Histologic Patterns of Thymic Involvement in Langerhans Cell Proliferations: A Clinicopathologic Study and Review of the Literature

Abstract

Thymic involvement by Langerhans cell histiocytosis (LCH) has been described mainly in isolated case reports. A description of the histopathologic patterns of LCH proliferations in the thymus, together with therapeutic implications, has not, to our knowledge, been previously addressed. The pathology consultation files at Children's Hospital of Pittsburgh of UPMC were reviewed for cases of thymic involvement by LCH. Relevant cases in the literature were also reviewed, and the histopathology and clinical course of those cases were collected. Nine consultation cases of thymic involvement were reviewed, together with 23 cases in the literature, which provided adequate pathologic description and ancillary confirmation (n = 32), revealing 4 distinct pathologic groups. Group 1 showed microscopic collection of hyperplastic LCH-like cells in incidental thymectomies of patients without LCH disease, requiring no further treatment (n = 7; 22%). Group 2 showed solitary and/or cystic LCH of the thymus with gland disruption, and at least 3 cases resolved without systemic therapy (n = 10; 31%). Group 3 showed more variable thymic involvement in multi-systemic LCH disease, with either a medullary restricted pattern or more diffuse gland involvement, requiring adjuvant therapy and having a higher mortality rate (n = 13; 41%). Group 4 showed a mixed histiocytic lesion with a concurrent LCH and juvenile xanthogranuloma-like proliferation (n = 2; 6%). Thymic involvement in LCH is quite rare. Based on our cases and those in the literature, we propose 4 distinct pathologic groups of thymic involvement in Langerhans cell proliferations with relevance for diagnosis and treatment.

Keywords

calcifications Langerhans cell histiocytosis LCH mixed histiocytosis thymus

INTRODUCTION

Thymic involvement by Langerhans cell histiocytosis (LCH) has been described mainly in isolated case reports. Older studies [1 –8] demonstrated diffuse thymic involvement in children with disseminated LCH who died of their disease. This older thymic LCH pathology literature, written before the advent of CD1a as a marker, is unreliable because macrophages could not be reliably distinguished from LCH cells and is omitted from further discussion here. Although thymic involvement by LCH is not new, until recently, there was little epidemiologic data on its incidence and effect on outcome. Two newer studies [9,10] support the notion that thymic involvement of multisystem (MS) LCH occurs at a younger age (0.7–2 years) and is associated with skin and high-risk involvement (ie, bone marrow, liver, spleen), along with higher rates of reactivation and mortality [10]. Both of these studies and isolated case reports highlight the importance of thymic involvement in MS LCH disease. However, there is little description in the literature [10 –19] of the pathologic patterns of thymic involvement in the context of Langerhans cell proliferations and LCH disease.

Normal Langerhans cells (CD1a⁺/langerin⁺) are present in the thymic medulla as single cells or in association with the squamous epithelial Hassall corpuscles as dispersed, small, branched dendritic cells. Langerhans cell histiocytosis is best regarded as a myeloid cell neoplasm, which is likely derived from a bone marrow precursor cell [20]. Although both endogenous thymic Langerhans cells and LCH show Birbeck granules on ultrastructural examination and have an immunophenotype of CD1a and langerin positivity, LCH displays collections of larger, oval, nonbranched cells with convoluted nuclei [1,2,21,22]. In general, langerin (CD207) is the preferred marker for LCH in the thymus because small cortical thymocytes are CD1a⁺ (but langerin-), and staining for both markers provides diagnostic confidence (21). For the purposes of our discussion, we use the term hyperplastic LCH-like cells to refer to solitary aggregates of nonbranched, oval cells with convoluted nuclei (ie, LCH-like) that are histologically different from the endogenous, spindly dendritic cells of the thymus but do not cause gland destruction. We propose that there are actually 4 distinct clinicopathologic groups related to Langerhans cell involvement of the thymus with divergent therapeutic implications. The histopathology and clinical course of these groups are illustrated in the context of the current literature on LCH disease in the thymus.

METHODS

Review of Children's Hospital of Pittsburgh Cases

A review of pathology files from Children's Hospital of Pittsburgh, University of Pennsylvania Medical Center, 2000 to 2014, revealed 9 consult cases of thymic involvement by LCH-like hyperplasia and LCH from our clinical consultation files. There was no excess material available for molecular diagnostic or additional ancillary testing.

Review of Cases from the Literature

The literature searched for any combination of LCH and thymus included 122 cases. Cases published before 1987 and/or with limited pathologic-based data made it difficult to determine whether those cases met the 1987 Histiocyte Society histopathologic criteria of LCH [23]. Most of these cases are not included in this review, including those cases diagnosed by imaging studies (n = 62) (Supplemental Table 1; http://dx.doi.org/10.2350/15-01-1593-OA.S1). Only 23 of 122 cases (19%) in the literature mention the histologic features of thymic involvement with ancillary confirmation of the LCH cell (ie, ultrastructural or immunohistochemical study).

Table 1.

Group 1: Cases of incidental, microscopic Langerhans cell histiocytosis–like hyperplasia in the thymus

Source	Age	Sex	Presentation, including sites of involvement	Thymic imaging	Surgical resection	Pathology	Systemic Rx	Follow-up Outcome
Child cases
Current case 1	11 mo	M	Incidental, TGA repair	NA	Thymectomy for cardiac access	15.3 g (age-normal); 2 lobules with LCH-like nodules langerin⁺/CD1a⁺/S100⁺	No	5 y/A
Current case 2	12 y	F	Incidental, cardiac repair	NA	Thymectomy for cardiac access	19 g (age-normal); LCH-like nodule langerin⁺/CD1a⁺/S100⁺	No; with negative staging workup	14 y/A
Novak and colleagues [24]	11 mo	F	Incidental TOF repair; enlarged thymus	NA	Thymectomy for cardiac access	83 g (enlarged); medullary aggregates of multiple LCH-like nodules CD1a⁺/S100⁺ (<0.6 cm), background thymic hyperplasia	No; with negative staging workup	19 mo/A
Adult cases
Kawano and colleagues [25]	43 y	M	Incidental finding on CT	CT: homogenous mass	Thymectomy	5 cm; right lobe: LCH-like nodules ×3 (0.8–1.5 cm) S100⁺/CD1a⁺; left lobe: unilocular bronchogenic cyst and thymic cyst	No further therapy	A
Gilcrease and colleagues [26]	30 y	F	MG; failure of medical Rx	No	Thymectomy	11 g; 0.6 cm LCH-like nodule S100⁺, EM Birbeck granules	NA	1.7 y/A
Pescarmona and colleagues [27]	21 y	M	MG	CXR/CT: mediastinal mass	Thymectomy	0.4 cm; LCH-like nodule, S100⁺ with background follicular hyperplasia	NA	NA/A
Bramwell and colleagues [28]	36 y	F	MG; failure of medical Rx	NA	Thymectomy	35 g (enlarged); 4 LCH-like nodules (2 each lobe), 0.4–0.8 cm, S100⁺ and EM Birbeck granules, LN with sinusoidal LCH	Prednisone	6 mo/A

Rx indicates therapy; M, male; TGA, transposition of the great arteries; NA, data not available or not provided in report; LCH, Langerhans cell histiocytosis; A, alive; F, female; TOF, tetralogy of Fallot; CT, computed tomography; MG, myasthenia gravis; EM, electron microscopy; CXR, chest x-ray; LN, lymph node.

RESULTS

Thirty-two cases (n = 9 study cases and n = 23 cases from the literature with pathologic confirmation) delineate into 4 separable clinicopathologic groups of Langerhans cell proliferations within the thymus, which included group 1: incidental, LCH-like hyperplasia requiring no further treatment (Table 1); group 2: single-site (SS), solitary, or cystic LCH of the thymus with gland disruption and fibrosis that has the propensity to resolve without systemic therapy (Table 2); group 3: variable histologic thymic involvement, from confined medullary LCH aggregates to architectural disruption in the context of MS LCH, requiring systemic therapy and having worse survival rates (Table 3); and group 4: a mixed histiocytic lesion of LCH with concurrent juvenile xanthogranuloma (JXG)/reticulohistiocytoma (RH) type proliferation.

Table 2.

Group 2: Solitary Langerhans cell histiocytosis lesions of the thymus

Source	Age	Sex	Presentation, including sites of involvement	Imaging	Surgical resection	Pathology	Systemic Rx	Follow-up outcome
Child cases
Current case 3	1.8 y	M	Fever, leg pain	CT: punctate calcs	Bx thymus	Medullary LCH infiltration with fibrosis; langerin⁺, CD1a⁺/S100⁺	No; resolved spontaneous	4.6 y/A
Current case 4	2.6 y	M	Left neck mass	CT: punctate calcs	Resection of ectopic thymus	Ectopic thymus replaced with LCH and necrosis, fibrosis; CD1a⁺/langerin⁺	Chem	12 y/A
Current case 5	15 y	F	Enlarged thymus	NA	Thymectomy	Nodular aggregates with reactive fibrosis and architecture distortion; CD1a⁺/langerin⁺/S100⁺	NA	NA
Poncelet and colleagues [32]	9 mo	NA	Fever, cough		CXR: enlargement US/CT: Calcs	FNA: CD1a/S100 + LCH cells	Chem	6 mo/A
Elliott and colleagues [30]	4 mo	F	FTT (loose stools, RSV bronchiolitis); subsequent 1.5-cm firm lump over SC-joint; SS	CXR: enlargement; CT: calcs; MRI 6 × 6 × 5 cm	Bx thymus	LCH infiltrate: CD1a⁺/S100⁺ with EM Birbeck granules	No; resolved spontaneous	3 y/A
Mogul and colleagues [29]	1.5 y	F	SVC syndrome; SS-mediastinal	CXR: enlargement; MRI: mediastinal mass	CT-guided FNA non-Dx; 2 weeks later, thymic biopsy	LCH infiltrate with S100⁺	Rad after FNA; chem.	1 y/A
Siegal and colleagues [12]	2.4 mo	M	Stridor	CXR: enlargement	Partial Thymectomy	LCH infiltrate, cystic, focal necrosis S100⁺	Rad	3.3 y/A
Adult cases
Oishi and colleagues [34]	43 y	F	H/o breast cancer s/p resection and hormonal Rx; incidental Anterior mediastinal mass on CT scan	CT: enlargement	Bx thymus	Langerin⁺/CD1a⁺/S100⁺, nodular infiltrate with BRAF V600E mutation +	No; resolved spontaneous	11 mo/A
Poncelet [33]	49 y	F	H/o Leiomyosarcoma s/p Rad; 3 years later with pleuritic chest pain	CT enlargement	Thymectomy	CD1a⁺/S100⁺, sheet-like LCH infiltrate with necrosis; little residual thymus	NA	NA
Wakely and colleagues [35]	58 y	M	Acute chest pain with dissecting aortic aneurysm; incidental thymic mass found during aortic surgery	Portable emergency CXR: No enlargement	Thymectomy	50 g; 10-cm thymus with a 7-cm multilocular cyst, with CD1a⁺/S100⁺ in cyst wall and residual thymus	NA	2 wk/D (myocardial infarction)

Rx indicates therapy; M, male; CT, computed tomography; calcs, calcifications; Bx, biopsy; LCH, Langerhans cell histiocytosis; A, alive; chem, chemotherapy regimen; F, female; NA, data not available or not provided in report; FFT, failure to thrive; RSV, respiratory syncytial virus; SC, sterno-clavicular joint; SS, single system; CXR, chest x-ray; MRI, magnetic resonance imaging; EM, electron microscopy; SVC, superior vena cava; FNA, fine-needle aspiration; non-Dx, nondiagnostic; rad, radiation therapy; H/o, history of; s/p, status post; D, dead.

Table 3.

Group 3: Thymic involvement in multisystem Langerhans cell histiocytosis disease

Source	Age	Gender	Presentation, including sites of involvement	Imaging	Surgical resection/Bx	Pathology	Systemic Rx	Follow-up/outcome
Current case 6	1.3 y	M	MS with polyostotic, questionable cystic thymus, and hepatosplenomegaly; 3.5-year-old cardiac surgery with incidental enlarged thymus	Questionable cystic change at 1.3 y	Thymectomy	1.3 y: LCH: bone Bx; 3.5 y: thymus, 46.7 g (enlarged), small nodules LCH (CD1a⁺/langerin⁺/S100⁺) confined to medulla with retained architecture	Chem	2 y/A
Current case 7 and Terry and colleagues [36]	Newborn	M	Respiratory failure; congenital MS w/placenta, skin, thymus, lung, and multiple viscera	NA	Autopsy	Atrophic lobules with medullary cystic change (CD1a⁺/langerin⁺/S100⁺) BRAF V600E (site tested not specified)	No; DOD	7 wk/D
Chen and colleagues [16]	14 y	M	MS with DI and thymus	MRI: pituitary and mediastinal nodular mass; CT: 6 mo later with enlargement	Thymectomy	LCH infiltrate (CD1a⁺/S100⁺)	NA	NA
Ducassou and colleagues [10], 2013 n = 37 (n = 4 with IHC confirmation)	8.4 mo	M, 18; F, 19	MS/thymus at Dx: N = 27; thymic relapse at reactivation: N = 3/37; mediastinal LN only: N = 10 At least one high-risk site: N = 26	CXR enlargement: n = 37 CT: 32 (calcs = 16, cysts = 2)	Bx thymus	LCH infiltrate (CD1a⁺, S100⁺), n = 2 BRAF V600E mutation, with n = 1 sample tested from thymic	N = 32/37, chem. N = 1, steroid alone	N = 32/A; N = 5/D, of which n = 2 likely DOD
Yagci and colleagues [15]	12 y	M	Dyspnea, chest/hip pain, wt loss, skin rash; MS with skin, bone, LN	CXR/CT thymic enlargement, multifocal bone, and LN	Bx thymus	Diffuse infiltrate of LCH (CD1a⁺)	Chem	1 y, residual mass, sclerotic bone lesions/A
Hatakeyama and colleagues [14]	2–11 mo	M	2 mo: skin, SS with elevated ESR (which normalized at 9 mo) 11 mo: cough, fever, supraclavicular swelling, and re-elevation of ESR and (thymus-MS)	6 mo: negative CXR; 11 mo: CXR, thymus enlargement; CT, calcs	6 mo: Skin Bx 11 mo: Bx thymus	Skin LCH (CD1a⁺); Thymus: LCH infiltrate (CD1a⁺)	2–9 mo: no therapy; 11 mo: chem.	2 y after 52-wk of treatment/A
Donnelly and Frush [17]	1.6 y	F	Dyspnea, FTT; MS with lung and thymus	CXR: lung cysts; CT: cystic lung, thymic enlargement with cystic mass with enhancing septa	Bx lung and thymus	Thymic LCH aggregates in fibroxanthomatous background with Birbeck granules	NA	NA
Kawasaki and colleagues [37]	3 mo	M	MS with lung, hepatomegaly and elevated enzymes	CT: thymic calcs	Bx thymus	LCH infiltrate S100⁺	Chem	4 wk CT resolution/A
Bove and colleagues [11]	1.5 y	M	MS with skin, mono-osteitic bone, thymus	NA	Bx thymus	Medulla with microcalcification and necrosis; LCH with Birbeck granules	Chem	5 mo bone recurrence/A
Siegal and colleagues [12]	5 y	F	Back pain; MS with bone and thymus	CXR; enlargement; bone: lytic	Thymectomy and bone Bx	LCH: thymus: diffuse, fibrosis, calcs; S100⁺	Chem	4 y/A

Bx indicates biopsy; Rx, therapy; M, male; MS, multisystem; LCH, Langerhans cell histiocytosis; chem, chemotherapy regimen; NA, data not available or not provided in report; DOD, died of disease; D, dead; DI, diabetes insipidus; MRI, magnetic resonance imaging; CT, computed tomography; Dx, diagnosis; LN, lymph node; IHC, immunohistochemistry; CXR, chest x-ray; calcs, calcifications; SS, single system; ESR, erythrocyte sedimentation rate; FTT, failure to thrive.

Group 1: Incidental LCH-like hyperplasia

Study cases

Case 1 —An 11-month-old, twin boy underwent cardiac surgery for repair of transposition of the great arteries and ventricular septal defect repair. The thymus was removed for cardiac access and was age-appropriate for weight (15.3 g) with no gross abnormalities. Histologically, there was a generous cortex and normal corticomedullary relationship. Microscopically, a small portion of 2 contiguous lobules were partially replaced by LCH-like nodules. The cells stained for S100, CD1a, and langerin (Fig. 1A and Table 1). At his last visit, 5 years later, the child was well, having received no adjuvant treatment for the thymic lesion.

Figure 1.

Group 1: Incidental Langerhans cell histiocytosis (LCH)–like hyperplasia. A. Case 1: The thymus shows a single lobule replaced by a nodule of LCH-like cells (hematoxylin and eosin [H&E], original magnification ×20). B. Case 2: Thymic structure is normal with preservation of the cortex and medulla. A single, small LCH-like nodule is present (top center, arrow) (H&E, original magnification ×20). A color version of this figure is available online.

Case 2 —A 12-year-old girl underwent left outflow tract myocardial resection for Friedreich ataxia–related hypertrophic subaortic stenosis. The thymus was removed for access and was age-appropriate for weight (19 g) with no gross abnormalities. Histologically, findings included a normal corticomedullary relationship and large, dilated Hassall corpuscles. A solitary, LCH-like nodule occupied much of a single lobule, which was positive for S100, CD1a, and langerin (Fig. 1B and Table 1). There was no evidence of LCH elsewhere at diagnosis or in the 14 years subsequently. The child was well, having received no adjuvant treatment for the thymic lesion.

Review of cases, including those from the literature

Five additional cases were found in the literature with small, incidental, LCH-like, microscopic hyperplasia of the thymus and are outlined in detail in Table 1. In all, 7 patients with LCH-like hyperplasia were found during incidental thymectomy or as an incidental finding during unrelated computed tomography (CT) imaging [24 –28]. None had evidence of LCH disease, either at the time of diagnosis or in subsequent follow-up. The histopathology showed a small nodule or single lobule replaced by a collection of hyperplastic LCH-like cells with oval cytoplasmic contours and a characteristic “coffee-bean” nucleus with interspersed eosinophils. The background thymic corticomedullary architecture was largely intact without evidence of fibrosis, but some showed dilated Hassall corpuscles. There was a bimodal age distribution, with younger age (mean [SD], 4.6 [6.4] years) in those patients undergoing thymectomy for cardiac access as compared with adults with thymectomy (mean [SD], 32.5 [9.3] years). There was no particular gender preference (3 males, 4 females). Only 3 adult patients had a history of myasthenia gravis (MG), and there was no reported history of lymphoma in any of these cases (Table 1).

Group 2: Solitary (unifocal) tumoral and/or cystic thymic SS LCH

Study cases

Case 3 —A 1.8-year-old boy presented with fever and atypical pain in the lower limbs. An anterior mediastinal mass was found on imaging that had punctate calcifications but no cysts. Thymic biopsy showed little residual thymic tissue, which was largely infiltrated by nodules of LCH cells surrounded by fibrosis with complex, folded nuclei and interspersed with binucleated and multinucleated giant cells and clusters of eosinophils. The nodules were mostly confined to the medullary region with architectural destruction of the gland, focal calcification, and an active myofibroblastic response. The LCH cells stained for S100 (nuclear and cytoplasmic) and crisp membranous CD1a. Staging survey showed no evidence of LCH elsewhere at the time of diagnosis or in the subsequent 4.6 years, and the child is well, having received no adjuvant treatment for the thymic lesion.

Case 4 —A2.6-year-old boy presented with a left-sided, 3-by 2.5-cm neck mass. The CT imaging showed the mass to be located in the left anterior cervical chain at the level of the mandible. By CT, the mass, thought to be lymph nodes, contained punctate calcifications but no cystic change. The mass excision was a 3-cm, ectopic cervical thymus, largely replaced by LCH (langerin⁺/CD1a⁺), with focal necrosis and areas of calcification. Microscopic cystic change was not appreciated. A small, attached lymph node had no LCH infiltrate. There was no other evidence of LCH on a staging survey, which included physical examination, total body bone scan, upper abdominal ultrasound, and bone marrow biopsy. The child was treated with methotrexate and prednisone. At most recent follow-up, 12 years later, he is alive and well.

Case 5 —A 15-year-old girl presented with an enlarged thymus. Thymectomy showed replacement of the thymic architecture by nodular aggregates and sheets of LCH cells with surrounding fibrosis and central areas of necrosis (Fig. 2). Staining with CD1a and langerin confirmed the nodular and diffuse medullary pattern of the LCH infiltrate (Fig. 2B,C).

Figure 2.

Group 2: Solitary mediastinal mass in single-site Langerhans cell histiocytosis (SS-LCH). A. Case 5: Thymic architecture is largely replaced by nodular aggregates of LCH cells with surrounding fibrosis (hematoxylin and eosin, original magnification ×20). B. The LCH infiltrate (upper left) is highlighted by CD1a with darker staining of the residual cortical thymocytes (lower right). Note the nodular medullary infiltrate adjacent to the residual thymic parenchyma (immunohistochemistry stain, original magnification ×20). C. Langerin confirms the nodular and diffuse medullary pattern of LCH infiltration (immunohistochemistry stain, original magnification ×20). A color version of this figure is available online.

Review of cases, including those from the literature

The SS LCH of the thymus differs from the incidental LCH-like hyperplasia largely in the extent of the process within the thymus, based on gland destruction with necrosis and punctate calcifications and a surrounding fibrotic response. The 11 cases from our literature review (including our 3 cases) that fall into this group are outlined in detail in Table 2 [12,29 –35]. There was a bimodal age distribution of young patients (mean [SD], 3.5 [5.3] years) and older patients (mean [SD], 50 [7.5] years), without a significant gender predilection (8 females, 5 males). Anterior mediastinal widening or mass, either on chest x-ray, CT scan, and/or magnetic resonance imaging (MRI) was the most frequent description, whereas punctate calcifications by CT and/or ultrasound were also common. None of these cases had a history of MG or lymphoma.

Group 3: Multisystem LCH with thymic involvement

Case study

Case 6 —A 1.3-year-old boy had multifocal LCH involving multiple bones, including the skull and the middle ear. He was in the high-risk group because of hepatosplenomegaly and liver dysfunction and was initially refractory to treatment. He was treated on the LCH-lll risk protocol with methotrexate and vincristine. At 3.5 years of age, the child underwent cardiac surgery to remove an organized, calcified thromboembolus from the superior vena cava; during which time, an enlarged thymus was noted and excised. On retrospective analysis, a CT scan at diagnosis had raised the question of a thymic cyst, which was never pursued further. At pathologic examination, the thymectomy specimen weighed 46.7 g (age expected: 21 g) but was otherwise grossly unremarkable. The thymic microstructure was normal with preserved lobulation and clear corticomedullary separation. Multifocal, small nodules of LCH cells were present, entirely confined to the medulla. Despite the questionable thymic cyst on the original CT scan, the thymectomy specimen showed no evidence of cystic change. Of note, the patient received chemotherapy during that 2-year interval. The thymic LCH cells stained positive for S100, CD1a, and langerin (Fig. 3). Bone scan abnormalities at the time of thymectomy identified new lesions, suggestive of disease reactivation, which were treated with intralesional steroids, 6-mercaptopurine, and systemic steroids for another 6 months. The child was well 2 years after treatment, with evidence of resolving bone lesions.

Figure 3.

Group 3: Multisystem Langerhans cell histiocytosis (MS-LCH). A. Case 6: Thymic architecture appears intact, but there are aggregates of LCH cells confined to the medulla (hematoxylin and eosin, original magnification ×40). B. The larger CD1a⁺ LCH cells are highlighted as are the smaller cortical thymocytes (immunohistochemical stain, original magnification ×400). C. Langerin highlights the LCH infiltrate but is negative in the cortical thymocytes (immunohistochemistry stain, original magnification ×400). A color version of this figure is available online.

Case 7 —A newborn infant had congenital MS LCH involving the placenta and widespread systemic disease, including the visceral organs, thymus, thyroid, skin, and placenta; however, no high-risk involvement was noted. He died at 7 weeks of age from extensive lung involvement and associated refractory respiratory failure before treatment could be initiated (previously published [36]). Postmortem examination showed that mostly extrathymic, mediastinal LCH involvement surrounded atrophic/remnant thymic lobules. Those thymic remnants showed cystic trans formation of the medulla, which was highlighted on cytokeratin stain with the immunohistochemical markers S100, CD1a, and langerin highlighting the medullary aggregates of LCH cells and a few LCH cells elsewhere. The LCH infiltrate also harbored the BRAF V600E mutation.

Review of cases, including those from the literature

Involvement in MS LCH represents the largest group of thymic LCH characterized in the literature. However, although our review identified numerous reported cases of thymic involvement in the context of MS LCH (Supplemental Table 1; http://dx.doi.org/10.2350/15-01-1593-OA.S1), only 11 cases [10 –12,14 –17,37] and our 2 consult cases (Table 3) had ancillary confirmation of LCH in the thymus. Of note, a case of a fibrosing mediastinitis in the context of bone LCH may represent a “burnt-out” type LCH pattern with the absence of LCH cells in the thymus (CD1a- and S100-) with a fibrotic background; however, for the purposes of this study, that case was not included in the cohort [18]. This group showed a predilection for younger children (mean [SD], 3.2 [5.3] years) with a skewed gender distribution of males (n = 9) compared with females (n = 2); however, gender could not be ascertained in 4 cases [10]. Although many MS LCH cases in the literature do not describe the histologic pattern of thymic LCH involvement, our cases, together a few reports with ancillary confirmation describe a variable histologic appearance that included confined medullary involvement to diffuse gland involvement with fibrosis (Table 3). Of note, 3 cases harbored the BRAF V600E mutation, in which one demonstrated a thymic LCH infiltrate [10,36]. In addition, none of these cases had a history of MG or lymphoma.

Group 4: Mixed histiocytic lesions with LCH and JXG/RH proliferation

Case study

Case 8 —A 3-year-old female with documented skin and bone marrow LCH subsequently developed a thymic mass and skin papules. The thymic mass was resected, and it showed a nodular, central, destructive mass with medullary nests of epithelioid histiocytes. The large epithelioid cells contained a single oval nucleus and abundant eosinophilic cytoplasm with some large cells showing prominent emperipolesis (Rosai-Dorfman type cells). These epithelioid cells had an RH/JXG-family immunophenotype, including CD14, CD68 (PGM-1) with a paranuclear dot to diffuse cytoplasmic staining pattern, CD163, and fascin, but were negative factor XIIIa and had a variable low S100 expression. Admixed with these cells was an LCH-type population with strong CD1a, S100, and langerin staining. These cells had slightly more elongate cytoplasmic projections than found in typical LCH, but they were still present as clusters of oval cells with convoluted nuclei, distinct from the spindled endogenous LCH cells of the thymus. A BRAF V600E immunostain (VE1 antibody) was negative. The bone marrow biopsy was involved with LCH with immunohistologic confirmation, whereas the skin biopsy was of the JXG family (reticulohistiocytoma type) but also showed high expression of factor XIIIa. No further follow-up is known.

Case 9 —A 2-year-old female with tetralogy of Fallot (TOF), who displayed an enlarged thymus on preoperative chest x-ray, which was felt to represent a typical, large toddler thymus exacerbated by prominent pulmonary vessels accompanying her TOF. However, intraoperatively, her thymus was found to be “pathologic with a firm granulomatous appearance,” and given her adoptive history from outside of the United States, there was a suspicion for tuberculosis. The excised thymus showed a diffuse, cellular proliferation and effacement of the architecture with a thick, fibrous capsule and hyalinized, fibrotic bands around the cellular nodules (Fig. 4). The discrete LCH nodules (CD1a and langerin positivity with lighter S100 staining) were surrounded by a xanthogranulomatous proliferation containing Toutontype giant cells and an immunophenotype of the JXG family (CD14, CD163, CD68, PGM-1), with variable positivity for fascin and factor XIIIa).

Figure 4.

Combined juvenile xanthogranuloma and Langerhans cell histiocytosis (LCH). A. Case 9: The thymic architecture is effaced with LCH nodules surrounded by inflammatory infiltrates of eosinophils and lymphocytes (H&E, original magnification ×100). Inlet of CD1a⁺ LCH cells in the nodule (immunohistochemistry stain, original magnification ×200). B. Surrounding, ill-defined nodules of xanthomatous cells with Touton giant cells (H&E, original magnification ×100). Inlet of CD163⁺ macrophages (immunohistochemistry stain, original magnification ×200).

Following her surgery and a diagnosis of LCH, a complete skeletal survey did not show evidence of bone lesions, and liver function tests were within reference range. The CT scan of the chest a few months after diagnosis showed a residual mediastinal mass and otherwise clear lung parenchyma. A repeat CT scan 9 month after diagnosis showed a stable-appearing mediastinal mass, indistinguishable from thymus. At the 1-year follow-up, she was alive and well without systemic therapy. Neither of these patients had a history of MG or lymphoma.

DISCUSSION

We describe an illustrative clinicopathologic case series with review of the pertinent literature to demonstrate 4 pathologic patterns of thymic involvement in LCH disease or LCH-like proliferations with distinct therapeutic implications.

We propose that the pathology of LCH-like hyperplasia is distinct from LCH disease, suggesting that this pattern of thymic involvement represents a distinctive population, likely reactive in nature. This pattern has been previously noted by others in incidental thymectomies [24 –28]. Christie and colleagues [38] described LCH-like proliferations and demonstrated that some were polyclonal, unlike LCH. We think it is important to separate these incidental, small lesions from LCH because they do not appear to occur outside of an SS, nor do they progress clinically, but they do cause confusion when diagnosed as LCH. The mechanism of proliferation and etiology of the cells is not currently known, but they appear different from the endogenous Langerhans cell population of the thymus that display spindled dendritic cell processes. Although the possibility of an early LCH cannot be entirely excluded, these nodules are found incidentally and are small, without the type of gland destruction that is seen in SS LCH of the thymus (vide infra). Foci of reactive, LCH-like proliferations with plump, round cells have previously been described in lymph nodes harboring other histiocytic lesions, such as Rosai-Dorfman disease, lymphomas/leukemia, and in association with soft tissue–treated tumors (ie, rhabdomyosarcoma and melanoma) [38]. An altered immunologic milieu was suggested as a driver for reactive and proliferate, LCH-like hyperplasia in these cases [38]. Of note, in 1984, Halícek and Rosai [39] described in myasthenic patients a series of thymuses with a reactive hypereosinophilic appearance similar to the reactive eosinophilic pleuritis seen in patients with spontaneous pneumothoraces. The pathology was described as nodular aggregates of histiocytes and eosinophils (ie, histioeosinophilic granulomas); however, unlike our cases, they could not demonstrate morphologic, immunohistochemical, or ultrastructural confirmation of Langerhans cells [39]. Our current case series is limited because we were unable to further assess clonality or BRAF mutation status in these cases. Patients in this group did not show evidence of LCH disease. Although one adult patient with MG from the older literature was treated with steroid therapy [28], most did well without the need for systemic therapy.

The histopathology of solitary thymic LCH has been not been previously described with detail in the literature. In SS LCH of the thymus, the architecture is largely replaced with an LCH infiltrate presenting as a solid or cystic mediastinal mass. That infiltrate forms nodular tumors comprising LCH cells with areas of punctate calcifications and/or foci of necrosis and a loose edematous to dense fibrotic response, which disrupts the architecture of the gland. Workup for LCH disease limited to the thymus includes diagnostic staging to exclude concomitant sites of involvement and to establish the disease as an SS LCH [19]. The use of systemic therapy seems to be variable and may be influenced by concern about airway compromise (31). Treatment with either radiation therapy [12,29] and/or chemotherapy [29,32] is more often described in the older literature of thymic SS LCH. Although this small case series and review of the literature cannot make definitive claims for treatment, there is at least the suggestion that thymic SS LCH has the propensity to undergo spontaneous regression (after biopsy or aspiration cytology) without systemic treatment, as demonstrated in case 3 and others in the literature [30,34]. Solitary, thymic LCH involvement may be similar to other instances of SS LCH in the bone, skin, and lymph nodes, in which an initial approach of close follow-up without systemic therapy may be the treatment of choice in the absence of other lesions after diagnostic staging. However, prospective studies are needed to confirm this conclusion.

Thymic involvement of MS LCH occurs predominately in the youngest (<1 year) patients with LCH, both with and without systemic symptoms, but all with active disease [9,10], which was also seen in our study cases. Thymic involvement may not be readily recognized at the time of LCH diagnosis if not directly imaged. Newer studies suggest that routine screening of young patients with LCH may be prudent in the initial staging evaluation, especially given the association with more high-risk involvement and propensity for reactivation in these youngest patients [9,10]. The presence of thymic enlargement, intrathymic punctate calcification, and/or cystic transformation all have been described as diagnostic radiographic features of involvement (Supplemental Table 1; http://dx.doi.org/10.2350/15-01-1593-OA.S1) [9,12 –14,31,40 –45]. In the literature, there have been about 32 reported cases of thymic involvement by imaging with associated LCH high-risk involvement of either the spleen, liver, or hematopoietic system; however, most cases did not have histologic confirmation of thymic involvement [10,46,47]. Ducassou and colleagues [10] have shown that mediastinal LCH, in the context of MS LCH, tends to have higher rates of reactivation and mortality, as compared with nonmediastinal MS LCH [10]. Unlike solitary thymic LCH, thymic involvement in the context of MS LCH may have a more-aggressive natural history. However, it remains unclear whether thymic involvement in MS LCH is an independent risk factor or merely related to these cases tending to occur in younger children with more associated high-risk organ involvement.

Lastly, there are reports in the literature of mixed histiocytic disorders either occurring sequentially or concurrently, in the same sites or in different locations. These include JXG lesions occurring after LCH [48,49] and concurrent LCH and Erdheim-Chester Disease (ECD) or ECD following LCH [50]. However, there have been no previous reports, to our knowledge, of concurrent LCH and JXG-family of lesions occurring in the thymus. Our 2 cases are both from young patients. One case had MS LCH with high-risk involvement (case 8), whereas the other case had apparent solitary thymic LCH that required no further treatment (case 9); however, the presence of a mediastinal mass after thymectomy in case 9 remains a concern. The therapeutic implications of mixed histiocytic disorders in the thymus are not well delineated, given the few cases, but should be at least be followed with complete clinical staging to rule out MS LCH involvement.

In conclusion, we describe 4 distinct histologic patterns of Langerhans cell proliferations and LCH of the thymus with relevance for diagnosis and treatment.

Future work exploring the clonality and molecular status of these lesions is needed to better understand the pathophysiology and biologic potential of these cells, especially in cases of incidental LCH-like proliferations and mixed histiocytic disorders.

Footnotes

Conflict of interest statement: The authors report no conflict of interest.

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