Gastrointestinal Langerhans cell histiocytosis with unifocal, single‐system involvement in adults: Cases report and literature review

Abstract

Background

Langerhans cell histiocytosis (LCH) is characterized by unifocal, multifocal single‐system, or multi‐system disease that occurs in all age groups, while it primarily attacks pediatric patients. Solitary gastrointestinal (GI) LCH in adults is exceedingly rare, so we aimed to investigate GI LCH in adults with unifocal single‐system involvement and clarified the clinicopathologic characteristics of this disease.

Methods

Two cases of solitary GI LCH in adults were presented, and the clinicopathologic features of this diagnosis in the literature were reviewed.

Results

The main diagnostic feature of LCH is the morphologic identification of the characteristic Langerhans cells with prominent nuclear grooves and abundant eosinophilic cytoplasm, accompanied by a variable number of lymphocytes, eosinophils, and plasma cells. The distinctive cells expressed S100, CD1a, and langerin (CD207) on immunohistochemistry. BRAF V600E mutations were detected in the two patients.

Conclusions

Gastrointestinal Langerhans cell histiocytosis in adults with unifocal, single‐system involvement is extremely rare. Most patients were asymptomatic and usually a small solitary polyp in GI tract can be observed under routine endoscopy. Although the overall prognosis of unifocal single‐system LCH is favorable, long‐term follow‐up is still necessary to rule out systemic disease.

Langerhans cell histiocytosis (LCH) may affect any system or organ of the body. In single organ disease, bone involvement is present in more than 90% of cases, while the incidence of gastrointestinal (GI) LCH in adults with unifocal, single‐system involvement is extremely rare.

1. INTRODUCTION

Langerhans cell histiocytosis (LCH) is characterized by unifocal, multifocal single‐system, or multi‐system disease that brings heterogeneous clinical presentation. Though it primarily attacks children between 1 and 4 years old, the disease occurs in all age groups. ¹ According to the extent of involvement, LCH results in benign or life‐threatening consequences. ² An indolent form of a single organ disease may remit spontaneously, while multiorgan disease presents with various conditions, including eosinophilic granuloma, characteristic papulosquamous granulomatous, diabetes insipidus, exophthalmos, radicular nerve pain, muscle weakness, bowel and bladder dysfunction, pituitary dysfunction, a range of thyroid, growth hormone, and gonadotropin disturbances. ³ Meanwhile, it may affect any system or organ of the body, but those more frequently affected are bone (80% of cases), skin (33%), pituitary gland (25%), liver (15%), lungs (15%), spleen (15%), the hematopoietic system (15%), lymph nodes (5%–10%), and the central nervous system excluding the pituitary (2%–4%). ⁴ Gastrointestinal (GI) LCH in adults is very rare, especially with unifocal, single‐system involvement. Owing to the vague pathogenesis and limited data available to guide the treatment of GI LCH in adults, the management of patients is still obscure or controversial. In this present article, two cases of solitary GI LCH in adults were described and the features of this disease in the literature were summarized in order to provide a consistent body of data.

2. CASE PRESENTATION

2.1. Case 1

A 45‐year‐old female without symptom underwent upper‐GI endoscopy for checkup. The endoscopy revealed a polypoid lesion with approximately 0.6 cm in size in her stomach, and there was a depression in the center of this lesion (Figure 1). Laboratory investigations, including complete blood cell count, biochemical analysis, and serum levels of carcinoembryonic antigen, were within normal ranges, and the biopsy specimen was sent for histopathology.

FIGURE 1.

Polypoid lesion (0.6 cm in size) with a depression in the center is observed upon gastroenteroscopy.

Microscopic examination showed that there were sheets of intermediate‐sized cells with ovoid nuclei, and inconspicuous nucleoli were observed in the mucosa lamina propria (Figure 2A), accompanied by a certain number of lymphocytes and eosinophils (Figure 2B). Neoplastic diseases such as carcinoma, lymphoma, melanoma, and metastatic breast cancer were suspected. Immunohistochemical analysis revealed that these intermediate‐sized cells strongly expressed S100 (Figure 2C), CD1a (Figure 2D), and moderately expressed langerin (Figure 2 E), but they were negative for pan‐cytokeratin, CAM5.2, CD20, CD79a, CD3, EBER, CD138, GATA‐3, and melanoma marker (HMB45). The BRAF V600E mutation was detected based on the finding of the protein with weakly positive immunohistochemistry (Figure 2F). No helicobacter pylori (HP) was discovered in the gastric foveola. Combined with the morphological features, the diagnosis of LCH was confirmed. Afterward, the patients underwent a complete removal of the lesion by endoscopic submucosal dissection (ESD). The ESD specimen revealed that no LCH lesion remnant was found.

FIGURE 2.

Morphological features (A, B) and immunohistochemical findings (C–F) of case 1. (A) Biopsy specimen revealed that intermediate‐sized cells aggregated in the mucosa lamina propria. (B) Lymphocytes and eosinophils intermixed with these intermediate‐sized cells. (C) These cells were strongly positive for S100, (D) CD1a, (E) moderately positive for langerin, (F) weakly positive for BRAF V600E protein. Scale bars: (A) 125 μm; (B) 20 μm; (C–F) 80 μm.

The patient was advised to rule out multi‐system involvement. According to the computed tomography (CT) scan of whole body, there was no evidence of multifocal diseases.

2.2. Case 2

A 67‐year‐old male complained stool blood for 1 year. The colonoscopy demonstrated that his sigmoid colon was local incrassation with approximately 3.5 cm in diameter, and his tumor marker CA125 elevated (21.60 U/ml, normal range ≤ 15.00 U/ml). Considering the possibility of colon tumor, the clinician advised him to perform surgery. Subsequently, the patient underwent laparoscopic sigmoid resection. The surgical specimen was examined for histopathology, and a pedunculated polyp with 4.0 × 2.0 × 1.0 cm was observed.

Histopathological examination exposed that the lesion was a tubular adenoma with high‐grade dysplasia, of which some areas evolved into a moderately differentiated adenocarcinoma with head invaded. Significantly, there were numbers of inflammatory cells, including neutrophils, eosinophils, and lymphocytes in the head and neck of the polyp (Figure 3A). These cells were admixed with coffee bean like cells with irregular nuclei and longitudinal nuclear grooves (Figure 3B). Immunohistochemical staining was performed to identify the distinctive cells that were diffusely positive for S100 (Figure 3C), strongly positive for CD1a (Figure 3D), but negative for CD68, CK7, CK20, and CDX‐2. No deletion of mismatch repair (MMR) protein was identified, but the BRAF V600E mutation was observed. The Ki‐67 index was approximately 20%. These findings supported the diagnosis of LCH.

FIGURE 3.

Morphological features (A, B) and immunohistochemical findings (C, D) of Case 2. (A) Neutrophils, eosinophils, and lymphocytes aggregate in the head and neck of polyp (boxes). (B) Langerhans cells with irregular nuclei and longitudinal nuclear grooves (arrows) are scattered in inflammatory background. (C) Diffusely positive expression of S100. (D) Strongly positive expression of CD1a. Scale bars: (A) 0.5 mm; (B) 10 μm; (C, D) 40 μm.

Imaging investigation for systemic had no sign of multi‐system involvement.

3. DISCUSSION

Langerhans cell histiocytosis is monoclonal Langerhans cell proliferation, of which the clinical classification depends on whether the disease affects localized single‐system or disseminated multisystem. In single‐organ disease, bone involvement is present in more than 90% of cases, ⁵ while the incidence of GI LCH in adults is rare. To the best of our knowledge, only about 21 cases have been reported in the English literature till date. Among the previous reported cases ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ and our two cases (Table 1), the age range was 29–77 years (mean 54.43 years). According to reports in the literature, it was more popular in Caucasians in Northern European countries than in both Africans Asians. ¹² However, the Asians to Caucasians ratio in our study was 11:12 that was the same as male‐to‐female ratio. The results of gender distribution were different from the reports made by Singhi et al. ¹³ that female occupied most of the GI LCH. Fourteen patients were asymptomatic, while nine patients presented with corresponding GI symptoms, such as abdominal pain (four patients), dysphagia (two patients), nausea/diarrhea (one patient), anemia (one patient), constipation (one patient), and stool blood (one patient). In our case 2, it is unclear if the stool blood was relevant to LCH, because the patient had malignant tumor at the same time. In upper‐GI, most cases occurred in stomach body (seven cases); other locations contained stomach fundus (two cases), stomach angle (one case), stomach antrum (one case), lower esophagus (one case), and middle esophagus (one case). In lower GI, most cases occurred in sigmoid (three cases), cecum (two cases), ascending colon (two cases), rectum (two cases), transverse colon (one case), and descending colon (one case). The lesion was described as an elevation or polypus (size: 0.2–4.0 cm) in seven cases of upper‐GI LCH and all cases (11 cases) of the lower‐GI LCH, while others involved erosion (two cases) and ulcer (two cases). There was nothing especially endoscopic finding in only one case. These results that LCH in adults is predominantly asymptomatic and usually presents a small solitary polyp with GI involving are similar to previous reports in the literature. ¹ , ⁵

TABLE 1.

Previous reported cases (no. 1–21) and present cases (no. 22–23) of isolated GI LCH in adults.

Case	Race	Sex/age	Symptom	Site	Endoscopic finding (size)	Treatment	BRAF V600E	Follow‐up (month)
Upper GI
1	Caucasian	F/59	Dysphagia	Middle Esophagus	Ulcer (*)	Biopsy	P	NA
2	Asians	M/61	Epigastric pain	Lower Esophagus	Solitary elevated lesion (0.4 cm)	Biopsy	N	4/NED
3	Asians	F/56	NO	Stomach body	Solitary submucosal elevation (0.5 cm)	Biopsy	P	3/NED
4	Asians	M/48	NO	Stomach body	Solitary elevation (<1 cm)	Biopsy	NA	12/NP
5	Asians	M/51	NO	Stomach body	Solitary elevation (0.5 cm)	Biopsy, ESD	NA	12/NED
6	Caucasian	F/29	NO	Stomach body	Normal	Biopsy	P	NA
7	Asians	M/37	Stomach discomfort	Stomach body	Erosion (*)	Biopsy	N	14/NS
8	Asians	F/47	Abdominal pain, diarrhea, nausea	Stomach body, fundus	Large area with scattering Erosions (7 cm area)	Surgical resection	NA	20/NED
9	Asians	M/64	NO	Stomach fundus	Solitary elevation (1.0 cm)	Biopsy, ESD	NA	6/NED
10	Caucasian	F/59	Epigastric pain	Stomach angle	Ulcerated lesion (1.5 cm)	Surgical resection	NA	NA
11	Caucasian	M/68	Dysphagia	Stomach antrum	Solitary Polyp (*)	Biopsy	NA	22/NED
Lower GI
12	Caucasian	M/60	NO	Cecum	Polyp (*)	Biopsy	NA	7/NED
13	Caucasian	F/60	NO	Cecum	Polyp (*)	Biopsy	NA	12/NED
14	Asians	M/49	NO	Ascending colon	Polyp (0.2 cm)	Biopsy	NA	NA
15	Caucasian	F/40	Anemia	Ascending colon	Polyp (*)	Biopsy	NA	21/NED
16	Caucasian	F/51	NO	Transverse colon	Polyp (*)	Biopsy	NA	5/NED
17	Caucasian	M/65	NO	Descending colon	Polyp (0.6 cm)	snare diathermy	NA	12/NED
18	Caucasian	F/55	NO	Sigmoid	Polyp (*)	Biopsy	NA	26/NED
19	Caucasian	F/77	Constipation	Sigmoid	Polyp (*)	Biopsy	NA	2/NED
20	Caucasian	F/53	NO	Rectum	Sessile polyp (0.4 cm)	CSP	NA	12/NED
21	Asians	M/51	NO	Rectum	Polyp (0.6 cm)	EMR	NA	NA
Present cases
22	Asians	F/45	NO	Stomach body	Polyp (0.6 cm)	Biopsy, ESD	P	3/NED
23	Asians	M/67	Blood in stool	Sigmoid	Polyp (4 cm)	Surgical resection	P	NA

Abbreviations: CSP, cold snare polypectomy; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; F, female; M, male; N, Negative; NA, not available; NED, no evidence of disease; NP, no progression; NS, no symptom; P, positive.

^*Size was not specified for the patient.

Although the recent discovery has suggested that LCH is neoplastic nature, the pathogenesis of LCH is still unclear. ¹⁴ A study proved that more than half LCH cases contained BRAF‐V600E mutations. ¹⁵ B‐raf is a serine/threonine kinase that belongs to the RAF kinase family, which is involved in many cellular functions, such as cell growth, proliferation, differentiation, and apoptosis. The BRAF‐V600E mutation is more common in multisystem than in single‐system and is connect with an increased risk of relapse. ¹² Nevertheless, the data of BRAF‐V600E mutation of GI LCH in adult cases is scarce up to now. In our study, the BRAF V600E mutation was present in 5 of 7 evaluable cases for a mutation frequency of 71.43%, and it is a pity that 16 cases were not available. Owing to the small sample size, whether GI LCH in adults is associated with BRAF V600E mutation or not is still indistinct.

Histologically, the main diagnostic feature of LCH is the morphologic identification of the characteristic Langerhans cells with prominent nuclear grooves and abundant eosinophilic cytoplasm, accompanied by a variable number of lymphocytes, eosinophils, and plasma cells. ¹³ This inflammatory infiltration of background serving as a good clue for diagnosis can be quite significant, when Langerhans cells are atypical. The aggregated histiocytic cells were positive for CD1a, S100, and langerin (CD207), and they played an important role in identifying other common tumors of the GI tract, such as carcinoma, lymphoma, and malignant melanoma. Like LCH, other S100 immunoreactive lesions that have been reported in the GI tract, including granular cell tumor and Rosai–Dorfman, also express CD68 with different degrees. However, the expression of CD1a is negative in granular cell tumor, which has been reported with variant results in Rosai–Dorfman disease. ¹⁶ Electron microscopy was formerly one of the criteria required for definitive diagnosis. Since it has been proved that the expression of langerin completely correlates with the existence on electron microscopy of Birbeck granules, it is no longer recommended. ⁴

Once the diagnosis of LCH is determined, on account of distinct treatment and prognosis for single‐system or multisystem involvement, a careful clinical workup for each patient should be attentive to.

Individuals with unifocal, single‐system involvement do not require systemic therapy, other than local excision or observation. ¹ Whereas, patients with multi‐system LCH predominantly need chemotherapy. ¹⁷ On the other hand, the prognosis of single‐system LCH is better than multi‐system LCH. The data of adult LCH is limited and standardized protocols are sparse, and thus most treatments are based on the pediatric experience. In unifocal bone lesion, therapy protocols depend on the size, location, and symptoms, which can provide a significant reference to the GI LCH patients with clinical symptoms. In all cases (Table 1), the treatments contained ESD (three cases), surgical resection (three cases), endoscopic mucosal resection (one case), snare diathermy (one case), and cold snare polypectomy (one case), and 14 patients did not undergo surgical resection after biopsy. All patients had a good prognosis during the follow‐up period, except for six cases. Nevertheless, careful follow‐up is still necessary to rule out systemic disease, because only one reported case had skin and bone involved during 2 years of follow‐up. The patient was not unifocal, but multiple polyps in upper GI. ⁶ Of note, due to the short follow‐up time within our cases study, future studies will be required for the definitive assessment of disease progression.

4. CONCLUSIONS

In summary, GI LCH in adults with unifocal, single‐system involvement is extremely rare and usually presents as an incidental finding. Most patients are asymptomatic, and a small solitary polyp in GI tract can be observed under routine endoscopy. Biopsy and immunohistochemistry are necessary for confirming and excluding malignant lesion. Clinical follow‐up is essential to rule out systemic disease, even though the overall prognosis of single‐system LCH is favorable.

CONFLICT OF INTEREST

All authors declare no conflicts of interest.

Wang L, Yang F, Ding Y, et al. Gastrointestinal Langerhans cell histiocytosis with unifocal, single‐system involvement in adults: Cases report and literature review. J Clin Lab Anal. 2022;36:e24765. doi: 10.1002/jcla.24765

DATA AVAILABILITY STATEMENT

The datasets used and analyzed during the current study are available from the corresponding author request.