Effective treatment of progressive nodular histiocytosis by intermediate-dose cytarabine: a case report and literature review

doi:10.21203/rs.2.22762/v1

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Effective treatment of progressive nodular histiocytosis by intermediate-dose cytarabine: a case report and literature review

https://doi.org/10.21203/rs.2.22762/v1

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Background

Progressive nodular histiocytosis (PNH) is a rare, clinically distinct non-Langerhans cell histiocytosis, affecting the skin and mucous membranes with no signs of spontaneous regression of the lesions, without any other system involved. Patients typically have hundreds of lesions of superficial xanthomatous papules to nodules and deep larger fibrous nodules. So far, very few universally accepted reports of PNH existed and no effective treatment have been reported to reverse the progressive clinical course.

Results

Twenty-five PNH cases were identified so far, with a median age of 34 years. 14 patients were male. All patients presented as papules and nodules over the skin and/or mucosal surfaces, including face (39%), fingers or palm (16%), laryngeal (12%) and eyes (8%). 7 cases (28%) reported PNH with systematic diseases. Treatment efficacy using steroids, chemotherapy or surgical excision were disappointing in previous case reports. One patient with laryngeal involvement died due to airway obstruction. In our case, traditional chemotherapy achieved favorable therapeutic effect with intermediate-dose cytarabine confirmed by clinical symptoms of the patient, as well as PET/CT imaging.

Conclusions

PNH is a rare, proliferative disorder with disfiguring lesions and deteriorative quality of life. Intermediate-dose cytarabine should be considered as a treatment option for PNH patients.

Internal Medicine

Progressive nodular histiocytosis (PNH)

non-Langerhans cell histiocytosis (NLCH)

cytarabine

Progressive nodular histiocytosis (PNH), first described in 1978 by Taunton et al(1), is a rare, non-Langerhans cell disorder of unknown cause that presents with widespread xanthomatous lesions with no spontaneous remission. The clinical presentation of PNH usually consists of yellow-brown or yellow-pink superficial papules or deep nodules ranging from 0.5 to 5 cm in size. Facial involvement is a prominent feature and may cause a leonine appearance, and lesions may coalesce on the eyelids, leading to ectropion(2). While PNH may involve mucous membranes, such as in the oral cavity, larynx and conjunctiva, flexural areas and joints are usually spared(3). To date, few PNH cases have been reported, and even fewer reports have mentioned treatment. Surgical resection of specific nodules seems to be the only therapeutic option, but recurrences were not uncommon(4). Here, we reported the successful treatment of a patient with refractory, disseminated PNH by intermediate-dose cytarabine. In order to better understand this rare disease, we searched the literature for all the PNH cases, analyzed the data, and depicted the basic clinical characteristics, histopathology, treatment options, and outcome of the disease.

Case presentation

A 22-year-old woman was referred to our hematology clinic with a 6-year history of papules and nodules appearing throughout the skin. Physical examination revealed reddish-brown papules and nodules involving the face, trunk and extremities (Supplemental Fig. 1A). The chest, flexural areas, palms and joints were spared. The nodules were perfectly delimited by healthy skin and were mostly mounted on the skin. The conjunctival mucosa was also affected by superficial yellowish papules. Her past medical history was insignificant, and there was no family history of note. Basic laboratory findings were generally within normal limits. Histopathological examination of multiple nodular lesions revealed subcutis and focal skeletal muscle infiltrate, which extended deeply into the reticular dermis and was composed of histiocytes, spindled cells within fibrous matrix and Touton giant cells (Supplemental Fig. 2A). Immunohistochemical staining showed the nodular tissue was positive for CD68 (Supplemental Fig. 2B) and S-100 but negative for CD1a (Supplemental Fig. 2C). Based on clinical manifestations and pathological findings, a diagnosis of non-Langerhans cell histiocytosis was made. Despite systemic chemotherapy including cyclophosphamide, doxorubicin, vincristine, etoposide and prednisolone, her lesions gradually increased in size. The patient was depressed and refused further treatment.

Four years later, she came to our clinic again. Those lesions on the face tended to be grouped, converging around the nasal root, forehead and palpebral areas, resulting in the characteristic leonine face (Supplemental Fig. 1B), and the nodules on her body became larger and denser (Supplemental Fig. 1D). ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) demonstrated an increased uptake in the cutaneous lesions throughout the body (Fig. 1A). Rebiopsy showed the same histopathological findings. Based on the two different disseminated skin lesions, histology and progressive course, PNH was diagnosed. We performed whole genome sequencing on this patient's peripheral blood and nodule tissue. The results showed 7 predisposed gene mutations, 119 somatic copy number variations and more than 80,000 structural variations. However, no mutation, fusion or translocation was found in the MAPKinase RAS–RAF–MEK–ERK cell signaling pathway, PI3K-AKT signaling pathway or mTOR pathway.

After signing informed consent, the patient was initially treated with 500 mg/m² cytarabine by 3-hour infusion every 12 hours for 3 days every 5 weeks. Skin lesions throughout her body became soft and small (Supplemental Fig. 1C, E). Repeated PET/CT scans after six courses of cytarabine showed the number and uptake of those hypermetabolic lesions were dramatically decreased, especially in the feet (Fig. 1B). So far, the patient received seven courses of intermediate-dose cytarabine, and no major adverse events occurred except for transient and manageable grade 4 myelosuppression without severe infection or hemorrhage. The patient herself was satisfied with the efficacy despite some tolerable side effects. She witnessed the decrease of nodules all over her body and was brave enough to go outside and get involved in social activities.

Review of the literature

Literature searches were performed in Medline database in December 2019 to retrieve articles related to PNH. Search items included "Progressive nodular histiocytosis" and "Progressive nodular histiocytoma". Ultimately, 21 reports published between 1978 to 2019 comprising 24 cases with detailed clinical data were identified and included for analysis. Detailed information for all the cases was summarized in Table 1.

Table 1

Characteristics of published PNH cases from 1978 to 2019.
Case No.	Year	Age/Sex	Special clinical features	Systematic disease	Histopathology	Treatment	Outcome
1	1978(1)	9/F	Mucosal involvement; Ocular involvement	Anemia	CD68 (+) S-100 (-)	N/A	N/A
2	1981(5)	29/M	Spontaneous regression	No	Factor XIIIa (+) Vimentin (+) CD68 (+)	N/A	N/A
3	1993(13)	60/M	Facial involvement	No	lysozyme(+) a-antitrypsin (+) S-100 (-)	Systemic steroids and antihistamines	No response
4	1995(22)	62/F	NA	No	Factor XIIIa (+) Vimentin (+) CD68 (+)	N/A	Eighteen months follow-up
5	1995(22)	52/M	NA	No	Factor XIIIa (+) Vimentin (+) CD68 (+)	N/A	Five years follow-up
6	2000(14)	25/M	Facial involvement	No	CD68 (+) CD15(+) S-100 (-) CD1a (-)	Systemic steroids and cyclophosphamide (150 mg/d)	No response
7	2000(9)	57/M	Facial involvement →Ectropion	Chronic myeloid leukaemia, hepatosplenomegaly, hypothyroidism, hyperuricaemia and hypocholesterolaemia	Factor XIIIa (+) CD68 (+) S-100 (-)	Carbon dioxide laser	Recurrence
8	2002(6)	13/F	Spontaneous regression	Hypothalamic tumor	CD68 (+) S-100 (-) CD1a (-)	Growth hormone releasing hormone agonist and growth hormone for hypothalamic tumor	N/A
9	2006(23)	24/F	NA	No	CD68 (+) S-100 (-) CD1a (-)	N/A	N/A
10	2006(10)	50/F	NA	TAR Syndrome and angiobromas	CD68 (+)	N/A	N/A
11	2008(4, 15)	13/F	Fingers and palms involvement	No	CD68 (+)	1. Systemic vincristine combined with prednisolone 2. Surgical excision	1.no response 2. difficult to achieve skin closure
12	2009(2)	34/F	Facial and mucosal involvement	No	CD68 (+) S-100 (+) Factor XIIIa (+) CD1a (-)	Surgical excision	Recurrence
13	2010(24)	9/M	Facial involvement	No	CD68 (+) MAC387 (+) S-100 (-) CD1a (-)	N/A	N/A
14	2010(25)	34/F	Laryngeal involvement	No	CD68 (+) S-100 (+) CD1a (-)	N/A	laryngeal Involvement but airway stable
15	2011(3)	52/F	Facial involvement	No	CD68 (+) CD1a (-)	Surgical excision	No recurrence at 1-year follow-up
16	2013(7)	29/M	NA	Anemia	CD68 (+) CD163 (+) S-100 (+) CD1a (-)	Surgical excision	Recurrence
17	2013(7)	55/M	Ocular involvement	No	CD68 (+) CD1a (-) langerin(-)	systemic steroids	N/A
18	2013(26)	38/M	Mucosa, palms, and soles were spared	No	CD68 (+) CD163 (+) S-100 (+) CD1a (-)	NA	NA
19	2013(8)	70/M	Eyelids, mucosa, palms, and soles were spared	Chronic lymphocytic leukemia	CD68 (+) CD163 (+) CD1a (-)	NA	NA
20	2015(11)	30/M	Facial involvement Ocular involvement	Eale's disase	CD68 (+) S-100 (-)	Imatinib Pazopanib	No response
21	2016(17)	60/M	Laryngeal involvement	No	CD68 (+) S-100 (-) CD1a (-)	N/A	Died of laryngeal Involvement
22	2017(27)	12/M	Facial (eyelids) and mucosa involvement		CD68 (+) CD163 (+) S-100 (+) CD1a (-)	NA	NA
23	2017(16)	78/F	Palms involvement	No	CD68 (+) S-100 (-) CD1a (-)	Methotrexate (15 mg once/week)	Recurrence after discontinuation
24	2019(12)	11/M	Palms and soles involvement	No	Factor XIIIa (+) CD68 (+) S-100 (-) CD1a (-)	Surgical excision	N/A
25	2019 current case	22/F	Facial (eyelids), mucosa, palms, and soles involvement; Laryngeal involvement;	No	CD68 (+) S-100 (+) CD1a (-)	Intermediate-dose cytarabine	Remission
Note: N/A. no available clinical information.

Since 1978, 24 PNH cases had been reported based on typical clinical features and histopathology findings. The present case was the 25th case reported so far. The demographic characteristics, clinical symptoms, diagnosis, treatment, and outcome for the 25 patients were listed in Table 1. Among them, 14 of the patients were male, with a median age of 34 years (range, 9–78). All patients presented as papules and nodules over the skin and/or mucosal surfaces. Only 2 cases showed spontaneous regression(5, 6) while the other 23 patients suffered progressive clinical course. 9 patients (39%) had facial involvement; 4 patients (16%) had fingers or palm involvement. Mucosal involvement was also presented in 6 cases (24%); 3 out of the 6 cases showed laryngeal involvement, which even led to death in one case. 2 patients had ocular involvement, even causing loss of vision. 7 cases (28%) reported PNH with systematic diseases. 2 out of the seven patients had anemia(1, 7); other 2 patients had chronic myeloid leukemia and chronic lymphocytic leukemia respectively(8, 9); the rest patients had metabolic disorders(9), thrombocytopenia and angiobromas(10), hypothalamic tumor(6) and Eale's disase(11). Histopathological examination of skin biopsies showed numerous foamy macrophages, inflammatory cells and few Touton giant cells, extended deeply into the reticular dermis. Immunohistochemical staining found strongly positive for CD68 and negative for CD1a. For 24 cases stained CD68, all cases (100%) were positive. Of the 16 patients who were tested for CD1a, skin tissues of the 16 patients were negative for CD1a. 17 cases revealed S-100 stain results, 11 cases (64.7%) were negative while 6 cases (35.3%), including our case were positive. Only 11 cases mentioned treatment regimens, including surgical excision(2–4, 7, 12) in 5 (20%), systemic steroids only(7, 13) in 2 (8%), chemotherapy(11, 14–16) in 5 (20%) and carbon dioxide laser(9) in 1(%). Surgical excision and carbon dioxide laser may remove disfiguring lesions and produced dramatic cosmetic improvement in short term, but recurrences were reported in 3 cases(2, 7, 9) (50%) out of 6, while another one case had difficulty in skin closure(4). One case reported no recurrence during one-year follow-up(3), however, the other one didn't provide follow-up information(12). Systemic steroids had been tried without any response. Chemotherapy in form of cyclophosphamide(14), vincristine(15), methotrexate(16) and targeted drug (imatinib/pazopanib)(11) for PHN were suggested to be ineffective, except our case that patient achieved remission after seven courses of cytarabine. Since PNH normally localized in skin and/or mucosa, patients remained in good general health without visceral involvement. However, one patient with laryngeal involvement died due to airway obstruction(17).

PNH is a distinct, unusual variant of cutaneous non-Langerhans cell histiocytosis (NLCH) that belongs to the "C" group (cutaneous and mucocutaneous histiocytoses)(18) and affects the skin and mucous membranes without visceral involvement. So far, only 25 PNH cases have been reported since the first description in 1978. We summarized these 25 cases and found the diagnosis of PNH relies heavily on clinical features and pathological results. Typically, patients may progressively develop hundreds of two distinct types of lesions: superficial xanthomatous papules to nodules of 2 to 10 mm in diameter and deep larger fibrous nodules(18). These lesions are widely and randomly distributed on different sites throughout the body, while the flexural areas and joints are usually spared(3). Facial and/or mucosa involvement is a prominent feature and may cause a leonine appearance, and eyelid, conjunctival, oral, or laryngeal lesions may also occur(2, 18). laryngeal involvement can be fatal sometimes due to airway obstruction(17). In addition, the widespread skin nodules and leonine face appearance are problematic for patients, especially for a young girl, and seriously affect quality of life, impair social interactions, even lead to suicidal tendencies.

Although PNH, like most NLCHs, typically does not have extra-cutaneous manifestations, various associated conditions have been reported, including a male with chronic myeloid leukemia and metabolic disorders(9), a woman with thrombocytopenia and angiobromas(10) and a 9-year-old girl with a hypothalamic tumor(6). Additionally, there have been reports of microcytic anemia due to massive iron deposition in the nodules(7). However, no relevance has been confirmed so far between PNH and those systematic disorders.

To our knowledge, this is the first study worldwide to perform whole genome sequencing on a PNH patient. However, those recurrent, activating mutations and fusions that are commonly found in histiocytic neoplasms, such as BRAF^V600E, ARAF, MAP2K1, NRAS, KRAS, PIK3CA mutations, BRAF, ALK, NTRK1 fusions(19), were not present in our patient. Therefore, BRAF inhibitors, MEK inhibitors or mTor inhibitors may exert little efficiency in PNH patients.

Treatment of PNH is difficult. No consensus treatment for PNH exists, and treatment efficacy for patients were disappointing in previous case reports. Surgical excision and carbon dioxide lasers may be options, but recurrence is common(2–4). Systemic steroids had been tried without any response. Traditional chemotherapies including prednisolone, vincristine, and cyclophosphamide as well as target drug like imatinib/pazopanib have been suggested to be unsuccessful in the literature and in our patient(15). Oral low-dose methotrexate (15 mg once/week) was also attempted, but a new flare of PNH lesions occurred after discontinuation of methotrexate(16). Recently, more evidence has shown that cytarabine is an important drug for treatment of histiocytosis, including Langerhans cell histiocytosis(20) and non-LCH, such as ECD in our previous report(21). As seen in our repoorted case, the patient achieved clinical improvement after six courses of this monotherapy, and efficacy was clearly suggested by the decreased size of her nodules and was confirmed by ¹⁸F-FDG PET/CT.

PNH is a rare type of non-Langerhans cell histiocytosis. Diagnosis of this extremely uncommon disorder is based essentially on its clinical characteristics and typical histopathology. However, treatment options were limited and ineffective. Intermediate-dose cytarabine may be a valuable therapeutic option for PNH, especially for refractory, disseminated PNH. Further clinical researches and observations are warranted in this histiocytic disease.

PHN

progressive nodular histiocytosis

NLCH

non-Langerhans cell histiocytosis

¹⁸F-FDG

¹⁸F-fluorodeoxyglucose

PET/CT

positron emission tomography/computed tomography

Ethics approval and consent to participate

No ethical approval is required.

Consent for publication

Consent to participate was obtained from the patient reported.

Availability of data and materials

All literatures included in the manuscript are listed in the references. Articles were identified in Medline database and access to full text is dependent on journal and institutional constraints.

Competing interests

The authors declare no competing interests.

Acknowledgments

The authors thank the patient and her family for their trust, respect and support.

Funding details

Institutional research funding provided by the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2019-RC-HL-001, for CXX), the CAMS Innovation Fund for Medical Sciences (Grant No. 2016-12M-1-002, for LJ) and the National Key Research and Development Program of China (Grant No. 2016YFC0901503, for LJ).

Contribution:

J.W., Y.Q., Y.J., T.Z., and X.C. proceeded clinical practice; J.W., Y.Q. collected, analyzed, and interpreted the data; J.S. carried out the pathological analysis; N.N., J.S. carried out the radiological analysis; J.W., J.L., X.C. wrote the manuscript; and all authors contributed to the final draft.

Taunton OD, Yeshurun D, Jarratt M. Progressive nodular histiocytoma. Archives of Dermatology. 1978;114(10):1505-8.
Glavin FL, Chhatwall H, Karimi K. Progressive nodular histiocytosis: a case report with literature review, and discussion of differential diagnosis and classification. Journal of Cutaneous Pathology. 2009;36(12):1286-92.
Nofal A, Assaf M, Tawfik A, Elsayed N, Nofal E, Elnakib N, et al. Progressive nodular histiocytosis: a case report and literature review. International journal of dermatology. 2011;50(12):1546-51.
Norihisa N, Hirotaka A, Wakako M, Daisuke W, Yasuo S, Yohko Y. Effective surgical treatment of progressive nodular histiocytosis. Journal of Plastic Surgery & Hand Surgery. 2014;48(1):80-3.
Burgdorf WH, Kusch SL, Nix TE, Pitha J. Progressive nodular histiocytoma. Archives of dermatology. 1981;117(10):644-9.
Beswick S, Kirk J, Bradshaw K, Sanders D, Moss C. Progressive nodular histiocytosis in a child with a hypothalamic tumour. British Journal of Dermatology. 2002;146(1):138-40.
Hilker O, Kovneristy A, Varga R, Neubert T, Wesselmann U, Flaig MJ, et al. Progressive nodular histiocytosis. Jddg Journal Der Deutschen Dermatologischen Gesellschaft. 2013;11(4):301-7.
Chapman LW, Hsiao JL, Sarantopoulos P, Chiu MW. Reddish-Brown Nodules and Papules in an Elderly Man. JAMA dermatology. 2013;149(10):1229-30.
Ruiz AG, Ruiz AIB, Fraile HA, Martinez IP, Munoz MG. Progressive nodular histiocytosis accompanied by systemic disorders. British Journal of Dermatology. 2000;143(3):628-31.
Rosón E, Flórez Á, Feal C, Torre CDL, Garcíadoval I. Progressive nodular histiocytoma associated with thrombocytopenia with absent radii (TAR syndrome) and angiofibromas. Acta dermato-venereologica. 2006;86(4):348-50.
Williams A, Thomas AG, Kwatra KS, Jain K. Progressive nodular histiocytosis associated with eale's disease. Indian journal of dermatology. 2015;60(4):388.
Kiyohara T, Makimura K, Miyamoto M, Shijimaya T, Nagano N, Nakamaru S, et al. Progressive Nodular Histiocytosis with Large Nodules and a Bulky Mass. Acta dermato-venereologica. 2019;99(5-6):610-1.
Loyda Torres M, Sánchez, Jorge L., Aníbal Rivera M, Anarda González M. Progressive nodular histiocytosis †. Journal of the American Academy of Dermatology. 1993;29(1):278-80.
Vadoud-Seyedi J, Vadoud-Seyedi R, De DG. Progressive nodular histiocytomas. Br J Dermatol. 2000;143(3):678-9.
Watanabe T, Watanabe D, Tamada Y, Matsumoto Y. Progressive nodular histiocytosis - A five-year follow up. European Journal of Dermatology Ejd. 2008;18(2):200.
Huet F, Brenaut E, Costa S, Lemasson G, Sonbol H, Misery L. Progressive nodular histiocytosis improved by methotrexate. European Journal of Dermatology. 2017;27(6):661-3.
Salunke A, Belgaumkar V, Chavan R, Dobariya R. Laryngeal involvement with fatal outcome in progressive nodular histiocytosis: A rare case report. Indian dermatology online journal. 2016;7(6):516.
Emile J, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127(22):2672-81.
Ozkaya N, Dogan A, Abdelwahab O. Identification and Targeting of Kinase Alterations in Histiocytic Neoplasms. Hematology-oncology Clinics of North America. 2017;31(4):705-19.
Allen CE, Ladisch S, Mcclain KL. How I treat Langerhans cell histiocytosis. Blood. 2015;126(1):26-35.
Cao X-x, Niu N, Sun J, Zhou D-b, Li J. Efficacy of intermediate-dose cytarabine in central nervous system-relapsed wild-type BRAF Erdheim-Chester disease. Annals of hematology. 2018;97(1):185-7.
Zelger B, Staudacher C, Orchard G, Wilson‐Jones E, Burgdorf W. Solitary and generalized variants of spindle cell xanthogranuloma (progressive nodular histiocytosis). Histopathology. 1995;27(1):11-9.
Lüftl M, Seybold H, Simon jr M, Burgdorf W. Progressive nodular histiocytosis–rare variant of cutaneous non‐Langerhans cell histiocytosis. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2006;4(3):236-8.
Kunimoto K, Uede K, Furukawa F. Progressive nodular histiocytosis. The Journal of dermatology. 2010;37(12):1071-3.
Karimi K, Jadidian A, Glavin FL, Chhatwal H, Adelson RT. Laryngeal involvement in progressive nodular histiocytosis: a case report. Archives of otolaryngology--head & neck surgery. 2010;136(5):513-6.
Amin SM, Christy R, Fraga GR, Beatriz CC, Rachel C, Douglas MG. Progressive nodular histiocytosis with normal karyotypic analysis. Dermatol Online J. 2013;19(6):18577-.
Guidolin L, Noguera‐Morel L, Hernández‐Martín A, Fernández‐Llaca H, Rodríguez‐Peralto JL, Torrelo A. A case with juvenile xanthogranuloma and progressive nodular histiocytosis overlap. Pediatric dermatology. 2017;34(2):e102-e3.

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Effective treatment of progressive nodular histiocytosis by intermediate-dose cytarabine: a case report and literature review

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