclei with conspicuous grooves, and eosinophilic cytoplasm infiltrating the thyroid parenchyma [Figure 2]. A rich admixture of eosinophils was also conspicuous. On immunohistochemistry (IHC), tumor cells were positive for CD1a and S100 and negative for thyroid transcription factor-1 (TTF1) and paired-box gene 8 (PAX8), thus confirming the diagnosis of LCH. Bone marrow aspiration was uninvolved. In view of lesions in the thyroid, liver, lymph nodes, pancreas, and pituitary gland on PET scan, she was diagnosed to have multisystem LCH and was started on combination therapy of cytarabine and prednisolone. The patient is responding well to the therapy and is on regular follow-up for 6 months without any complaints.
Figure 1: Imaging and cytology features: (a). Positron emission tomography (PET) scan showing heterogeneously enhancing hypermetabolic thyroid lesion. (b and c). Cytology smears from the thyroid lesion showed sheets and few clusters of cells with elongated convoluted/reniform nuclei, prominent nuclear grooves (black arrows), and moderate to abundant cytoplasm

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Figure 2: Histology features: (a). Scanner view showing sheets of elongated cells along with many eosinophils. (b). Low-power (H & E 100×) showing sheets of neoplastic cells with scattered eosinophils in between. (c and d). High power (H & E 400×) showing cells with histiocytoid morphology, nuclear grooves (black arrows), and moderate eosinophilic cytoplasm. These neoplastic histiocytic cells showed diffuse and strong positivity for CD1a (e) and S100 protein (f) on immunohistochemistry

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 » Discussion Top

LCH was first described in 1893 by Hand in association with polyuria and tuberculosis, and subsequently recognized by a triad of exophthalmos, lytic bone lesion, and diabetes insipidus (DI) as Hand–Schuller–Christian disease. Disseminated inflammatory lesions in infants were classified as Letterer–Siwe disease.[4] The male-to-female ratio in LCH is 3.7:1.[5] The most common endocrine involvement associated with LCH is central DI and growth hormone deficiency, reported in 20–50% of LCH due to involvement of the posterior pituitary gland.[6] Our patient had prolactinemia due to the involvement of the pituitary gland, which is very well described in the literature.[7]

LCH can be a unisystem or a multisystem disorder; however, the involvement of the thyroid gland even in the disseminated form of LCH is extremely rare.[2] Literature review reveals less than 75 cases of thyroid involvement in LCH, the majority being a part of multisystem disease. Thyroid involvement in LCH is more prevalent in adults with a men-to-women ratio of 1:1.4.[5] On USG, diffuse involvement of the entire thyroid is seen in 59%, nodular enlargement in 25.8%, and irregular enlargement in 13.6% cases.[5] Our patient also had diffuse thyroid gland involvement. Clinical and radiologic diagnosis is difficult, often indistinguishable from other thyroid disorders such as cystic degeneration in goiter, poorly differentiated carcinoma, lymphoma, or lymphocytic thyroiditis; not infrequently, antithyroid antibodies are elevated compounding the diagnostic challenge.[3],[7],[8]

For thyroid nodules, FNAC is a frontline investigation. While as such, the diagnosis of LCH on FNAC may not pose a challenge in the hands of an experienced and skilled cytopathologist, the extreme rarity, low clinical index of suspicion, and overlapping cytology with commoner primary thyroid pathologic entities make the diagnosis of thyroid LCH fraught with diagnostic pitfalls. While on one hand, histiocytoid morphology may simulate benign chronic granulomatous thyroiditis, tuberculosis, and Hurthle cell-rich lymphocytic thyroiditis, on the other hand, grooved, enlarged, and pale nuclei may be especially misinterpreted as papillary thyroid carcinoma (PTC) on FNAC smears owing to nuclear grooves, and at times for Hurthle cell neoplasm, and due to convoluted nuclei and in cases with marked cytologic atypia for anaplastic large cell lymphoma (ALCL).[5],[9],[10] Cellular smears, dyshesive population, histiocytoid cells with longitudinal 'coffee-bean' nuclear groove, and background infiltrate of eosinophils are diagnostic hallmarks of LCH on FNAC. The degree of eosinophilic infiltrate may vary from scant to abundant;[9] however, the presence of eosinophils or Charcot–Leyden crystals is a useful clue. In PTC, the neoplastic cells are in clusters, whereas those in LCH are singly scattered and isolated. Also, the nuclear grooves, which are a prominent histologic feature in PTC, are less frequently observed in cytology smears and are almost nonexistent in the case of liquid-based cytology. In difficult cases, immunocytochemistry can help to confirm the diagnosis.

Histological findings usually mirror cytology features. Immunoreactivity for CD1a, S100 protein, and Langerin (CD207) facilitates the diagnosis of LCH and aids in excluding the differential diagnosis of granulomatous thyroiditis, primary thyroid carcinoma (PTC, Hurthle cell carcinoma and anaplastic thyroid carcinoma), and ALCL among the hematolymphoid malignancies. The presence of convoluted atypical nuclei negates the benign histiocytic/granulomatous differential diagnoses. Absence of follicular or papillary differentiation; TTF1, PAX8, and thyroglobulin negativity on IHC; and presence of eosinophil-rich infiltrate exclude a primary thyroid carcinoma. Identification of anaplastic embryoid cells raise an alarm of ALCL; further, ALCL is negative for CD1a, S100, and Langerin on IHC. Electron microscopy shows the pathognomonic tennis racquet-shaped or zipper-shaped structures, 33 nm wide with a central serrated line, known as Birbeck granules.[11]

Recent molecular studies in the understanding of LCH pathogenesis have revealed recurrent BRAF-V600E mutations in more than 50% of the cases with downregulation of MAPK/ERK kinase (MEK) and extracellular signal-regulated kinase (ERK) pathways. Sequencing studies identified recurrent mutations in MAP2K1 which encodes MEK1 in 33-50% of LCH cases where BRAF is nonmutated.[4] Somatic point mutations in the BRAF gene are also frequently reported in melanoma, colorectal carcinoma, hairy cell leukemia, brain tumors, ovarian carcinoma, thyroid cancer, and lung cancers. Interestingly, BRAFV600E mutations common in LCH are also identified in 40–45% of PTC. Indeed, a rare coexistence of LCH and PTC within the same thyroid has been reported in 13 cases.[12],[13],[14],[15] In such situation of synchronous tumors in the thyroid, diagnosis may be extremely challenging and use of immunocytochemistry employing TTF1 and CD1a may be very useful.[13],[14],[15]

Treatment and outcome of thyroid LCH depend upon the extent of disease and its progression. Solitary lesions may remain static or even regress requiring only observation, or topical steroids, or local excision. However, elaborate imaging including computed tomography chest, MRI brain, abdominal USG, and bone scintigraphy are necessary to rule out disease elsewhere to decide the line of treatment as isolated thyroid LCH has a very good prognosis.[8] For disseminated disease, combination chemotherapy, steroids along with radiotherapy are recommended. Following treatment, more than 80% of cases of thyroid LCH respond and do not recur while 5% of cases develop nonfatal recurrence.[2],[4],[8] With emerging knowledge of BRAFV600E mutations in LCH, BRAF inhibitors promise a potential for targeted treatment in disseminated cases.

 » Conclusion Top

LCH of the thyroid gland is exceptionally rare and presents a challenging scenario for radiologists, pathologists, endocrinologists, and oncologists. Owing to its rarity, it can be mistaken for commoner pathologic entities in the thyroid; hence, a high-index of suspicion is required for an accurate diagnosis and subsequent appropriate treatment.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

 » References Top

Patten DK, Wani Z, Tolley N. Solitary Langerhans histiocytosis of the thyroid gland: A case report and literature review. Head Neck Pathol 2012;6:279-89.  Back to cited text no. 1
Elliott DD, Sellin R, Egger JF, Medeiros LJ. Langerhans cell histiocytosis presenting as a thyroid gland mass. Ann Diagn Pathol 2005;9:267-74.  Back to cited text no. 2
Ya ci B, Kandemir N, Yazici N, Yalçin B, Varan A, Akyüz C, et al. Thyroid involvement in Langerhans cell histiocytosis: A report of two cases and review of the literature. Eur J Pediatr 2007;166:901-4.  Back to cited text no. 3
Allen CE, Ladisch S, McClain KL. How I treat langerhans cell histiocytosis. Blood 2015;126:26-35.  Back to cited text no. 4
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:e7954.  Back to cited text no. 5
el-Halabi DA, el-Sayed M, Eskaf W, Anim JT, Dey P. Langerhans cell histiocytosis of the thyroid gland. A case report. Acta Cytol 2000;44:805-8.  Back to cited text no. 6
Pandyaraj RA, Sathik Mohamed Masoodu K, Maniselvi S, Savitha S, Divya Devi H. Langerhans cell histiocytosis of thyroid-a diagnostic dilemma. Indian J Surg 2015;77:49-51.  Back to cited text no. 7
Behrens RJ, Levi AW, Westra WH, Dutta D, Cooper DS. Langerhans cell histiocytosis of the thyroid: A report of two cases and review of the literature. Thyroid 2001;11:697-705.  Back to cited text no. 8
Saqi A, Kuker AP, Ebner SA, Ausiello J, Jobanputra V, Bhagat G, et al. Langerhans cell histiocytosis: Diagnosis on thyroid aspirate and review of the literature. Head Neck Pathol 2015;9:496-502.  Back to cited text no. 9
Bucau M, Dahan H, Meignin V, Toubert ME, Tazi A, Cochand-Priollet B. FNA cytology revealing Langerhans cell histiocytosis and papillary thyroid carcinoma. Cytopathology 2015;26:130-2.  Back to cited text no. 10
Merad M, Ginhoux F, Collin M. Origin, homeostasis and function of Langerhans cells and other Langerin-expressing dendritic cells. Nat Rev Immunol 2008;8:935-47.  Back to cited text no. 11
A. Al Hamad M, Albisher HM, Al Saeed WR, Almumtin AT, Allabbad FM, A Shawarby M. 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;19:170.  Back to cited text no. 12
Loo E, Khalili P, Beuhler K, Siddiqi I, Vasef MA. BRAF V600E mutation across multiple tumor types: Correlation between DNA-based sequencing and mutation-specific immunohistochemistry. Appl Immunohistochem Mol Morphol 2018;26:709-13.  Back to cited text no. 13
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;27:220-3.  Back to cited text no. 14
Johnson WT, Patel P, Hernandez A, Grandinetti LM, Huen AC, Marks S, et al. Langerhans cell histiocytosis and Erdheim-Chester disease, both with cutaneous presentations, and papillary thyroid carcinoma all harboring the BRAF(V600E) mutation. J Cutan Pathol 2016;43:270-5.  Back to cited text no. 15


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