Histiocytosis

Question 1

List the L group histiocytoses?

Answer 1

1. Langerhan cell histiocytosis
2. Congential self healing LCH
3. Indeterminate cell histiocytosis
4. Erdheim Chester disease

Question 2

Langerhan cell immunostains?

Answer 2

CD1a
CD207 (langerin)

Question 3

What are birbeck granules?

Answer 3

Rod or raquet shaped cytoplasmic organelles seen on electron microscopy; they are pathognomonic for LCH, confirming the Langerhans cell lineage

Question 4

Describe the typical histopathologic features observed in LCH?

Answer 4

Histiocytes in ther dermis,
with some epidermotropism,

Kidney bean shaped nuclei (reniform), lymphocytes,
eosinophils

Immunostains positive for:
- S100
- CD1a
- CD207 (langerin)
- CD68

Question 5

What mutation is common in LCH?

Answer 5

BRAF V600E

somatic BRAF V600E mutation leading to activation of the MAPK/ERK signal

Question 6

What diseases are ass. with LCH?

Answer 6

1. Diabetes Insipidus
2. Haematological malginancy - AML, ALL, CML, Lymphoma
3. Solid organ malignancies (normally secondary to treatment)

Diabetes insipidus, especially when there is involvement of the cranial

Question 7

What are the subtypes of LCH?

Answer 7

Acute
Chronic
Localised
Congenital self healing LCH

Question 8

Explain the role of the mitogen–activated protein kinase (MAPK) pathway in the pathophysiology of LCH.

Answer 8

Activation of the MAPK pathway (often by BRAF V600E or other mutations) leads to **uncontrolled proliferation and survival of Langerhans cells, **which results in the neoplastic behavior seen in LCH.

Question 9

What are the “risk organs” in LCH? and the significance of these?

Answer 9

Haemapoetic system
Liver
Lungs
Spleen

indicates a higher risk of morbidity and mortality

Question 10

How is acute LCH different from chronic?

Answer 10

Acute: Age 0 - 2 years, 1-2 mm papules, pustules or vesicles in the scalp, flexural areas and trunk. Ass with visceral and bone lesions.

Chronic: 2 - 6 years, DI, exopthalmus and bone lesions with 30% having mucocutaneous lesions

Question 11

What is congential self healing langerhans cell histiocytosis?

Answer 11

Present at birth or first few days of life

Vesicles, pustules, red- brown papular crusted lesions with central necrosis

Ususally bengin

Question 12

What is juvenile xanthogranuloma?

Answer 12

The most common histiocytosis

Class C = non-langerhan cell

Question 13

Associations with juvenile xanthogranumola?

Answer 13

NF1 (and cafe au lait macules)

juvenile AML

Question 14

Dx

Answer 14

Juvenile xanthogranuloma

Question 15

Description?

Answer 15

Touton giant cells
Pink cytoplasms
Foamy ring

= JXG

Question 16

Answer 16

HIstiocytotoid cells
Pale cytoplasm
eosinophils

Question 17

Answer 17

Busy - Papillary dermis and epidermal invovlement

Question 18

Describe DDx

Answer 18

Yellow pink, smooth, plaques on medial cheek

DDx: Necrobiotic xanthogramuloma, systemic amyloidosis, Xanthomas, other histiocytoses, sarcoidosis

Question 19

What is erdheim chester disease

Answer 19

Severe from of histiocytosis

Gain of function mutation in BRAF V600E

Characterised by:
- Cutaneous lesions (25%)
= bilateral symmetrical periocular xanthelasma like lesions, yellow - brown nodules can also occur on the trunk / extremities

• Symmetrical diaphyseal and metaphyseal osteosclerosis of the long bones
• Periaortic and retroperitoneal and perirenal fibrosis

Question 20

What is the hallmark histologic feature of Rosai-Dorfman disease (RDD)?

Answer 20

Emperipolesis (intact lymphocytes or plasma cells within histiocytes)
Explanation: Emperipolesis is the pathognomonic feature seen on histology in RDD.

Question 21

What is the immunohistochemical profile of histiocytes in RDD?

Answer 21

S100+, CD68+, CD1a–
Explanation: RDD histiocytes are S100 and CD68 positive, but unlike LCH, they are CD1a negative.

Question 22

What clinical feature most commonly presents in Rosai-Dorfman disease?

Answer 22

Massive painless bilateral cervical lymphadenopathy
Explanation: This is the classic presentation, often in children and young adults.

Question 23

True or False: Rosai-Dorfman disease is a malignant condition requiring chemotherapy.

Answer 23

False
Explanation: RDD is a benign, self-limited condition in many cases. Systemic therapy is reserved for severe or organ-threatening disease.

Question 24

Which gene mutations have been identified in a subset of RDD cases, supporting a clonal origin?

Answer 24

KRAS, NRAS, MAP2K1 mutations
Explanation: These mutations suggest that at least some RDD cases may be clonal and neoplastic.

Question 25

Name two extranodal sites commonly involved in Rosai-Dorfman disease.

Answer 25

Skin and nasal cavity (others include orbit, bone, CNS) Explanation: RDD frequently involves extranodal sites, especially in cutaneous or disseminated disease.

Question 26

What syndrome may overlap clinically and histologically with RDD and shares S100+ histiocytes?

Answer 26

Erdheim-Chester Disease (ECD) Explanation: ECD and RDD can both involve S100+ histiocytes and systemic manifestations, but differ in IHC and clinical course.

Question 27

Which laboratory abnormality is frequently seen in Rosai-Dorfman disease?

Answer 27

Polyclonal hypergammaglobulinemia Explanation: Elevated immunoglobulin levels are common, reflecting immune dysregulation.

Question 28

Which of the following features best distinguishes JXG from Langerhans Cell Histiocytosis on immunohistochemistry?

Answer 28

Langerin negativity Explanation: JXG is Langerin-negative, while LCH is Langerin-positive. Both may be CD68-positive, but Langerin is specific to LCH.

Question 29

True or False: Most cases of JXG require treatment with systemic corticosteroids.

Answer 29

False Explanation: Most JXG lesions resolve spontaneously without treatment. Systemic therapy is reserved for systemic or ocular disease.

Question 30

What is the most characteristic giant cell seen in JXG histology?

Answer 30

Touton giant cell Explanation: These have a ring of nuclei surrounded by lipid-rich cytoplasm—hallmark of JXG.

Question 31

Which of the following patient groups is most at risk for ocular involvement in JXG? A. Adolescents with a single lesion B. Adults with multiple nodules C. Infants with solitary scalp nodules D. Infants with multiple cutaneous lesions

Answer 31

D. Infants with multiple cutaneous lesions Explanation: Infants with multiple JXG lesions are at highest risk for ocular involvement and should be screened.

Question 32

What hematologic malignancy has a known association with multiple JXG lesions, especially in the context of NF1?

Answer 32

Juvenile Myelomonocytic Leukemia (JMML) Explanation: This association is especially noted in patients with NF1 and multiple JXG lesions.

Question 33

Which of the following best describes the natural history of cutaneous JXG? A. Rapidly progressive with systemic spread B. Chronic and scarring C. Self-limited and spontaneously involuting D. Requires excision to resolve

Answer 33

C. Self-limited and spontaneously involuting Explanation: Most cutaneous JXG lesions regress on their own without intervention.

Question 34

True or False: JXG lesions typically involve the epidermis and often ulcerate.

Answer 34

False Explanation: JXG lesions are dermal and do not usually ulcerate or involve the epidermis.

Question 35

A 9-month-old infant presents with 4 yellow-orange papules on the upper chest and back. No systemic symptoms. What is the most appropriate next step in management?

Answer 35

Observation and reassurance Explanation: Classic presentation of cutaneous JXG. No intervention is needed unless systemic signs appear.

Question 36

Which of the following findings on histopathology is least characteristic of JXG? A. Touton giant cells B. Dense dermal infiltrate of foamy histiocytes C. Birbeck granules on electron microscopy D. Mixed inflammatory infiltrate with eosinophils

Answer 36

C. Birbeck granules on electron microscopy Explanation: Birbeck granules are specific to LCH, not JXG.

Question 37

True or False: JXG is considered part of the non-Langerhans cell histiocytosis group.

Answer 37

True Explanation: JXG is a type of non-Langerhans cell histiocytosis (NLCH).

Question 38

Which histopathological feature best supports a diagnosis of JXG over xanthoma disseminatum?

Answer 38

Touton giant cells in a localized dermal infiltrate Explanation: JXG features discrete dermal involvement with Touton giant cells. Xanthoma disseminatum has mucosal/systemic involvement.

Question 39

Which intracellular signaling pathway is implicated in both JXG and JMML, especially when co-occurring with NF1?

Answer 39

RAS/MAPK pathway Explanation: Dysregulation of this pathway is seen in NF1, JMML, and sometimes systemic JXG.

Question 40

A 2-year-old child with neurofibromatosis type 1 presents with >10 yellowish papules and monocytosis. What condition should be urgently ruled out?

Answer 40

Juvenile Myelomonocytic Leukemia (JMML) Explanation: The combination of NF1 + multiple JXG + monocytosis raises concern for JMML.

Question 41

Biopsy shows CD68+, Factor XIIIa+, S100–, CD1a–, Langerin–. What is the most likely diagnosis? A. Langerhans Cell Histiocytosis B. Juvenile Xanthogranuloma C. Rosai-Dorfman Disease D. Erdheim-Chester Disease

Answer 41

B. Juvenile Xanthogranuloma Explanation: This immunophenotype is classic for JXG, distinguishing it from LCH and other histiocytoses.

Question 42

Name two organ systems that may be involved in systemic JXG, especially in infants.

Answer 42

Ocular and CNS (others include liver, lungs, bone marrow) Explanation: Systemic JXG may involve the eye and CNS and must be carefully monitored.

Question 43

What is Hand-Schüller-Christian disease?

Answer 43

A classic presentation of chronic disseminated LCH. Triad: Lytic bone lesions (usually skull) Exophthalmos (retro-orbital infiltration) Central diabetes insipidus (pituitary involvement)