Lymphangioma of the Tongue: Differential Diagnosis

Background

I. CLINICAL DIFFERENTIAL DIAGNOSIS

1. Haemangioma of the Tongue

• Most important and common clinical mimic
• Also causes macroglossia; may present as a soft, compressible swelling
• Key distinction: Haemangioma has a blue/red/purple discoloration due to blood content; lymphangioma has a pale/skin-colored or translucent vesicular surface with clear/straw-colored fluid. Haemangioma is compressible and empties on pressure; lymphangioma is non-compressible. Transillumination is positive in both, but lymphangioma transilluminates brilliantly.
• Haemangioma may bleed on surface trauma; lymphangioma oozes clear lymph fluid

2. Cystic Hygroma (extending to floor of mouth/tongue base)

• Large macrocystic lymphatic malformation, usually from neck, may extend to tongue base
• Clinically soft, brilliantly transilluminant, fluctuant
• Distinguished by its location (neck/posterior triangle primarily) and multilocular nature

3. Neurofibroma / Plexiform Neurofibroma

• Can cause macroglossia (especially in neurofibromatosis type 1)
• Firm, non-fluctuant, non-transilluminant; associated with cafe-au-lait spots, cutaneous neurofibromas
• Does NOT transilluminate

4. Muscular Macroglossia

• Diffuse enlargement with normal surface texture
• Common in Cretinism (hypothyroidism), Beckwith-Wiedemann syndrome
• No vesicles or cystic spaces; tongue musculature is hypertrophied uniformly

5. Lingual Thyroid

• Midline mass at tongue base (posterior third)
• Firm, reddish-pink, nodular mass; may be associated with absence of normal thyroid
• Distinguished by radionuclide scan; patients may be hypothyroid
• • S Das: A Manual on Clinical Surgery, 13th Ed

6. Haemangioma associated with AV Fistula

• Pulsatile, with an audible bruit; may show dilatation of feeding vessels
• Never seen in lymphangioma

7. Amyloidosis of the Tongue

• Causes firm, rubbery, diffuse macroglossia
• Tongue is firm, not soft/fluctuant; no vesicles; systemic features of amyloidosis present
• • Harrison's Principles of Internal Medicine, 22nd Ed

8. Ranula (for floor of mouth/tongue swellings)

• Mucous retention cyst of sublingual gland, presenting as a bluish, translucent swelling in the floor of mouth
• Doesn't cause true macroglossia; unilateral soft tissue cyst only
• • Cummings Otolaryngology

9. Dermoid Cyst / Epidermoid Cyst

• Midline floor-of-mouth or tongue swelling in young patients
• Doughy consistency (pastry feel); does NOT transilluminate (sebaceous content)

10. Macroglossia Due to Storage Diseases

• Von Gierke disease (glycogen storage type I), Hurler syndrome (mucopolysaccharidosis)
• Associated with systemic features; no vesicles
• • K.J. Lee's Essential Otolaryngology

11. Lymphangioma-like Kaposi Sarcoma

• HIV-positive patients; may closely mimic oral lymphangioma clinically
• Distinguished by context (immunosuppression), and immunohistochemistry (HHV-8 positive)

12. Macrocheilia / Cheilitis Granulomatosa (for lip involvement)

• Solid edema, angioedema, cheilitis glandularis, sarcoidosis, oral Crohn's disease must be considered when lymphangioma affects the lips
• • Andrews' Diseases of the Skin

II. HISTOPATHOLOGICAL DIFFERENTIAL DIAGNOSIS

Key Histological Features of Lymphangioma

• Dilated, thin-walled lymphatic channels of varying caliber
• Flat, bland endothelial lining (no nuclear atypia or mitoses)
• Channels contain pale eosinophilic proteinaceous fluid, lymphocytes, and occasionally red blood cells
• Stroma may show lymphoid aggregates/nodules
• In tongue: channels insinuate between muscle fibers (cavernous type)
• IHC: D2-40 (podoplanin) positive, PROX1 positive, VEGFR3 positive, CD31 positive

Histopathological Mimics:

1. Haemangioma (Capillary / Cavernous)

• Most important histological mimic
• Distinction: Haemangioma channels contain red blood cells (erythrocytes); lymphangioma channels contain clear proteinaceous fluid and lymphocytes, rarely a few RBCs
• Hemangioma endothelium: CD31+, CD34+, D2-40 negative
• Lymphangioma endothelium: D2-40+, PROX1+, CD34 negative/weak

2. Lymphangiohemangioma (Mixed Vascular Malformation)

• Contains both blood-filled and lymph-filled channels
• IHC panel required to distinguish component channels

3. Angiosarcoma (Well-Differentiated / Low-Grade)

• Anastomosing vascular channels, but endothelial cells show nuclear atypia, hyperchromasia, multilayering, mitoses
• Destructive infiltration; no proteinaceous lymphatic fluid
• CD31+, CD34+; variable D2-40; clinical malignant behavior

4. Well-Differentiated Angiosarcoma of the Tongue

• Rare but critical to exclude; anastomosing vascular channels with atypical endothelium
• Infiltrates muscle destructively vs. lymphangioma which separates muscle fibers without destruction

5. Cystic Hygroma (Macrocystic Lymphatic Malformation)

• Histologically similar but shows large macrocysts lined by flat endothelium
• Wall may contain smooth muscle; often with lymphoid aggregates in wall
• D2-40 positive; separated from cavernous lymphangioma only by cyst size (>2 cm conventionally)

6. Lymphangiectasia (Acquired)

• Dilated lymphatic channels secondary to obstruction (surgical, radiation, infection)
• Histologically nearly identical to lymphangioma; distinction is clinical context (acquired vs. congenital)
• Lacks the deep infiltrative pattern of true lymphangioma

7. Benign Lymphangioendothelioma (Acquired Progressive Lymphangioma)

• Anastomosing, thin-walled vascular channels in dermis; superficially resembles lymphangioma
• Channels are more irregular and dissecting; may simulate low-grade angiosarcoma
• D2-40 positive; no cytologic atypia
• • Andrews' Diseases of the Skin, Clinical Dermatology

8. Venous Malformation

• Large thin-walled blood-filled venous channels; no lymphatic content
• Endothelium is CD34+, D2-40 negative
• Stroma may show phleboliths (calcified thrombi - pathognomonic)

9. Mucocele / Ranula

• Mucous extravasation or retention cyst lined by compressed connective tissue or respiratory/ductal epithelium
• Contents are mucin-rich (not clear proteinaceous fluid); mucin stains positive (PAS, mucicarmine)
• No endothelial lining of the cyst space

10. Lymphangioma-like Kaposi Sarcoma

• Vascular channels lined by cells expressing HHV-8 (LANA-1 positive)
• Irregular, slit-like, anastomosing channels; background lymphoplasmacytic infiltrate; hyaline globules
• D2-40 may be positive but HHV-8 is the definitive marker

Summary Table

Lymphangioma vs. Hemangioma - Are They the Same?

Core Difference

Detailed Comparison

1. Definition

• Lymphangioma: A benign proliferation/malformation of lymphatic channels that fail to connect to the normal lymphatic system. It is congenital in almost all cases.
• Hemangioma: A benign proliferation of blood vessel endothelium (capillaries, cavernous sinuses, or venous channels filled with blood).

2. Clinical Appearance

3. Common Sites on Tongue

• Both can affect the tongue and cause macroglossia
• Lymphangioma: tongue surface shows multiple small vesicles (frog-spawn appearance)
• Hemangioma: tongue appears dark blue/purple and spongy

4. Behavior

5. Histopathology

6. Treatment

• Lymphangioma: Surgical excision is the mainstay; sclerotherapy (OK-432, bleomycin) used for cystic types. Does NOT respond to propranolol.
• Infantile hemangioma: Propranolol is now first-line medical treatment; many involute spontaneously. Surgical excision for residual lesions.

Why They Are Often Confused

• Are benign, congenital/developmental in origin
• Occur in the same locations (tongue, neck, lip, axilla)
• Present as soft, painless swellings
• Are grouped under the umbrella term "vascular malformations" in older classifications
• Can both cause macroglossia

Lymphangioma of the Tongue

Lymphangioma of the right half of the tongue causing macroglossia - S Das: A Manual on Clinical Surgery

1. Definition

2. Epidemiology

• Age: Congenital in almost all cases; present at birth or appears within the first 2 years of life. Occasionally may manifest for the first time in young adults.
• Sex: No significant sex predilection
• Frequency: The tongue is one of the most common sites for lymphangioma in the head and neck region (along with neck, lips, cheeks)
• Cavernous type represents ~40% of all lymphangiomas and most commonly affects the tongue
• Lymphangioma is the most common cause of congenital macroglossia

3. Etiology and Pathogenesis

4. Classification (Types Occurring in the Tongue)

Type 1: Simple / Capillary Lymphangioma (Lymphangioma Circumscriptum)

• Composed of thin-walled capillary-sized lymphatic channels
• Presents as small, pale vesicles (0.5-4 mm) on the tongue surface
• Multiple vesicles give a characteristic "frog-spawn" or "tapioca pudding" appearance on the tongue dorsum
• Usually superficial; vessels insinuate into superficial tongue musculature
• Most common type seen clinically on the tongue surface

Type 2: Cavernous Lymphangioma

• Composed of larger dilated lymphatic spaces with fibrous adventitia
• Situated deeper within tongue musculature
• The most important type causing macroglossia
• Presents as a diffuse, painless, soft lobulated swelling
• Cyst interspersed among muscle fibers - makes surgical excision difficult
• Represents 40% of all lymphangiomas

Type 3: Cystic Hygroma (Macrocystic Type)

• Large cyst-like cavities containing clear watery fluid
• Primarily in the neck but can extend to the tongue base
• Most common overall form of lymphangioma

5. Clinical Features

Symptoms

• Macroglossia - the tongue protrudes from the mouth (most dramatic feature)
• Painless in most cases (pain occurs if infected)
• Difficulty with eating, chewing, swallowing (dysphagia)
• Speech difficulties (dysarthria) due to enlarged tongue
• Drooling of saliva
• Open-mouth posture and mouth breathing
• Cosmetic disfigurement

Signs

Involvement pattern

• May involve half the tongue (unilateral) or entire tongue
• The tongue often shows an irregular, nodular, cobblestone surface due to submucosal lymphatic channels
• Surrounding tissues (lip causing macrocheilia, floor of mouth) may also be involved

6. Complications

1. Recurrent infections - lymph stasis predisposes to bacterial infection; episodes of swelling, fever, tenderness
2. Sudden rapid enlargement - after infection or internal hemorrhage (blood enters lymphatic channels, turning vesicles dark red/brown)
3. Airway obstruction - life-threatening; tongue can obstruct the oropharynx, especially in neonates
4. Lymphorrhoea - leakage of clear lymph fluid after trauma or ulceration of surface vesicles
5. Dental/occlusal problems - open bite, dental spacing, prognathism from persistent macroglossia
6. Difficulty with feeding in neonates and infants
7. Psychological impact due to cosmetic deformity

7. Investigations

Imaging

• CT scan - determines size, extent, and relationship to vital structures; shows low-density multilocular mass within tongue musculature
• MRI - best investigation; shows T2 hyperintense multilocular lesion; distinguishes microcystic from macrocystic components; assesses deep extent
• Ultrasonography - High-definition intraoral ultrasonography (IHDUS) is a newer, non-invasive tool to assess lesion depth and vascularity (Limongelli et al., J Pediatr Surg, 2025)
• Doppler ultrasound - shows absence of arterial flow (unlike hemangioma/AVM)

Aspiration

• Aspiration of clear, watery, straw-colored fluid confirms the diagnosis
• Fluid does NOT coagulate (unlike blood)
• Fluid contains lymphocytes and cholesterol crystals

8. Histopathology

Macroscopy

• Cut surface shows multiple locules of varying sizes filled with clear lymph
• In depth: larger locules; towards surface: smaller locules
• Contents: clear watery lymph, cholesterol crystals, lymphocytes

Microscopy

• Dilated, thin-walled lymphatic channels of varying caliber insinuating between tongue muscle fibers
• Channels lined by flat, bland endothelial cells with no atypia or mitoses
• Channel lumen contains: pale eosinophilic proteinaceous fluid, lymphocytes, rarely a few red blood cells
• Stroma shows lymphoid aggregates around channel walls
• Fibrous adventitia in cavernous type
• Surface epithelium may show hyperplasia; lymphatic channels may reach up close to mucosal surface (explaining vesicle formation)

Immunohistochemistry (IHC)

9. Treatment

Surgical Excision

• Primary treatment for tongue lymphangioma
• Partial glossectomy for large lesions causing functional problems
• The cyst is often interspersed among tongue muscle fibers, making complete excision difficult - high recurrence rate
• Pre-operative tracheostomy may be needed for airway protection in large lesions
• Post-operative antibiotics + steroids to reduce swelling

Sclerotherapy

• Used for macrocystic lesions; less effective for microcystic tongue lesions
• Agents used:
  • OK-432 (Picibanil) - most commonly used; streptococcal preparation
  • Bleomycin - effective for macrocystic type
  • Doxycycline
  • Ethanol (for deep lesions)
• Multiple sessions often required
• May reduce lesion before surgery

Laser Therapy

• CO2 laser / Diode laser - used for superficial vesicular lesions on tongue surface
• Diode laser-assisted excision is a newer minimally invasive approach, showing good results in pediatric patients with tongue lymphangioma circumscriptum (Limongelli et al., 2025 - PMID: 40714024)

Sirolimus (mTOR inhibitor)

• For life-threatening or refractory lymphatic malformations
• Systemic treatment that reduces lesion size by inhibiting lymphatic endothelial proliferation
• Particularly useful in extensive, surgically unresectable lesions

Observation

• Small, asymptomatic lesions may be observed
• Unlike infantile hemangioma, spontaneous regression is rare

10. Prognosis

• Benign - no malignant transformation
• Recurrence is common after incomplete excision (due to deep infiltration of muscle)
• Prognosis is generally good for localized lesions
• Airway compromise is the most serious threat in large/giant lesions - can be life-threatening
• Functional outcomes (speech, swallowing) are usually good after appropriate treatment

Clinical Differential Diagnosis of Lymphangioma of the Tongue

• Macroglossia (diffuse tongue enlargement)
• Vesicular/nodular surface lesions on tongue
• Soft cystic swelling of tongue

A. DIFFERENTIALS BASED ON MACROGLOSSIA

1. Haemangioma of the Tongue

2. Muscular Macroglossia

• Diffuse, uniform enlargement of the tongue with no surface vesicles or cystic spaces
• The tongue musculature is hypertrophied throughout
• Associated conditions: Cretinism (congenital hypothyroidism), Beckwith-Wiedemann syndrome (also associated with omphalocele, neonatal hypoglycemia), Down syndrome
• Tongue is firm and uniformly enlarged - NOT soft/spongy/fluctuant
• No transillumination; no punctum; no vesicles
• - K.J. Lee's Essential Otolaryngology; The Developing Human - Moore's Embryology

3. Neurofibroma / Plexiform Neurofibroma

• Causes macroglossia; associated with Neurofibromatosis Type 1 (von Recklinghausen disease)
• Tongue is soft but with a firm, rubbery feel in areas
• Not fluctuant; not transilluminant
• Associated with: cafe-au-lait spots, cutaneous neurofibromas, axillary freckling, Lisch nodules
• - S Das: A Manual on Clinical Surgery, 13th Ed

4. Amyloidosis of the Tongue

• Causes firm, rubber-like, diffuse macroglossia - the tongue is hard and indented by teeth
• No vesicles, no fluctuation, no transillumination
• Usually in adults with systemic amyloidosis (primary or secondary)
• Associated features: periorbital purpura ("raccoon eyes"), carpal tunnel syndrome, cardiac disease, proteinuria
• Biopsy with Congo red stain shows apple-green birefringence under polarized light
• - Harrison's Principles of Internal Medicine, 22nd Ed

5. Storage Diseases

• Von Gierke disease (glycogen storage disease type I) - hepatomegaly, hypoglycemia + macroglossia
• Hurler syndrome (mucopolysaccharidosis type I) - coarse facies, corneal clouding, hepatosplenomegaly + macroglossia
• Tongue is firm and uniformly enlarged; no vesicles
• Diagnosis by enzyme assay and urinary glycosaminoglycans
• - K.J. Lee's Essential Otolaryngology

6. Acromegaly

• Macroglossia from growth hormone excess in adults
• Associated features: enlargement of hands, feet, jaw (prognathism), wide spacing of teeth, coarse facial features, hypertension, diabetes
• NOT congenital; presents in adults
• Tongue is firm, NOT cystic

7. Myxoedema (Hypothyroidism)

• Acquired macroglossia in adults from mucopolysaccharide infiltration of tongue
• Associated with: dry skin, bradycardia, weight gain, constipation, cold intolerance
• Tongue is pale, puffy, firm - not fluctuant or transilluminant
• - S Das: A Manual on Clinical Surgery, 13th Ed

B. DIFFERENTIALS BASED ON CYSTIC TONGUE SWELLING

8. Cystic Hygroma Extending to Tongue Base

• The macrocystic type of lymphangioma itself - technically within the spectrum
• Primarily in the posterior triangle of the neck; can extend to the floor of mouth/tongue base
• Brilliantly transilluminant, brilliantly fluctuant
• Distinguished by: predominantly cervical location, massive size, "hydrocele of the neck" appearance
• Partial compressibility (fluid shifts between locules)

9. Ranula

• Mucous retention/extravasation cyst of the sublingual salivary gland
• Located in the floor of mouth - NOT in the tongue itself (though it can displace the tongue upward)
• Bluish, translucent swelling in floor of mouth
• Unilocular; contains viscous mucin (NOT clear watery lymph)
• A "plunging ranula" extends through mylohyoid into the neck
• Mucin positive on PAS staining; no lymphocytes in fluid
• - Cummings Otolaryngology

10. Dermoid / Epidermoid Cyst

• Midline swelling of the tongue or floor of mouth
• Doughy, "pastry-like" consistency (sebaceous content)
• Does NOT transilluminate (opaque sebaceous content)
• Smooth surface; no vesicles
• Cyst wall lined by squamous epithelium + skin appendages (dermoid) or just squamous epithelium (epidermoid)

11. Lingual Thyroid

• Midline mass at the base of tongue (posterior third)
• Firm, reddish-pink, nodular, sessile mass
• Associated with absence of normal thyroid gland in the neck (check for ectopic thyroid before removal!)
• Patient may be hypothyroid
• Never transilluminates; no fluctuation
• Confirmed by: thyroid radionuclide scan (Tc-99m), MRI
• - S Das: A Manual on Clinical Surgery, 13th Ed

C. DIFFERENTIALS BASED ON VESICULAR / SURFACE LESIONS

12. Herpes Simplex / Herpes Zoster

• Painful vesicles on the tongue/oral mucosa
• Vesicles contain clear fluid initially, become turbid/purulent, then ulcerate with a yellow base
• Painful, burning - vs. lymphangioma vesicles which are painless
• Acute onset with fever; NOT congenital
• Dermatomal distribution in zoster

13. Pemphigus Vulgaris

• Oral bullae and erosions in middle-aged adults
• Nikolsky's sign positive
• Vesicles rupture easily leaving painful erosions
• NOT congenital; autoimmune (anti-desmoglein antibodies)

14. Angioedema

• Acute, transient swelling of the tongue (and lips) - resolves within 24-48 hours
• Associated with allergic trigger, ACE inhibitor use, or hereditary C1-esterase deficiency
• No vesicles; NOT persistent like lymphangioma
• Responds to antihistamines / epinephrine

D. KEY DISTINGUISHING POINTS SUMMARY

1. Brilliantly transilluminant - separates it from solid lesions
2. Non-compressible - separates it from hemangioma
3. Clear, non-clotting fluid on aspiration - the single most definitive clinical test

Histopathological Differential Diagnosis of Lymphangioma of the Tongue

First: Key Histological Features of Lymphangioma (The Reference Standard)

IHC Profile of Lymphangioma

Histopathological Differentials

1. Haemangioma (Capillary / Cavernous)

• Capillary hemangioma: small, closely packed capillary-sized vessels filled with RBCs, lobular architecture, plump endothelium
• Cavernous hemangioma: large blood-filled sinusoidal spaces - but always RBCs in lumen, CD34+, D2-40-
• Key rule: If lumen contains RBCs = hemangioma. If lumen contains clear proteinaceous fluid + lymphocytes = lymphangioma

2. Venous Malformation

• Large, blood-filled dilated venous channels with thin walls and flat endothelium
• Channels may show irregular, angulated shapes (not round/oval)
• Pathognomonic feature: phleboliths (calcified thrombi within vessel lumens - appear as round laminated calcifications)
• Vessel wall contains smooth muscle (SMA positive) - absent in lymphangioma
• CD34 positive, D2-40 negative
• Lumen: blood, not lymph

3. Arteriovenous Malformation (AVM)

• Contains a mixture of arteries, veins, and abnormal shunting vessels
• Arteries identified by: thick muscular walls, internal elastic lamina (visible on Elastin stain/EVG stain)
• Veins: thinner walls but contain RBCs
• Endothelial cells flat to plump; NO atypia
• CD34+, SMA+ (arterial walls), D2-40 negative
• Distinguished from lymphangioma by: presence of arterial walls with elastic laminae + blood-filled channels

4. Angiosarcoma (Well-Differentiated / Low-Grade)

• This distinction is critical: if you see endothelial atypia, multilayering, mitoses, or destructive infiltration - it is NOT lymphangioma
• Some angiosarcomas of the head and neck can be D2-40 positive, making IHC alone insufficient; nuclear atypia is the deciding feature

5. Lymphangiohemangioma (Mixed Vascular Malformation / Hemangiolymphangioma)

• Contains both lymphatic channels (D2-40+) and blood-filled channels (CD34+) in the same specimen
• A documented entity in oral/tongue lesions (Correia-Neto et al., Spec Care Dentist 2025 - PMID 40913588)
• On H&E alone, identical to either lymphangioma or hemangioma
• Full IHC panel (D2-40 + CD34 + CD31) is mandatory to classify correctly
• Mixed channels may be adjacent or interdigitated

6. Acquired Progressive Lymphangioma (Benign Lymphangioendothelioma)

• Anastomosing, thin-walled vascular channels dissecting through dermis/submucosa in a pattern mimicking low-grade angiosarcoma
• Endothelial cells are flat with minimal/no atypia - key distinguishing feature from angiosarcoma
• D2-40 positive (lymphatic origin)
• Distinguished from ordinary lymphangioma by: more irregular, anastomosing channel pattern and acquired clinical history (post-radiation, post-surgery)
• - Andrews' Diseases of the Skin

7. Granular Cell Tumor (GCT) of the Tongue

• Involves the tongue in 25% of cases - a common tongue lesion to differentiate
• Histology: sheets of polygonal cells with abundant eosinophilic granular cytoplasm, small round central nuclei, distinct cell borders
• Pseudo-epitheliomatous hyperplasia of overlying epithelium is characteristic (can mimic SCC on superficial biopsy)
• Cells infiltrate along small nerves and muscle fibers (similar infiltrative pattern to lymphangioma)
• NO vascular channels or cystic spaces (solid tumor, not channel-based)
• IHC: S100 positive, CD68 positive, PGP9.5 positive - completely different profile from lymphangioma
• - K.J. Lee's Essential Otolaryngology; Fitzpatrick's Dermatology

8. Mucocele / Ranula

• Mucous extravasation or retention cyst of salivary gland origin
• Histology of extravasation type: No epithelial lining - cyst space surrounded by granulation tissue, macrophages (foamy/muciphages), fibrous wall
• Histology of retention type: Lined by ductal epithelium (low cuboidal/columnar)
• Contents: mucin (not proteinaceous lymph fluid)
• PAS positive, Mucicarmine positive lumen contents
• Muciphages (foamy macrophages) in wall
• NO lymphoid aggregates; NO lymphatic endothelial markers
• D2-40, PROX1 - negative

9. Dermoid / Epidermoid Cyst

• Cyst lined by keratinizing stratified squamous epithelium
• Dermoid: contains skin appendages (hair follicles, sebaceous glands, sweat glands) in the wall
• Epidermoid: squamous lining only; lumen filled with laminated keratin (cheesy material)
• Contents: keratin flakes, not lymphatic fluid
• No endothelial lining whatsoever
• All vascular markers: negative

10. Lymphangioma-like Kaposi Sarcoma

• D2-40 positivity in Kaposi sarcoma is a major pitfall - both lesions are D2-40 positive
• HHV-8 immunostaining (LANA-1) is the definitive distinguishing marker
• - Andrews' Diseases of the Skin; JOMFP 2018

11. Amyloidosis of the Tongue

• Homogeneous, amorphous, eosinophilic extracellular deposits in the stroma and vessel walls
• Deposits show apple-green birefringence under polarized light with Congo red stain - pathognomonic
• The deposits surround and obliterate vessel lumens
• No dilated lymphatic channels; amyloid replaces normal tissue architecture
• AA protein / AL protein can be typed by IHC

12. Lipoma of the Tongue

• Sheets of mature adipocytes with thin fibrous septa
• No vascular channels, no proteinaceous fluid
• On H&E: clear vacuolated cells with peripheral nuclei (signet-ring appearance)
• S100 positive; all vascular markers negative

Master IHC Comparison Table

Three Golden Histological Rules

1. Lumen contents are the first clue: Clear proteinaceous fluid + lymphocytes = lymphangioma. RBCs = hemangioma/venous malformation.
2. Endothelial atypia excludes lymphangioma: Any nuclear atypia, multilayering, mitoses, or destructive infiltration = consider angiosarcoma.
3. When D2-40 is positive, always add HHV-8: Both lymphangioma and Kaposi sarcoma are D2-40 positive. HHV-8 (LANA-1) is the only way to separate them definitively.