Pediatric histiocytoses in the United States: incidence and outcomes

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e9

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.JournalofSurgicalResearch.com

Pediatric histiocytoses in the United States: incidence and outcomes Samuel Golpanian, MD, Jun Tashiro, MD, MPH, David J. Gerth, MD, and Seth R. Thaller, MD, DMD, FACS* Division of Plastic, Aesthetic, and Reconstructive Surgery, Department of Surgery, University of Miami, Leonard M. Miller School of Medicine, Miami, Florida

article info

abstract

Article history:

Background: Histiocytoses are rare disorders affecting the pediatric population.

Received 24 December 2013

Materials and methods: Surveillance, Epidemiology, and End Results database was searched

Received in revised form

for pediatric cases (<20 y old) of histiocytosis diagnosed between 1973 and 2010. De-

9 March 2014

mographics, clinical characteristics, and survival outcomes were analyzed using standard

Accepted 21 March 2014

statistical methods. Class I disease (Langerhans cell histiocytosis) and class III (malignant

Available online xxx

histiocytosis) were included in the data set. Results: A total of 828 cases were identified. Overall incidence was 0.142/100,000 persons per

Keywords:

annum. Incidence was highest in younger children and those of Asian or Native American

Pediatrics

descent. Class III disease had a higher incidence versus class I. Adolescents tended to

Epidemiology

present with class III, whereas young children presented with class I. Disseminated disease

Histiocytosis

was present in most cases of class III, whereas class I had more localized cases. Surgical

Langerhans cell histiocytosis

excision was more likely to be performed in class I. Overall median survival was 349 mo. Patients 15e19 y old and children <1 y old had the worst outcomes. Class I had higher survival compared with class III, which had a median survival of 33 mo. Cases with hematologic spread carried the worst prognosis. Surgical excision conferred a survival advantage while radiation had no effect. Survival improved over the study period. Gender and race had no association with survival. Conclusions: Class I disease had localized cases and showed benefit from surgical intervention. Class III disease had a higher incidence and was associated with disseminated disease and lower survival. Radiation therapy did not affect survival. Overall survival increased over the previous 40 y. ª 2014 Elsevier Inc. All rights reserved.

1.

Introduction

Histiocytosis is a rare disease characterized by an abnormal proliferation of histiocytes. These cells can be grouped into two main categories: tissue macrophages and dendritic cells, depending on their morphological, functional, and immunohistochemical properties. The associated disease is divided

into three major classes: I, II, and III. Previously, they corresponded to Langerhans cell histiocytosis (LCH), histiocytoses of mononuclear phagocytes, and malignant histiocytosis (MH), respectively [1]. Over the past several decades, however, these classes have been broadened by the inclusion of additional distinct cell-type disorders. A contemporary classification scheme of the histiocytoses can be seen in Table 1. These

* Corresponding author. Division of Plastic, Aesthetic, and Reconstructive Surgery, Department of Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 410, Miami, FL 33136. Tel.: þ1 305 243 4500; fax: þ1305 243 4535. E-mail address: [email protected] (S.R. Thaller). 0022-4804/$ e see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2014.03.063

2

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e9

Table 1 e Histiocytic disorders classification table. Disorders of varied biological behavior Class I Dendritic cell-related Langerhans cell histiocytosis Secondary dendritic cell processes Juvenile xanthogranuloma and related disorders Solitary histiocytomas of various dendritic cell phenotypes

Malignant disorders

Class II Macrophage-related Hemophagocytic syndromes Primary hemophagocytic lymphohistiocytosis (familial and sporadic; commonly elicited by viral infections) Secondary hemophagocytic syndromes (infection associated, malignancy associated, and other) RosaieDorfman disease (sinus histiocytosis with massive lymphadenopathy) Solitary histiocytoma with macrophage phenotype

Class III Monocyte-related Leukemias (FrencheAmericaneBritish [FAB] and revised FAB classifications) Monocytic leukemia M5A and B Acute myelomonocytic leukemias M4 Chronic myelomonocytic leukemias Extramedullary monocytic tumor or sarcoma (monocytic counterparty of granulocytic sarcoma) Dendritic cell-related histiocytic sarcoma (localized or disseminated) Specify phenotype, follicular dendritic cell, interdigitating dendritic cell, etc. Macrophage-related histiocytic sarcoma (localized or disseminated)

Adapted from the study by Favara, et al. [7].

disorders are uncommon and predominately found in childhood. Because of their rarity, their incidences and outcomes are sparsely documented [2]. LCH is the most common subtype of the class I disorders. It tends to affects young children and may present as a multisystemic syndrome. The more benign and localized forms of LCH present with unifocal or multifocal osseous lesions, most frequently involving the skull [3e6]. MH, or class III, is an umbrella term used to describe the malignant transformation of histiocytes. This type often has a disseminated nature, affecting multiple organ systems, including the liver, spleen, lymph nodes, skin, bone, and lungs [1,7e10]. This syndrome should not be confused with the multisystemic form of LCH, which is a separate entity. Bony lesions, specifically those affecting the calvarium, are not uncommon in histiocytosis. Calvarial lesions arise in up to 70% of patients diagnosed with bony LCH [11]. Although some lesions may be left for observation, many require major excision. This procedure can pose great challenges requiring a multidisciplinary approach. Therefore, an improved understanding of this disease is crucial for effective treatment. For this purpose, we analyzed data from the largest available national cancer registry to delineate the epidemiology and clinical outcomes of pediatric histiocytoses in the United States.

2.

Materials and methods

The Surveillance, Epidemiology, and End Results (SEER) database April 2013 release was used to identify and analyze cases of pediatric histiocytosis in the United States diagnosed between 1973 and 2010. The database contains information on class I or III histiocytic disorders only. Because SEER uses the International Classification of Diseases for Oncology, 3rd revision to classify diseases and does not make a distinction between histiocytic disorder subtypes, we considered LCH synonymous with class I for classification purposes, as it is the most common subtype. Cases were limited to children aged <20 y. Demographic, clinical, and survival data were analyzed using values grouped in categories previously defined for the SEER database by the National Cancer Institute. Duplicate cases were excluded.

All incidence data were age adjusted and normalized to the 2000 US standard population. Annual percentage change was calculated using the weighted least-squares method. Categorical variables were compared using chi-square or Fisher’s exact tests as appropriate. Continuous measures were compared using student’s t-tests. Survival curves were derived using the KaplaneMeier method and comparisons were made using the log-rank test. SEER*Stat software, version 18.0 (National Cancer Institute; Bethesda, MD) was used to obtain incidence and survival data. All other statistical analyses were performed using SPSS, version 21.0 (IBM; Armonk, NY). Only cases with available data were included in each respective analysis. Statistical significance was determined for each analysis at alpha level 0.05.

3.

Results

A total of 828 children and adolescents diagnosed with histiocytosis were identified within the data set. Overall annual incidence rate was 0.142/100,000; Table 2. This rate remained stable throughout the study period with an annual percentage change of 0.96%. Caucasian children had a higher incidence compared with African Americans, P < 0.05. However, children of Asian and/or Pacific Islander or Native American descent had the highest rate, 0.179/100,000 persons per annum. Children <1 y old had the highest incidence rate (0.669/100,000), followed by those aged 1e4 and 10e14 y, P < 0.05. Annual variations in the incidence of each histologic type are depicted in Figure 1. Boys did not have a significantly different incidence compared with girls over the study period. Demographics and clinical characteristics of our study cohort are summarized in Table 3. The ratio of boys to girls was 1.12:1.0. Caucasian children comprised most cases (80%). Most patients were aged <5 y at the time of diagnosis (58%). Approximately, half of this group was <1 y of age. Distribution of histologic type was approximately equal in the cohort. Cases affecting head and neck were most frequent for localized disease (8%), followed by musculoskeletal sites (5%). The vast majority of patients, however, had hematologic

3

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e9

Table 2 e Incidence rates of pediatric histiocytoses, 1973e2010 from SEER database. Overall Gender Female Male Race White Black Other Age (y) <1 1e4 5e9 10e14 15e19 Type Class I Class III

Table 3 e Demographic characteristics of cohort. Category 0.142 0.135 0.148 0.144 0.094 0.179 0.669 0.230 0.068 0.089 0.101 0.030 0.112

Rates are per 100,000 population, standardized to the US population based on 2000 census data.

involvement (82%). Only a small minority of patients underwent surgical resection (10%) or radiation therapy (10%). Histologic type according to age of diagnosis is illustrated in Figure 2. Demographics and clinical data according to class type are displayed in Table 4. Class I disease tended to require surgical excision (odds ratio [OR] [95% confidence interval {CI}]: 11.5 [5.23, 25.4]) compared with class III, P < 0.0001. In addition, class I tended to be localized to the head and neck region (OR [95% CI]: 30.1 [9.36, 96.9]) or musculoskeletal system (19.9 [6.11, 65.0]) compared with class III. Dermatologic manifestations were found only in class I patients. Class III had a higher overall incidence compared with class I, P < 0.05. Class III disease was 5.23 (95% confidence interval, lower/upper bounds: 3.28, 8.33) times more likely to occur versus class I in the 15- to 19-y group compared with the 1- to 4-y-old reference group, P < 0.0001. Similarly, class III was 1.70 (95% CI: 1.09, 2.65) times more likely in children aged 10e14 y compared with 1e4 y olds, P ¼ 0.018. Meanwhile, class III presented systemically in most cases (98.0%), P < 0.0001. No significant differences were observed in gender or race between class type distributions.

Gender Female Male Race White Black Other Age (y) <1 1e4 5e9 10e14 15e19 Type Class I Class III Site Head and neck Musculoskeletal Hematologic Dermatologic Other Surgery Surgery No surgery Radiation Radiation No radiation Diagnosis year 1973e1978 1979e1984 1985e1991 1992e1997 1998e2003 2004e2010

% of total

380 448

46 54

658 71 89

80 9 11

204 275 99 111 139

25 33 12 13 17

419 409

51 49

65 44 666 18 17

8 5 82 2 2

77 732

10 90

86 740

10 90

49 63 66 88 187 375

6 8 8 11 23 45

Survival measures according to clinical characteristics are displayed in Table 5. Overall median survival was 349 mo. Adolescents diagnosed at 15e19 y old had the worst survival rates, followed by children <1 y old, P < 0.0001. Class I disease had improved survival compared with class III, P < 0.0001. To address the change in classification occurring in 1987, we performed a subset analysis comparing pre- and post-1987 diagnoses. We found that cases diagnosed after 1987 had improved survival compared with those diagnosed before 1987 (Table 5). Cases with hematologic spread had the worst outcomes, with a 30-y survival rate of 40%. Comparatively, cases with other sites of presentation had higher survival rates. Surgical excision, performed in approximately 10% of patients, resulted in significantly higher survival, P ¼ 0.007. In contrast, the use of radiation therapy in a small number of patients did not confer any survival advantage. Gender and race did not affect survival. KaplaneMeier survival curves depicting outcome by statistically significant categories are found in Figure 3.

4. Fig. 1 e Incidence rates by histologic type, 1973e2010 (Color version of figure is available online).

n

Discussion

SEER is the largest cancer registry and a major source of incidence and survival data in the United States. It gathers

4

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e9

Table 4 e Comparison of demographic distribution between classes I and III histiocytoses. Category

Class I

Class III

n ¼ 419

n ¼ 409

P value

n (% of total)

Fig. 2 e Tumor histology by the age of diagnosis, 1973e2010 (Color version of figure is available online).

information from 18 population-based registries to provide a nationally representative perspective on malignant disease. SEER collects data on patient demographics, tumor site and morphology, treatment methods, and long-term outcomes. Many rare pediatric malignancies have been described in the literature using the SEER registry [12e15]. As noted throughout our findings, histiocytoses are extremely rare. In addition, effective classification of disease has been challenging because of their propensity to be associated with a wide array of syndromes. Since 1987, investigators have collaborated to standardize diagnostic criteria and terminology to help better clarify the subtypes [1]. Changes in the classification scheme allow the potential for many cases of histiocytosis to be misdiagnosed or, at times, remain undocumented [7,9]. In accordance with previous literature, most of our cohort was Caucasian, and their incidence was higher than that of African Americans [16]. We found, however, that children of Asian and/or Pacific Islander or Native American descent had the highest incidence rates. This finding is particularly concerning, because disease prevalence in this population was relatively low for the study period. This may signify disparate growth in this subpopulation in the future. Our finding of the highest incidence in younger children is in agreement with other studies [17e19]. We found that class I histiocystosis had a lower incidence compared with previously published literature on the US population, which describes annual rates at approximately 0.05/100,000 [16,20e22]. Differences in age limits defining pediatric patients may have affected these findings however, as several studies included children only up to age 15 y. In addition, some studies only included LCH but not other class I subtypes. Lower incidence rates found in our study may be a reflection of undiagnosed patients secondary to fluctuations in diagnostic criteria [9,19]. Further, some subtypes of class I histiocytosis are considered benign and may not have been included in the data set. Unlike the information available for LCH, there has been a dearth of data on class III histiocytosis over the last half century [8,23e27]. Although several reports are available, these include less than seven cases of MH per year [7,28]. Throughout our study period, class III had a consistently higher incidence

Gender Female Male Race White Black Other Age (y) <1 1e4 5e9 10e14 15e19 Site Head and neck Musculoskeletal Hematologic Dermatologic Other Surgery Surgery No surgery Radiation Radiation No radiation Diagnosis year 1973e1978 1979e1984 1985e1991 1992e1997 1998e2003 2004e2010

NS 186 (49) 233 (52)

194 (51) 215 (48)

335 (51) 28 (39) 49 (55)

323 (49) 43 (61) 40 (45)

121 165 50 52 31

(59) (60) (51) (47) (22)

83 (41) 110 (40) 49 (49) 59 (53) 108 (78)

62 41 271 18 15

(95) (93) (41) (100) (88)

3 (5) 3 (7) 395 (59) 0 (0) 2 (12)

NS

<0.0001

<0.0001

<0.0001 70 (91) 340 (46)

7 (9) 392 (54)

50 (58) 368 (50)

36 (42) 372 (50)

30 31 25 46 82 205

19 (39) 32 (51) 41 (62) 42 (48) 105 (56) 170 (45)

NS

0.028 (61) (49) (38) (52) (44) (55)

P values are calculated based on chi-square test analyses for association between demographic or clinical category and histiocytic classification.

compared with class I. A marked increase was noted in 2010, which may be attributed to the development of more accurate classification schemes. Neither histologic type was associated with gender predominance. This finding is similar to those found in D’Ambrosio et al. and Zucker et al. [27,29] regarding LCH and MH, respectively. Other studies on LCH, however, have reported significant gender differences with male to female ratios ranging between 1.6 and 2.8 to 1 [17,18,30e35]. With regard to age, we found that class I tended to affect children <5 y old, consistent with studies on pediatric LCH from the US and Europe [17,36,37]. Conversely, we found class III disease to be associated with adolescence. This result corroborates the few reports of MH [10,27]. Although the histiocytoses can affect many organ systems, we found a clear association between histologic type and site affected. Class I disease was more frequently localized compared with class III, with a predilection toward the head and neck or musculoskeletal system. Previous studies have found craniofacial involvement to be a frequent presentation in children with LCH [36,38e42].

5

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e9

Table 5 e Survival outcomes for pediatric histiocytoses in the United States, 1973e2010. Category Overall Gender Female Male Race White Black Other Age (y) <1 1e4 5e9 10e14 15e19 Histologic type Class I (overall) Pre-1987 Post-1987 Class III (overall) Pre-1987 Post-1987 Site Head and neck Musculoskeletal Hematologic Dermatologic Other Surgery Surgery No surgery Radiation Radiation No radiation Diagnosis year 1973e1978 1979e1984 1985e1991 1992e1997 1998e2003 2004e2010

Median survival (mo)

5-y survival (%)

15-y survival (%)

30-y survival (%)

349

59

55

45

212 349

55 63

53 57

46 45

349 212 NR

60 50 61

56 50 54

47 d d

203 NR NR NR 29

53 76 67 55 33

51 73 51 55 29

28 69 d d d

P NS

NS

<0.0001

<0.0001* NR 349 NR 33 12 111

84 61 87 44 29 54

82 61 84 39 27 48

62 45 d 35 26 d

NR NR 203 NR NR

99 84 54 76 1000

99 d 50 76 84

75 d 40 d d

NR 349

84 59

84 55

d 45

349 NR

64 59

62 54

d 51

10 16 47 NR NR NR

23 20 47 52 65 71

23 20 38 50 d d

19 18 d d d d

0.003y

<0.0001y <0.0001

0.007

NS

<0.0001

NR ¼ not reached, signifying median survival >360 mo; NS ¼ not significant at alpha 0.05. Some values could not be calculated because of lack of available data. P values are calculated on a log-rank test comparison of KaplaneMeier survival curves. * Log-rank test for comparison of class I (overall) versus class III (overall). y Log-rank test for comparison of pre- and post-1987 within each histologic class.

According to the literature, the skull is the most common bony location for pediatric LCH, followed by the mandible [5,29,31,32]. In contrast, there was no distinct association noted between tumor site and class III, as most cases presented with hematologic involvement. In agreement, Lampert et al. [8,10,25] and others have demonstrated that >50% of their patients with MH presented with anemia, leucopenia, and thrombocytopenia. Indications for treatment remain controversial for class I diseases. Shahlaee et al. suggested that single bony lesions do not necessitate surgical excision [9]. Instead, the authors recommended that these lesions should be biopsied and observed. Others have cited the use of local steroid injections for recurrent lesions. Expectant management, however, is the most prevalent type of therapy [37,43]. Still, the use of surgical

excision is advocated by most authors, especially when lesions are solitary [4,6,32,39,44]. We do not support any specific recommendation regarding surgical management and intend only to describe the experience recorded in the SEER database. In contrast to class I disease, little data are available regarding the role of surgery in MH. As found in our study, surgical intervention is extremely uncommon in these cases. Nevertheless, some reports have noted the diagnostic and therapeutic benefits of splenectomies in certain circumstances [8,10,25,45,46]. Large defects remaining after excision often pose challenges in reconstruction, particularly with those affecting the skull. These include long operative times, delicate anatomy, and donor site morbidity [40]. Reconstruction in this region is not only crucial in improving function and appearance but also in preventing infection [47,48]. A variety

6

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e9

Fig. 3 e (A) Survival by age group. Log-rank test demonstrates significance, P < 0.0001. (B) Survival by histologic type. Logrank test demonstrates significance, P < 0.0001. (C) Survival by surgical intervention. Log-rank test demonstrates significance, P [ 0.007. (D) Survival by site affected. Log-rank test demonstrates significance, P < 0.0001. (E) Survival by year of diagnosis. Log-rank test demonstrates significance, P < 0.0001.

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e9

of free flaps and bone grafts have been used to reconstruct anatomic structures [49e51]. Ultimately, the clinician must weigh the possible benefits of surgical management against the significant challenges of reconstruction in these potentially morbid cases. Our analysis demonstrated that radiation treatment was performed infrequently in either histologic class. Low-dose radiation has been recommended in some cases of LCH, such as those with spinal cord compression, surgical inaccessibility, or recurrence [18,32,52,53]. Recently, however, the use of radiation therapy in LCH has decreased as chemotherapy has gained popularity [54]. Furthermore, radiation treatment has been discouraged because of the potential for additional malignancy and hindrance of musculoskeletal development [55,56]. Although infrequent, there are reports that describe the use of radiation therapy in cases of MH [10,25]. These are mostly in conjunction with chemotherapeutic agents. Several reports have emphasized the role of chemotherapy in achieving remission for MH [10,25,27,57]. Chemotherapy has also been advocated for multisystem or disseminated forms of LCH [4,5,38,58]. Commonly used agents include etoposide, vinblastine, methotrexate, and 6mercaptopurine [3,5]. SEER does not provide information regarding administration of chemotherapeutics. Although our findings did not demonstrate a survival benefit with radiation, stratifying patients into groups receiving chemotherapy and chemoradiation may elucidate these patients’ outcomes in a future investigation. There have been numerous reports on allogeneic stem cell transplantation in patients with refractory multisystem LCH and other class subtypes demonstrating success in achieving long-term survival [57,59e65]. Others have found unrelated cord blood transplantation in infants with chemotherapy-resistant high-risk LCH to be a therapeutic treatment strategy [66,67]. Previous literature on LCH has associated outcomes with patient age and extent of disease, rather than treatment type [3,7,21,22,39,42]. Children with LCH who are <2 y with multisystem disease have been found to have a worse prognosis [7,9,22,68,69]. Our findings agree, with lower survival in the youngest and oldest age groups. Furthermore, localized disease has resulted in higher survival rates compared with systemic disease [70]. In a case series by Guyot-Goubin et al. [17], survival rates at 12 and 24 mo were 99% overall. Most cases in this series, however, were unifocal disease. Lahey et al. [44] found a 33% mortality rate during their study period, excluding those with only solitary lesions. Our study corroborates these results, as median survival is >360 mo and the 30y survival rate is approximately 62% for class I diseases. Prior descriptions of class III disease, mostly consisting of MH, depict extremely poor survival rates. Tseng et al. [46] demonstrated a median survival of 24 mo for MH. In addition, their study noted a 5-y survival rate at 40% [46]. We found similarly poor prognoses for class III disease, with a median survival of 33 mo and 30-y survival of 35%. For both class types, survival rates have improved significantly over the previous 40 y. Although fluctuations in the classification scheme may have affected these results, overall 5-y survival has risen from 23%e71% within the study period. Outcomes are presumed to have improved primarily because of the introduction of intensive chemotherapy regimens [10,27].

7

Demographic factors, including gender and race, were found to have no effect on long-term survival. SEER is an excellent source of information for describing clinical and survival characteristics associated with malignant disease. However, limitations are inevitable. SEER covers approximately 28% of the US population. As a result, some regions and ethnicities are overrepresented, which may skew the analyses. SEER only contains information on class I and III histiocytoses, and therefore, histologic type was limited to the two classes of histiocytoses described. The classification scheme has changed over time. To address the potential for this to affect our survival analyses, we performed subanalyses of pre- and post-1987 cases; a significant difference was apparent. From the information available in this database however, we cannot discern whether these changes are due to changes in treatment patterns, such as chemotherapy, or whether the cases diagnosed under the new scheme are less aggressive on average. Cancer-related surgery and radiation therapy data lack details regarding the extent of procedure and dosage of treatment. In addition, chemotherapy is not included in the database. However, SEER remains among the most favorable resources in providing information on longterm cancer outcomes.

5.

Conclusions

Histiocytic disorders are rare occurrences in children and adolescents. Overall incidence has been stable over the last three decades. Incidence was highest among class III diagnoses, children aged <1 y, and those of Asian or Native American decent. Class I disorders tended to affect younger children and have localized manifestations. Conversely, class III disorders presented more commonly in adolescents and disseminate systemically. Class III was associated with significantly lower survival, as were cases diagnosed in the youngest or oldest age groups. Surgical excision was more likely to be performed for class I disease and conferred a significant survival advantage when the lesion was amenable. Radiation therapy did not affect survival. Survival rates improved significantly over the study period. Additional research is required to evaluate the effectiveness of specific excision procedures and to elucidate the effects of chemotherapy on long-term survival.

Acknowledgment The author S.G. participated in study conception and design and writing the article; J.T. participated in study conception and design, analysis and interpretation, and critical revision of the article; D.J.G. participated in study conception and design, analysis and interpretation, data collection, and critical revision of the article; and S.R.T. participated in study conception and design and critical revision of the article.

Disclosure The authors have no financial disclosures to report.

8

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e9

references

[1] Histiocytosis syndromes in children. Writing Group of the Histiocyte Society. Lancet 1987;1:208. [2] Jaffe R. The histiocytoses. Clin Lab Med 1999;19:135. [3] Arkader A, Glotzbecker M, Hosalkar HS, Dormans JP. Primary musculoskeletal Langerhans cell histiocytosis in children: an analysis for a 3-decade period. J Pediatr Orthop 2009;29:201. [4] Martinez-Lage JF, Poza M, Cartagena J, Vicente JP, Biec F, de las Heras M. Solitary eosinophilic granuloma of the pediatric skull and spine. The role of surgery. Child’s Nervous Syst: ChNS: Official J Int Soc Pediatr Neurosurg 1991;7:448. [5] Lee SK, Jung TY, Jung S, Han DK, Lee JK, Baek HJ. Solitary Langerhans cell histocytosis of skull and spine in pediatric and adult patients. Child’s Nervous Syst: ChNS: Official J Int Soc Pediatr Neurosurg; 2013. [6] Sbordone L, Guidetti F, Menchini Fabris GB, Sbordone C. Langerhans’ cell histiocytosis: a case report of an eosinophilic granuloma of the mandible treated with bone graft surgery and endosseous titanium implants. The Int J Oral Maxill Implants 2006;21:124. [7] Favara BE, Feller AC, Pauli M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 1997;29:157. [8] Ruuskanen O, Kero P, Rajamaki A, Ekfors T, Vilkki P, Nordman E. Malignant histiocytosis. Histiocytic medullary reticulosis. Acta Paediatr Scand 1978;67:249. [9] Shahlaee AH, Arceci RJ. Histiocytic disorders. In: Arceci RJ, Hann IM, Smith OP, editors. Pediatric Hematology. 3rd ed. Hoboken, NJ: John Wiley & Sons; 2008. p. 340e59. [10] Warnke RA, Kim H, Dorfman RF. Malignant histiocytosis (histiocytic medullary reticulosis). I. Clinicopatholigic study of 29 cases. Cancer 1975;35:215. [11] Khung S, Budzik JF, Amzallag-Bellenger E, et al. Skeletal involvement in Langerhans cell histiocytosis. Insights Into Imaging 2013;4:569. [12] Hogan AR, Zhuge Y, Perez EA, Koniaris LG, Lew JI, Sola JE. Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. J Surg Res 2009;156:167. [13] McAteer JP, Huaco JA, Gow KW. Predictors of survival in pediatric adrenocortical carcinoma: a Surveillance, Epidemiology, and End Results (SEER) program study. J Pediatr Surg 2013;48:1025. [14] Perez EA, Gutierrez JC, Koniaris LG, Neville HL, Thompson WR, Sola JE. Malignant pancreatic tumors: incidence and outcome in 58 pediatric patients. J Pediatr Surg 2009;44:197. [15] Wong JR, Harris JK, Rodriguez-Galindo C, Johnson KJ. Incidence of childhood and adolescent melanoma in the United States: 1973-2009. Pediatrics 2013;131:846. [16] David R, Oria RA, Kumar R, et al. Radiologic features of eosinophilic granuloma of bone. AJR Am J Roentgenology 1989;153:1021. [17] Guyot-Goubin A, Donadieu J, Barkaoui M, Bellec S, Thomas C, Clavel J. Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000-2004. Pediatr Blood Cancer 2008;51:71. [18] Kwon SH, Choi JW, Kim HJ, Youn SW. Langerhans cell histiocytosis: a retrospective analysis in a Korean tertiary hospital from 2003 to 2012. J Dermatol 2013;40:824. [19] Salotti JA, Nanduri V, Pearce MS, Parker L, Lynn R, Windebank KP. Incidence and clinical features of Langerhans cell histiocytosis in the UK and Ireland. Arch Dis Child 2009; 94:376.

[20] Grundy P, Ellis R. Histiocytosis X: a review of the etiology, pathology, staging, and therapy. Med Pediatr Oncol 1986;14:45. [21] Leonidas J. Langerhans’ cell histiocytosis. In: Taveras J, Ferrucci J, editors. Radiology: diagnosis, imaging, intervention. Vol. 5. Philadelphia: Lippincott; 1990. p. 1. [22] Starling K, Fernbach D. Histiocytosis. In: Sutow W, Fernbach D, Vietti T, editors. Clinical pediatric onology. 3rd ed. St. Louis: Mosby; 1984. p. 498. [23] Abele DC, Griffin TB. Histiocytic medullary reticulosis. Report of two cases and review of the literature. Arch Dermatol 1972;106:319. [24] Ho FC, Todd D. Malignant histiocytosis: report of five Chinese patients. Cancer 1978;42:2450. [25] Lampert IA, Catovsky D, Bergier N. Malignant histiocytosis: a clinico-pathological study of 12 cases. Br J Haematol 1978; 40:65. [26] Rilke F, Carbone A, Musumeci R, Pilotti S, De Lena M, Bonadonna G. Malignant histiocytosis: a clinicopathologic study of 18 consecutive cases. Tumori 1978;64:211. [27] Zucker JM, Caillaux JM, Vanel D, Gerard-Marchant R. Malignant histiocytosis in childhood: clinical study and therapeutic results in 22 cases. Cancer 1980;45:2821. [28] Lauritzen AF, Ralfkiaer E. Histiocytic sarcomas. Leuk Lymphoma 1995;18:73. [29] D’Ambrosio N, Soohoo S, Warshall C, Johnson A, Karimi S. Craniofacial and intracranial manifestations of langerhans cell histiocytosis: report of findings in 100 patients. Am J Roentgenology 2008;191:589. [30] al-Ammar AY, Tewfik TL, Bond M, Schloss MD. Langerhans’ cell histiocytosis: paediatric head and neck study. J Otolaryngol 1999;28:266. [31] Cochrane LA, Prince M, Clarke K. Langerhans’ cell histiocytosis in the paediatric population: presentation and treatment of head and neck manifestations. J Otolaryngol 2003;32:33. [32] Irving RM, Broadbent V, Jones NS. Langerhans’ cell histiocytosis in childhood: management of head and neck manifestations. Laryngoscope 1994;104(1 Pt 1):64. [33] Malpas JS. Langerhans cell histiocytosis in adults. Hematol Oncol Clin North Am 1998;12:259. [34] Nicholson HS, Egeler RM, Nesbit ME. The epidemiology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1998;12:379. [35] Quraishi MS, Blayney AW, Walker D, Breatnach FB, Bradley PJ. Langerhans’ cell histiocytosis: head and neck manifestations in children. Head & neck 1995;17:226. [36] Hindman BW, Thomas RD, Young LW, Yu L. Langerhans cell histiocytosis: unusual skeletal manifestations observed in thirty-four cases. Skeletal Radiol 1998;27:177. [37] Stalemark H, Laurencikas E, Karis J, Gavhed D, Fadeel B, Henter JI. Incidence of Langerhans cell histiocytosis in children: a population-based study. Pediatr Blood Cancer 2008;51:76. [38] Azouz EM, Saigal G, Rodriguez MM, Podda A. Langerhans’ cell histiocytosis: pathology, imaging and treatment of skeletal involvement. Pediatr Radiol 2005;35:103. [39] Eckardt A, Schultze A. Maxillofacial manifestations of Langerhans cell histiocytosis: a clinical and therapeutic analysis of 10 patients. Oral Oncol 2003;39:687. [40] Kwon SG, Kim YO, Rah DK. Anterior cranial base reconstruction with a reverse temporalis muscle flap and calvarial bone graft. Arch Plast Surg 2012;39:345. [41] Prayer D, Grois N, Prosch H, Gadner H, Barkovich AJ. MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. Ajnr Am J Neuroradiology 2004;25:880.

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e9

[42] Stull MA, Kransdorf MJ, Devaney KO. Langerhans cell histiocytosis of bone. Radiographics 1992;12:801. [43] Yasko AW, Fanning CV, Ayala AG, Carrasco CH, Murray JA. Percutaneous techniques for the diagnosis and treatment of localized Langerhans-cell histiocytosis (eosinophilic granuloma of bone). J Bone Joint Surg Am 1998;80:219. [44] Lahey M. Prognosis in reticuloendotheliosis in children. J Pediatr 1962;60:664. [45] Sullivan JR, Ungar B, Hicks JD, Hurley TH. Histiocytic medullary reticulosis. Aust N Z J Med 1975;5:347. [46] Tseng A Jr, Coleman CN, Cox RS, et al. The treatment of malignant histiocytosis. Blood 1984;64:48. [47] Gil Z, Abergel A, Leider-Trejo L, et al. A comprehensive algorithm for anterior skull base reconstruction after oncological resections. Skull Base: Official J North Am Skull Base Soc [et al.] 2007;17:25. [48] Smith JE, Ducic Y, Adelson RT. Temporalis muscle flap for reconstruction of skull base defects. Head & neck 2010;32:199. [49] Mohammed-Ali RI, Robbins AE, Hussain O, et al. Six-year retrospective study of reconstructive options for defects of the skull base after resection of tumour. Br J Oral Maxill Surg 2013;51:719. [50] Mucke T, Loeffelbein DJ, Kolk A, et al. Comparison of outcome of microvascular bony head and neck reconstructions using the fibular free flap and the iliac crest flap. Br J Oral Maxill Surg 2013;51:514. [51] Onoda S, Kimata Y, Sugiyama N, Onoda T, Mizukawa N. Secondary head and neck reconstruction using free flap to improve the postoperative function or appearance of cancer survivors. Microsurgery; 2013. [52] Fernando Ugarriza L, Cabezudo JM, Porras LF, Lorenzana LM. Solitary eosinophilic granuloma of the cervicothoracic junction causing neurological deficit. Br J Neurosurg 2003;17:178. [53] Rawlings CE 3rd, Wilkins RH. Solitary eosinophilic granuloma of the skull. Neurosurgery 1984;15:155. [54] Lavin PT, Osband ME. Evaluating the role of therapy in histiocytosis-X. Clinical studies, staging, and scoring. Hematol Oncol Clin North America 1987;1:35. [55] Donadieu J, Rolon MA, Pion I, Thomas C, Doz F, Barkaoui M. French LCHSG. Incidence of growth hormone deficiency in pediatric-onset Langerhans cell histiocytosis: efficacy and safety of growth hormone treatment. J Clin Endocrinol Metab 2004;89:604. [56] Greenberger JS, Cassady JR, Jaffe N, Vawter G, Crocker AC. Radiation therapy in patients with histiocytosis: management of diabetes insipidus and bone lesions. Int J Radiat Oncol Biol Phys 1979;5:1749. [57] Steiner M, Matthes-Martin S, Attarbaschi A, et al. Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant 2005;36:215.

9

[58] Windebank K, Nanduri V. Langerhans cell histiocytosis. Arch Dis Child 2009;94:904. [59] Akkari V, Donadieu J, Piguet C, Bordigoni P, Michel G, Blanche S. French Langerhans Cell Study G. Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group. Bone Marrow Transplant 2003;31:1097. [60] Blanche S, Caniglia M, Girault D, Landman J, Griscelli C, Fischer A. Treatment of hemophagocytic lymphohistiocytosis with chemotherapy and bone marrow transplantation: a single-center study of 22 cases. Blood 1991;78:51. [61] Conter V, Reciputo A, Arrigo C, Bozzato N, Sala A, Arico M. Bone marrow transplantation for refractory Langerhans’ cell histiocytosis. Haematologica 1996;81:468. [62] Hale GA, Bowman LC, Woodard JP, et al. Allogeneic bone marrow transplantation for children with histiocytic disorders: use of TBI and omission of etoposide in the conditioning regimen. Bone Marrow Transplant 2003;31:981. [63] Jabado N, de Graeff-Meeder ER, Cavazzana-Calvo M, et al. Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplantation from HLA genetically nonidentical donors. Blood 1997;90:4743. [64] Kinugawa N, Imashuku S, Hirota Y, et al. Hematopoietic stem cell transplantation (HSCT) for Langerhans cell histiocytosis (LCH) in Japan. Bone Marrow Transplant 1999; 24:935. [65] Ringden O, Ahstrom L, Lonnqvist B, Baryd I, Svedmyr E, Gahrton G. Allogeneic bone marrow transplantation in a patient with chemotherapy-resistant progressive histiocytosis X. New Engl J Med 1987;316:733. [66] Nagarajan R, Neglia J, Ramsay N, Baker KS. Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 2001;23:629. [67] Suminoe A, Matsuzaki A, Hattori H, Ishii S, Hara T. Unrelated cord blood transplantation for an infant with chemotherapyresistant progressive Langerhans cell histiocytosis. J Pediatr Hematol Oncol 2001;23:633. [68] Mowery NT, Gunter OL, Collier BR, et al. Practice management guidelines for management of hemothorax and occult pneumothorax. J Trauma 2011;70:510. [69] Meyer A, Stark M, Karstens JH, Christiansen H, Bruns F. Langerhans cell histiocytosis of the cranial base: is low-dose radiotherapy effective? Case Rep Oncological Med 2012;2012: 789640. [70] Broadbent V, Gadner H, Komp DM, Ladisch S. Histiocytosis syndromes in children: II. Approach to the clinical and laboratory evaluation of children with Langerhans cell histiocytosis. Clinical Writing Group of the Histiocyte Society. Med Pediatr Oncol 1989;17:492.