Langerhans Cell Histiocytosis

Overview

Definition

Langerhans cell histiocytosis (LCH) is a rare, idiopathic Idiopathic Dermatomyositis neoplastic disorder of dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions (Langerhans cells), which are involved in antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination presentation to T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions.

Epidemiology

• Most common histiocytic disorder
• Estimated incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency:
  • Children (< 15 years of age):
    • 5–8 cases per million per year
    • More common in children 1–3 years of age
  • Adults: 1–2 cases per million per year
• More common in males than in females
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is higher in White populations.
• Heavy smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases increases the risk of single-system pulmonary LCH.

Classification

The Histiocyte Society and WHO both have classifications for histiocyte disorders. 

• Histiocyte Society classification includes both malignant and nonmalignant disorders.
• The WHO classification addresses only malignant disorders.

Histiocyte Society classification

The Histiocyte Society divides the histiocytic disorders into 5 categories based on the following:

• Clinical features
• Histologic features 
• Immunophenotypic features 
• Molecular features

Etiology and Pathophysiology

Etiology

LCH is caused by somatic mutations of genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure regulating the MAPK/ERK signaling pathway, such as: 

• BRAF
• MAP2K1
• RAS RAS Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis
• ARAF

Pathophysiology

• Gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations → activation of the MAPK pathway → clonal expansion Clonal Expansion Seborrheic Keratosis of myeloid precursors
• Dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions proliferate and accumulate because of continuous immune stimulation.
• Abnormally proliferating dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions then infiltrate ≥ 1 organ → clinical manifestations

Clinical Presentation

Sites involved

LCH can present as a single-system or multisystem disorder. 

Single-system LCH:

• Systemic symptoms are often absent. 
• Organs affected can present with unifocal Unifocal Retinoblastoma or multifocal Multifocal Retinoblastoma involvement. 
• Often includes:
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
  • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy
  • Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types
  • CNS
  • Lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy

Multisystem LCH: 

• Involves ≥ 2 organs
• Combination of organs involved varies but can include:
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
  • Hypothalamic– pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types
  • Lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy
  • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy
  • CNS
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
  • Spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy
  • Oral mucosa Oral mucosa Lining of the oral cavity, including mucosa on the gums; the palate; the lip; the cheek; floor of the mouth; and other structures. The mucosa is generally a nonkeratinized stratified squamous epithelium covering muscle, bone, or glands but can show varying degree of keratinization at specific locations. Stomatitis
• In children < 3 years of age, LCH is often a multisystem disease Multisystem disease Mitochondrial Myopathies.

Pulmonary LCH

• Most common histiocytic lung disorder 
• Previously known as eosinophilic granuloma of the lung
• More common in adults
• Associated with smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases (90% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are former or current smokers)
• Constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (e.g., fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery) are seen in 20% of cases.

Nonpulmonary LCH

Signs and symptoms depend on the number and location of involved sites.

Complications

Complications depend on the organ system involved, but may include:

• Pneumothorax Pneumothorax A pneumothorax is a life-threatening condition in which air collects in the pleural space, causing partial or full collapse of the lung. A pneumothorax can be traumatic or spontaneous. Patients present with a sudden onset of sharp chest pain, dyspnea, and diminished breath sounds on exam. Pneumothorax
• Pulmonary vascular disease
• Chronic pulmonary dysfunction 
• Pathologic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures 
• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis 
• Bowel perforation Bowel perforation Perforated viscus or GI perforation represents a condition in which the integrity of the GI wall is lost with subsequent leakage of enteric contents into the peritoneal cavity, resulting in peritonitis. The causes of perforated viscus include trauma, bowel ischemia, infections, or ulcerative conditions, all of which ultimately lead to a full-thickness disruption of the intestinal wall. Perforated Viscus
• GI bleeding
• Secondary malignancies such as acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia
• Blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity (rare)

Diagnosis

Laboratory evaluation

Laboratory studies generally demonstrate findings consistent with the organ systems involved and help rule out other diagnoses (list is not exhaustive):

• General studies:
  • Complete blood count (with differential) → evaluate for bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis involvement:
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
    • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Leukopenia
  • Prothrombin time Prothrombin time Clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen; prothrombin; factor V; factor VII; and factor X. Hemostasis (PT) and activated partial thromboplastin time Partial thromboplastin time The time required for the appearance of fibrin strands following the mixing of plasma with phospholipid platelet substitute (e.g., crude cephalins, soybean phosphatides). It is a test of the intrinsic pathway (factors VIII, IX, XI, and XII) and the common pathway (fibrinogen, prothrombin, factors V and X) of blood coagulation. Hemostasis (aPTT) → coagulopathy (particularly with liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy involvement)
  • Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes → may demonstrate abnormalities related to endocrine disorders
  • Renal function tests → evaluate for renal involvement
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy panel → ↑ with hepatobiliary involvement
• Detailed endocrine evaluation may include:
  • Thyroid-stimulating hormone Thyroid-stimulating hormone A glycoprotein hormone secreted by the adenohypophysis. Thyrotropin stimulates thyroid gland by increasing the iodide transport, synthesis and release of thyroid hormones (thyroxine and triiodothyronine). Thyroid Hormones (TSH), free T4 T4 The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form triiodothyronine which exerts a broad spectrum of stimulatory effects on cell metabolism. Thyroid Hormones
  • Prolactin Prolactin A lactogenic hormone secreted by the adenohypophysis. It is a polypeptide of approximately 23 kd. Besides its major action on lactation, in some species prolactin exerts effects on reproduction, maternal behavior, fat metabolism, immunomodulation and osmoregulation. Breasts: Anatomy and insulin-like growth factor 1 (IGF-1)
  • Serum cortisol Cortisol Glucocorticoids, adrenocorticotropic hormone Adrenocorticotropic hormone An anterior pituitary hormone that stimulates the adrenal cortex and its production of corticosteroids. Acth is a 39-amino acid polypeptide of which the n-terminal 24-amino acid segment is identical in all species and contains the adrenocorticotropic activity. Upon further tissue-specific processing, acth can yield alpha-msh and corticotropin-like intermediate lobe peptide (clip). Adrenal Hormones (ACTH)
  • Serum and urine osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation
  • Follicle-stimulating hormone ( FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle) and luteinizing hormone ( LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle)
  • Testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens (men)
  • Estradiol Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Noncontraceptive Estrogen and Progestins (women)

Imaging and additional ancillary studies

• Baseline radiography on initial presentation:
  • Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests → initial imaging for pulmonary symptoms:
    • Ill-defined or stellate nodules
    • Diffuse bilateral reticulonodular pattern (mid and upper zones)
    • Upper zone cysts Cysts Any fluid-filled closed cavity or sac that is lined by an epithelium. Cysts can be of normal, abnormal, non-neoplastic, or neoplastic tissues. Fibrocystic Change or honeycombing
    • Preserved lung volume
    • Sparing of the costophrenic angle 
  • X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests of the involved bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types/joint: Lesions are typically osteolytic (“punched out” appearance).
• Full-body fluorodeoxyglucose (FDG) PET-CT scan:
  • LCH is FDG-avid, thus PET-CT detects organ involvement.
  • Superior to radiography, CT, or MRI in detecting LCH bone lesions Bone Lesions Multiple Myeloma
  • Performed in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship ≥ 2 years of age
  • Recommended for staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis
• Other studies depend on the sites of involvement:
  • MRI brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification with gadolinium Gadolinium An element of the rare earth family of metals. It has the atomic symbol gd, atomic number 64, and atomic weight 157. 25. Its oxide is used in the control rods of some nuclear reactors. Magnetic Resonance Imaging (MRI) contrast:
    • For CNS involvement
    • Detects cranial mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast lesions
    • Useful in evaluating the pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types gland
  • CT:
    • Can evaluate GI, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy, mediastinal, and pulmonary involvement Pulmonary involvement Coccidioides/Coccidioidomycosis
    • In pulmonary LCH, reticulonodular opacities and cysts Cysts Any fluid-filled closed cavity or sac that is lined by an epithelium. Cysts can be of normal, abnormal, non-neoplastic, or neoplastic tissues. Fibrocystic Change are seen (mid and upper zones).
  • Pulmonary function tests:
    • Assess pulmonary involvement Pulmonary involvement Coccidioides/Coccidioidomycosis
    • May be normal with early disease
    • May show reduced diffusing capacity with obstructive, restrictive, or mixed abnormalities
  • Ultrasonography: can be used in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy/ thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy evaluation

Pathology

• Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis examination (especially with an abnormal CBC)
• Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma of lesion/ tumor Tumor Inflammation recommended in all cases:
  • Examples:
    • Osteolytic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types lesion 
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesion 
    • Bronchoalveolar lavage Bronchoalveolar lavage Washing out of the lungs with saline or mucolytic agents for diagnostic or therapeutic purposes. It is very useful in the diagnosis of diffuse pulmonary infiltrates in immunosuppressed patients. Pulmonary Fibrosis
    • Lung biopsy Lung Biopsy Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis
  • Histopathologic features vary depending on the site of biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, with tissue showing:
    • Langerhans cells (folded or grooved nuclei, with moderately abundant cytoplasm)
    • Surrounding inflammatory cells (e.g., eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation)
    • Varying degrees of fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans 
    • Cytologic atypia Atypia Fibrocystic Change in neoplastic cells
  • Immunohistochemistry Immunohistochemistry Histochemical localization of immunoreactive substances using labeled antibodies as reagents. Myeloperoxidase Deficiency → may be positive for:
    • CD1a
    • CD207 (langerin)
    • S100 S100 A family of highly acidic calcium-binding proteins found in large concentration in the brain and believed to be glial in origin. They are also found in other organs in the body. They have in common the ef-hand motif (ef hand motifs) found on a number of calcium binding proteins. The name of this family derives from the property of being soluble in a 100% saturated ammonium sulfate solution. Acoustic Neuroma
  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
    • BRAF V600E mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations testing (positive in > 50%)
    • Consider next-generation sequencing for MAPK-ERK signaling pathway

Management and Prognosis

The choice in management for LCH is based on the type of LCH, clinical presentation, organs involved, extent of involvement, and organ function. Treatment is usually guided by an oncologist (and potentially other specialists).

Management of pulmonary LCH

• Supportive management:
  • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases cessation
  • Regular Regular Insulin assessment of pulmonary function
  • Inhaled bronchodilators Bronchodilators Asthma Drugs and/or glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids for reversible airflow limitation
  • Pulmonary rehabilitation in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with exertional dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Seasonal influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza and pneumococcal vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination
• Mildly symptomatic/impaired pulmonary function: observation
• Symptomatic/progressive pulmonary LCH:
  • Systemic glucocorticoids Systemic Glucocorticoids Glucocorticoids
  • Chemotherapy Chemotherapy Osteosarcoma options:
    • Cladribine Cladribine An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia. Antimetabolite Chemotherapy
    • Cytarabine Cytarabine A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the s phase of the cell cycle. It also has antiviral and immunosuppressant properties. Antimetabolite Chemotherapy

Management of nonpulmonary LCH

Approach:

• Factors affecting management:
  • CNS involvement 
  • Other organs involved
  • Single or multisystem disease Multisystem disease Mitochondrial Myopathies
  • Unifocal Unifocal Retinoblastoma or multifocal Multifocal Retinoblastoma involvement 
  • Presence and degree of symptoms
• General principles:
  • Unifocal Unifocal Retinoblastoma, single system without critical organ (CNS, heart, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy, bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis) involvement:
    • Local therapy
    • Observation
  • Multifocal Multifocal Retinoblastoma, multisystem, or unifocal Unifocal Retinoblastoma with critical organ involvement:
    • Systemic therapy
    • If asymptomatic or without organ dysfunction, may consider observation.

Multisystem involvement in children: 

• Vinblastine Vinblastine Antitumor alkaloid isolated from vinca rosea. Microtubule and Topoisomerase Inhibitors
• Prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants

Multisystem involvement in adults: 

• Chemotherapy Chemotherapy Osteosarcoma options:
  • Cytarabine Cytarabine A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the s phase of the cell cycle. It also has antiviral and immunosuppressant properties. Antimetabolite Chemotherapy
  • Cladribine Cladribine An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia. Antimetabolite Chemotherapy
• Targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted and Other Nontraditional Antineoplastic Therapy for known gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations:
  • BRAF inhibitors (e.g., vemurafenib Vemurafenib An indole sulfonamide compound and inhibitor of BRAF kinases that is used for the treatment of unresectable or metastatic melanoma. Targeted and Other Nontraditional Antineoplastic Therapy or dabrafenib DaBRAFenib Targeted and Other Nontraditional Antineoplastic Therapy)
  • MEK inhibitors (e.g., cobimetinib Cobimetinib Targeted and Other Nontraditional Antineoplastic Therapy)

Single-system involvement:

• Single bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types lesion (non-CNS risk):
  • Curettage Curettage A scraping, usually of the interior of a cavity or tract, for removal of new growth or other abnormal tissue, or to obtain material for tissue diagnosis. It is performed with a curet (curette), a spoon-shaped instrument designed for that purpose. Benign Bone Tumors
  • Radiotherapy:
    • For a recurrent or persistent lesion
    • Not used in children 
  • Bisphosphonate therapy may reduce pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways.
• Multiple bone lesions Bone Lesions Multiple Myeloma:
  • Systemic therapy ( chemotherapy Chemotherapy Osteosarcoma and targeted therapies similar to those used for multisystem involvement)
  • Adjunctive treatments:
    • Surgery
    • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy
• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions:
  • Skin-only LCH may spontaneously regress or progress to multisystem LCH. 
  • Asymptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship: observation
  • Symptomatic or with extensive skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions involvement:
    • Topical steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors or nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle mustard 
    • Methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy, which may be combined with other immunosuppressive agents (e.g., prednisolone Prednisolone A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. Immunosuppressants, 6-mercaptopurine 6-Mercaptopurine An antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia. Antimetabolite Chemotherapy, hydroxyurea Hydroxyurea An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. Antimetabolite Chemotherapy)
    • Lenalidomide Lenalidomide Has immunomodulatory (↓ tumor necrosis factor-⍺, ↑ natural killer cells and IL-2) and antiangiogenic activity. Induces cell-cycle arrest and death → inhibiting tumor cell growth. Cancer Immunotherapy 
    • Thalidomide Thalidomide A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppressive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. Immunosuppressants

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• The clinical course and prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with LCH are variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables:
  • Associated with good prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas:
    • Unifocal Unifocal Retinoblastoma disease or single-system disease
    • Single node involvement or isolated skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions disease
    • Absence of lesions 1 year into follow-up 
    • Pulmonary LCH (without smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases)
  • Associated with worse prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas:
    • Multifocal Multifocal Retinoblastoma disease or high-risk patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 
    • LCH with BRAF mutations (higher chance of relapse Relapse Relapsing Fever) 
    • High-risk organ involvement (e.g., CNS, bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy)
• Chronic focal LCH may progress to multifocal Multifocal Retinoblastoma or disseminated disease.

Differential Diagnosis

• Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma: a malignancy Malignancy Hemothorax wherein plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cells proliferate abnormally in the bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis, causing displacement Displacement The process by which an emotional or behavioral response that is appropriate for one situation appears in another situation for which it is inappropriate. Defense Mechanisms of hematopoietic cell lines. The clinical presentation can include bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, pathologic fractures, and signs of renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome. Osteolytic bone lesions Bone Lesions Multiple Myeloma can be seen on imaging. Distinguishing diagnostic features are serum and urine monoclonal protein, histology (e.g., plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cells with abundant basophilic cytoplasm), and immunophenotype. Management includes corticosteroids Corticosteroids Chorioretinitis, chemotherapy Chemotherapy Osteosarcoma, and/or immunomodulating agents. 
• Erdheim-Chester disease (ECD): often an adult illness, ECD is a multisystem histiocytic disorder. Xanthogranulomatous Xanthogranulomatous A chronic inflammatory condition of the kidney resulting in diffuse renal destruction, a grossly enlarged and nonfunctioning kidney associated with nephrolithiasis and kidney stones. Pyelonephritis and Perinephric Abscess infiltrates affect ≥ 1 organ system (e.g., skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, lung, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types, cerebral, pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types, retroperitoneum, cardiovascular system). Osteosclerosis Osteosclerosis An abnormal hardening or increased density of bone tissue. Paget’s Disease of Bone in long bones Long bones Length greater than width. Bones: Structure and Types is seen, and the diagnosis is confirmed by pathologic features, such as foamy histiocytes Histiocytes Macrophages found in the tissues, as opposed to those found in the blood (monocytes) or serous cavities (serous membrane). Chronic Granulomatous Disease and Touton giant cells Giant cells Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In aids, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. Giant Cell Arteritis (multinucleated histiocytes Histiocytes Macrophages found in the tissues, as opposed to those found in the blood (monocytes) or serous cavities (serous membrane). Chronic Granulomatous Disease) in a background of fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans (CD1a is not expressed). 
• Langerhans cell sarcoma: a high-grade neoplasm that presents with single-organ or multisystem involvement. Clinical presentation is similar to that for LCH but can be distinguished by cytologic analysis. Langerhans cell sarcoma is characterized by malignant cytology (cellular atypia Atypia Fibrocystic Change and atypical mitoses). 
• Juvenile xanthogranuloma: most common form of non-LCH. Juvenile xanthogranuloma predominantly affects children and clinically presents with solitary or multiple cutaneous lesions. Dermoscopy Dermoscopy A noninvasive technique that enables direct microscopic examination of the surface and architecture of the skin. Seborrheic Keratosis aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS in the diagnosis. The condition may resolve spontaneously or may require curative skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions excisions. 
• Rosai-Dorfman disease: abnormal proliferation and accumulation of histiocytes Histiocytes Macrophages found in the tissues, as opposed to those found in the blood (monocytes) or serous cavities (serous membrane). Chronic Granulomatous Disease in the lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy, with rare occurrence of extranodal involvement. Individuals may present with (cervical) lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, pallor, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, malaise Malaise Tick-borne Encephalitis Virus, and chronic rhinitis Rhinitis Inflammation of the nasal mucosa, the mucous membrane lining the nasal cavities. Rhinitis. Diagnosis involves examination of histopathology (negative for CD1a and CD207). Spontaneous remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches may occur. Treatments include supportive therapy, administration of steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors or alfa-interferon, or chemotherapy Chemotherapy Osteosarcoma.