Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2012056
Category:	Radiology
Initiated:	August 2012
Last Review:	November 2023

PET or PET/CT for Histiocytic Neoplasms (eg Pulmonary Langerhans Cell Histiocytosis)

Description:

Histiocytic neoplasms are rare neoplasms (annual incidence of < 5 cases per million population) originating from myeloid progenitor cells from the bone marrow. Clinical overlap is observed among the three most commonly seen disorders: Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD). These neoplasms may present clinically as focal or diffuse multiple organ disease, with the disease spectrum varying from incidental lesions on imaging studies to critical illness arising from severe organ dysfunction. Common sites of involvement include the axial/appendicular skeleton and skull, hypothalamus/pituitary gland, lungs, skin, heart, kidneys/retroperitoneum and less commonly arterial blood vessels, spleen, and liver.

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder most commonly characterized by single or multiple osteolytic bone lesions demonstrating infiltration with histiocytes having bean-shaped nuclei on biopsy. These histiocytes, along with lymphocytes, macrophages, and eosinophils may infiltrate nearly every organ (most notably the skin, lymph nodes, lungs, thymus, liver, spleen, bone marrow, or central nervous system with the exception of the heart and kidneys).

Pulmonary Langerhans cell histiocytosis (previously known as Histiocytosis X or eosinophilic granuloma of the lung) is an inflammatory lung disease involving the small airway and interstitium of the lung, strongly associated with cigarette smoking and an increased risk of malignant neoplasms. PLCH belongs to the spectrum of Langerhans cell histiocytosis diseases that are characterized by uncontrolled proliferation and infiltration of various organs by Langerhans cells.

The usual radiographic findings in PLCH include the presence of nodules and cysts predominantly in the upper lung zones with sparing of the lung bases. The lung nodules may be mistaken for malignancy. Other pulmonary findings include mediastinal adenopathy, solitary pulmonary nodule, consolidative opacities, and pleural effusions.

Biopsy of pulmonary lesions is the standard approach to diagnosis, and PET/PET-CT is not commonly performed in patients with PLCH because 1) it is not definitive in diagnosing or excluding PLCH; 2) older lesions may not have uptake of the radioisotope; 3) other inflammatory and malignant diseases may demonstrate uptake of 2-3 FDG; 4) patients with predominantly cystic disease often show no uptake of 2-3 FDG; and p5) patients with small isolated florid granulomas may not demonstrate radioisotope uptake due to small size.

The major value of PET/PET-CT following histologic diagnosis of PLCH is for possible demonstration of activity in other organs, which may be helpful in management of the patient’s disease.

Definitions

Screening – testing in the absence of an established or clinically suspected diagnosis

Diagnosis - testing based on a reasonable clinical suspicion of a particular condition or disorder

Diagnostic Workup – initial staging of documented malignancy

Management – testing to direct therapy of an established condition, which may include preoperative or postoperative imaging, or imaging performed to evaluate the response to nonsurgical intervention. In oncologic imaging, management applies to patients with measurable disease and to imaging performed before or after planned treatment intervention, therapy response, restaging or clinically suspected recurrence.

Surveillance – periodic assessment following completion of therapy. In oncologic imaging, surveillance applies to asymptomatic patients in remission and/or without measurable disease

Cannot be performed or is nondiagnostic – applies when the test:

Is positive or indeterminate for clinically significant pathology when the information provided about the abnormality by the test is not sufficient to direct subsequent management
Is negative when the negative likelihood ratio of the test is both insufficient to confidently exclude the absence of suspected disease and unable to direct subsequent management. This typically applies in scenarios with moderate to high clinical pretest probability with negative testing or low pretest probability with clear evidence for net benefit
Has been previously nondiagnostic because of a persistent clinical factor (e.g., body habitus, immobility) that is very likely to make retesting nondiagnostic as well Cannot be performed due to a medical contraindication (e.g., contrast nephrotoxicity, allergy, or in highly radiation sensitive populations such as pediatrics and pregnancy) or reasonable unavailability related to lack of local expertise or service availability

Standard or conventional imaging: Refers to imaging that does not require a PET/CT. Depending on the clinical scenario and individual patient circumstances, this may include computed tomography, magnetic resonance imaging, ultrasound and/or scintigraphy.

Policy/
Coverage:

Effective April 09, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

FDG-PET/CT for Langerhans Cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD) meets primary coverage criteria and is covered for:

Diagnostic Workup:

Indicated in EITHER of the following scenarios:

Patients with LCH and high-risk bone lesions and/or suspected multisystem disease; or
Patients with ECD or RDD

Management:

Indicated for ANY of the following scenarios:

Following radiation therapy
Treatment response after 2-3 cycles of systemic therapy and at completion
Treatment response of ECD
After completion of surgical curettage

Surveillance:

Indicated for EITHER of the following scenarios:

LCH: every 3-6 months for first 2 years following treatment completion, then annually; or
ECD/RDD: every 3-6 months after starting therapy until stabilization of disease

For all fully insured contracts, all self-funded church-sponsored health plans and all self-funded government-sponsored health plans other than the Arkansas State and Public School Employees program, the Federal Employee Health Benefit Program and Medicare Advantage plans, as required by Act 583 of the Arkansas Legislature, please see ABCBS policy 2021004, Surveillance and Other PET Oncologic Applications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

PET/CT for Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD) does not meet member certificate of benefit Primary Coverage Criteria for effectiveness and is not covered for any indication or any circumstance other than those listed above.

For members with contracts without primary coverage criteria, PET/CT for Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD) is considered investigational and is not covered for any indication or any circumstance other than those listed above. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective March 13, 2022 to April 08, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

FDG-PET/CT for Langerhans Cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD) meets primary coverage criteria and is covered for:

Diagnostic Workup:

Indicated in EITHER of the following scenarios:

Patients with LCH and high-risk bone lesions and/or suspected multisystem disease
Patients with ECD or RDD

Management:

Indicated for ANY of the following scenarios:

Following radiation therapy
Treatment response after 2-3 cycles of systemic therapy and at completion
Treatment response of ECD
After completion of surgical curettage

Surveillance:

(As clinically) indicated

For all fully insured contracts, all self-funded church-sponsored health plans and all self-funded government-sponsored health plans other than the Arkansas State and Public School Employees program, the Federal Employee Health Benefit Program and Medicare Advantage plans, as required by Act 583 of the Arkansas Legislature, please see ABCBS policy 2021004, Surveillance and Other PET Oncologic Applications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

For members with contracts without primary coverage criteria, PET/CT is considered investigational and is not covered for any other indication not specifically listed as covered. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Note: Standard or conventional imaging: Refers to imaging that does not require a PET/CT. Depending on the clinical scenario and individual patient circumstances, this may include computed tomography, magnetic resonance imaging, ultrasound and/or scintigraphy.

Effective Prior to March 13, 2022

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

PET or PET/CT for initial staging of patients with biopsy confirmed pulmonary Langerhans Cell histiocytosis meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

PET or PET/CT for re-staging, surveillance, or monitoring does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, PET or PET/CT for re-staging, surveillance, or monitoring is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Literature Review:

Brauner MW, Grenier P, Mouelhi MM, Mompoint D, Lenoir S. (1989)

Eighteen patients with pulmonary lesions of histiocytosis X were studied with high-resolution computed tomography (CT). Thin-walled cysts were found in all but one patient. The other abnormalities included nodules (n = 14), cavitated nodules (n = 3), thick-walled cysts (n = 7), reticulation (n = 4), ground-glass opacities (n = 4), and irregular interfaces (n = 4). The lesions were most often diffuse (n = 16), with a topographic predominance in the upper or middle lung zones in nine patients. Comparison of CT scans and chest radiographs shows that small and large cysts and micronodules are better detected with CT. Comparison of abnormalities found in patients in the early and late stages of the disease, as well as the evolution observed in one case, suggests that CT patterns progress from nodules to cavitated nodules and thick-walled cysts to cysts to confluent cysts.

Brauner MW, Grenier P, Tijani K, Battesti JP, Valeyre D. (1997)

The purpose of the study was to document the evolution of pulmonary lesions of Langerhans cell histiocytosis (LCH) with sequential computed tomography (CT).

Initial and final CT scans of 21 patients with LCH and CT evidence of pulmonary disease were compared retrospectively. Histologic confirmation of pulmonary involvement was available in 11 patients.

Results: On initial CT images, a nodular pattern (n = 14) was seen more frequently than a cystic pattern (n = 7). On final CT images, a cystic pattern (n = 14) was seen more often than a nodular one (n = 6). There was complete resolution of parenchymal abnormality in one case. Nodular opacities, thick-walled cysts, and ground-glass opacities underwent regression. Thin-walled cysts, linear opacities, and emphysematous lesions remained unchanged or progressed.

The authors concluded that pulmonary CT allows good assessment of the evolution of LCH lesions. Nodular lesions probably represent active disease and often undergo regression or transform into cysts.

Khoor A, Myers JL, Tazelaar HD, Swensen SJ. (2001)

Solitary pulmonary nodules are an uncommon manifestation of pulmonary Langerhans cell histiocytosis (PLCH). We describe a 45-year-old male cigarette smoker who presented with an asymptomatic solitary pulmonary nodule that showed histologic and immunophenotypic characteristics of PLCH. Twenty-one years after excision of the nodule, at the age of 66 years, he is asymptomatic with a new contralateral lung nodule but no evidence of interstitial disease. The new nodule has remained unchanged after 36 months of observation. This case affirms that PLCH can occasionally cause solitary lesions, which should not be interpreted as a harbinger of interstitial lung disease. Isolated PLCH should be included in the differential diagnosis of unusual solitary pulmonary nodules.

Howarth DM, Gilchrist GS, Mullan BP, et al. (1999)

The objective of this descriptive analysis of a large cohort of patients with Langerhans cell histiocytosis (LCH) was to add to the understanding of the natural history, management, and outcome of this disease.

Three hundred fourteen Mayo Clinic patients (age range 2 months to 83 years) with histologically proven LCH were categorized into those patients with multisystem disease and those patients with single system disease. Clinical features, treatment, and outcome were determined from the case history notes and tumor registry correspondence. Treatment included chemotherapy, radiotherapy, and surgical excision. The end points were disease free survival, active disease, or death. The median time of follow-up was 4 years. Of the 314 patients, there were 28 deaths. Multisystemic LCH was found in 96 patients, 25 of whom had continuing active disease after treatment. Isolated bone LCH lesions were observed in 114 of the 314 patients, 111 of whom (97%) achieved disease free survival after treatment. The most common sites of osseous LCH were the skull and proximal femur. Of the 87 patients with isolated pulmonary involvement, only 3 were nonsmokers.

The authors concluded that patients with isolated bone LCH lesions have the best prognosis compared with patients with LCH involvement of other systems. By contrast, 20% of patients with multisystem involvement have a progressive disease course despite treatment. The identification of prognostic indicators to facilitate appropriate treatment and long term follow-up surveillance is recommended.

2013 Update:

A review of literature on PubMed through July 2013 was performed. There were no published

articles identified that would prompt a change in the coverage statement. Studies published included small numbers of patients.

Lee HJ, Ahn BC, Lee SW, Lee J.

Lee and colleagues (2012) published the results of a retrospective review of 12 patients who were diagnosed with LCH. The aim of the study was to evaluate the clinical usefulness of F-18 FDG PET/CT in LCH patients. Two patients underwent F-18 FDG PET/CT before and after therapy, 6 patients underwent only before therapy and 4 patients underwent only after therapy.

Results: Nine (75.0%) and 3 patients (25.0%) had single-system (single site and multiple sites) and multisystem involvements, respectively. Pretreatment SUV(max) of patients with multisystem or multiple site involvement of a single-system was significantly higher than that of patients with single site involvement of a single-system (3.29 ± 2.52 vs. 1.63 ± 0.52, p = 0.025). One patient showed multisystem risk organs (lung and bone marrow) involvement. In 2 patients, F-18 FDG PET/CT detected additional active LCH lesions not identified on conventional imaging modalities. In follow-up F-18 FDG PET/CT scans, complete resolution was identified in 2 patients and reactivation in another 2 patients.

These results suggest that F-18 FDG PET/CT is useful for identification of active lesions, stratification of disease stages, monitoring of therapeutic response, and detection of reactivation in LCH patients.

Krajicek BJ, Ryu JH, Hartman TE, Lowe VJ, Vassallo R.

Krajicek and colleagues identified 11 patients with PLCH who underwent PET scanning over a 6-year period from July 2001 to June 2007. The presenting clinicoradiologic features including PET scan and chest CT scan findings were analyzed.

Five of 11 patients had positive PET scan findings. Of the five PET scan-positive patients, 4 (80%) were women, 4 (80%) were current smokers, and the median age was 45 years. PET scan-positive findings were more likely to be present if the scan was performed early in the clinical course. Three PET scan-positive patients (60%) had multiorgan involvement. PET scan-positive patients had predominantly nodular inflammatory lung disease (> 100 nodules) with most nodules measuring < 8 mm, whereas all PET scan-negative patients had predominantly cystic lung disease with fewer nodules (< 25 nodules). Notable abnormal PET scan findings included foci of increased uptake in nodular lung lesions, thick-walled cysts, bone, and liver lesions.

The authors concluded that PLCH may be associated with abnormal thoracic and extrathoracic PET scan results. Patients with nodular disease seen on chest CT scans appear more likely to have abnormal PET scan findings. The results of the study suggest that PET scan imaging cannot reliably distinguish between the benign inflammatory nodular lesions of PLCH and malignant lesions.

A search of clinicaltrials.gov was performed with no studies identified re: PET and PLCH.

2014 Update

A search of the MEDLINE database was conducted through July 2014. There were no new randomized controlled trials identified that would prompt a change in the coverage statement.

2015 Update

A literature search conducted using the MEDLINE database through July 2015 did not reveal any new information to prompt a change in the coverage statement.

2016 Update

A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement.

2018 Update

Annual policy review completed with a literature search using the MEDLINE database through February 2018. No new literature was identified that would prompt a change in the coverage statement.

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through February 2019. No new literature was identified that would prompt a change in the coverage statement.

2020 Update

A literature search was conducted through February 2020. There was no new information identified that would prompt a change in the coverage statement.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement.

November 2021 Update

A literature review was performed through September 2021. Following is a summary of the key literature to date.

DIAGNOSTIC WORKUP

A presumptive diagnosis (without tissue diagnosis) is typically made with characteristic radiographic/clinical findings (e.g., typical pattern of lung nodules, cysts, and cavitated nodules on high-resolution Chest CT), but definitive diagnosis requires tissue examination and immunohistochemistry stains. Because neoplastic cells are often sparsely distributed amongst fibrosis and inflammatory cells, biopsy and histologic evaluation can be challenging. Whole-body PET/CT is recommended by several guidelines (including the National Comprehensive Cancer Network, NCCN) as part of the workup/evaluation of histiocytic neoplasms, to assess both presence and extent of disease (1).

MANAGEMENT

NCCN recommends PET/CT as the preferred modality for treatment response assessment, including post radiation therapy, systemic therapy, and completion of surgical curettage.

SURVEILLANCE

Guidelines are in concordance with the National Comprehensive Cancer Network (NCCN) Guidelines for Histiocytic Neoplasms.

Current References

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Histiocytic Neoplasms (Version 1.2021). Available at http://www.nccn.org. ©National Comprehensive Cancer Network, 2021.
Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, Requena-Caballero L, Jordan MB, Abdel-Wahab O, Allen CE, Charlotte F, Diamond EL, Egeler RM, Fischer A, Herrera JG, Henter JI, Janku F, Merad M, Picarsic J, Rodriguez-Galindo C, Rollins BJ, Tazi A, Vassallo R, Weiss LM; Histiocyte Society. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016 Jun 2;127(22):2672-81. doi: 10.1182/blood-2016-01-690636. Epub 2016 Mar 10. PMID: 26966089; PMCID: PMC5161007.

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through September 2022.

NCCN Guidelines for Histiocytic Neoplasms (Version 1.2022) were reviewed. The guidelines include frequency and duration interval recommendations for surveillance imaging post initiation of therapy.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

78811	Positron emission tomography (PET) imaging; limited area (eg, chest, head/neck)
78812	Positron emission tomography (PET) imaging; skull base to mid thigh
78813	Positron emission tomography (PET) imaging; whole body
78814	Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; limited area (eg, chest, head/neck)
78815	Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; skull base to mid thigh
78816	Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; whole body

References:

Brambilla E, Fontaine E, Pison CM, et al.(1990) Pulmonary histiocytosis X with mediastinal lymph node involvement. Am Rev Respir Dis, 1990; 142:1216-1218.

Brauner MW, Grenier P, Monelhi MM, et al.(1989) Pulmonary histiocytosis X: evaluation with high-resolution CT. Radiology, 1989; 172:255-258.

Brauner MW, Grenier P, Tijani K, et al.(1997) Pulmonary Langerhans cell histiocytosis: evolution of lesions on CT scans. Radiology. 1997 Aug;204(2):497-502.

Fichtenbaum CJ, Kleinman GM, Haddad RG.(1990) Eosinophilic granuloma of the lung presenting as a solitary pulmonary nodule. Thorax, 1990; 45:905-906.

Howarth DM, Gilchrist GS, Mullan BP, et al.(1999) Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer, 1999; 85:2278-2290.

Khoor A, Myers JL, Tazelaar HD, et al.(2001) Pulmonary Langerhans cell histiocytosis presenting as a solitary nodule. Mayo Clin Proc, 2001; 76:209-211.

Krajicek BJ, Ryu JH, Hartman TE, et al.(2009) Abnormal fluorodeoxyglucose PET in pulmonary Langerhans Cell Histiocytosis. Chest, 2009; 135:1542-1549.

Lee HJ, Ahn BC, Lee SW, Lee J.(2012) The usefulness of F-18 fluorodeoxyglucose positron emission tomography/computed tomography in patients with Langerhans cell histiocytosis. Ann Nucl Med. 2012 Nov;26(9):730-7.

Nagaoka S, Maruyama R, Koike M, et al.(1996) Cytology of Langerhans cell histiocytosis in effusions: a case report. Acta Cyto, 1996; 40:563-566.

National Comprehensive Cancer Network(2022) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Histiocytic Neoplasms (Version 1.2022). Available at http://www.nccn.org. ©National Comprehensive Cancer Network, 2022.

Szturz P, Rehák Z, Koukalová R, et al.(2012) Measuring diffuse metabolic activity on FDG-PET/CT: new method for evaluating Langerhans cell histiocytosis activity in pulmonary parenchyma. Nucl Med Biol. 2012 Apr;39(3):429-36.

Thomashefski JF, Khiyami A, Kleinerman J.(1991) Neoplasms associated with pulmonary eosinophilic granuloma. Arch Pathol Lab Med, 1991; 115:449-506.

Tittel PW, Winkler CF.(1981) Chronic recurrent pleural effusion in adult histiocytosis-X. Br J Radiol, 1981; 54:68-69.

Vassalo R, Ryu JH, Colby TV, et al.(2000) Pulmonary Langerhans cell histiocytosis. N Engl J Med, 2000; 342:1969-1978.

Vassalo R, Ryu JH, Schroeder DR, et al.(2002) Clinical outcomes of pulmonary Langerhans-cell histiocytosis in adults. N Engl J Med, 2002; 340L484-490.

Weber WN, Margolin FR, Nielsen SL.(1969) Pulmonary histiocytosis X: a review of 18 patients with reports of 6 cases. Am J Roentgenol Radium Ther Nucl Med, 1969; 107:280-289.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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