Acantholytic Variant of Squamous Cell Carcinoma

Angiosarcoma

Age

Typically elderly adults

Typically elderly adults

Location

Most common in the skin. In the upper aerodigestive tract, most commonly affects the oral cavity, particularly the vermillion border of the lip

May occur at essentially any site, but most common in the skin and soft tissues of the head and neck, especially the scalp. Often multifocal. Rare in the mucosal head and neck

Symptoms

Dependent on site. In the oral cavity, a mass, often with associated pain

Dependent on site

Signs

Irregular fleshy mass, often large and exophytic

Varies from a red-purple plaque to large irregular fleshy masses

Etiology

Disruption of intercellular connections in the nests of invasive carcinoma. Tumors of the vermillion border often seen in association with chronic sun exposure

Risk factors include long-standing lymphedema, therapeutic radiation, and exposure to Thorotrast

Histology

1. 
   

   Highly infiltrative, unencapsulated proliferation of anastomosing slit-like structures that merge with other foci of recognizable squamous cell carcinoma with overt cytoplasmic keratinization, keratin pearls, and intercellular bridges (Figs. 5.1.1 and 5.1.2)

   
   
2. 
   

   The pseudovascular spaces represent foci of dyscohesion in the squamous carcinoma

   
   
3. 
   

   Pseudovascular spaces are ragged and usually contain cellular debris or dyskeratotic cells within the false lumen (i.e., acantholysis) (Fig. 5.1.2)

   
   
4. 
   

   Overlying surface epithelium typically demonstrates squamous dysplasia or carcinoma in situ (Fig. 5.1.3)

   
   
5. 
   

   Marked cellular atypia, with frequent mitotic figures and atypical mitotic figures (Fig. 5.1.2)

1. 
   

   Highly infiltrative, unencapsulated proliferation of anastomosing slit-like structures, without recognizable squamous cell carcinoma (overt cytoplasmic keratinization, keratin pearls, and intercellular bridges) (Fig. 5.1.5)

   
   
2. 
   

   Vascular spaces often contain blood, hemosiderin, and inflammatory cells but not dyskeratotic cells (Figs. 5.1.6 and 5.1.7)

   
   
3. 
   

   No squamous dysplasia or carcinoma in situ of the overlying squamous epithelium

   
   
4. 
   

   Variably cellular atypia in the form of nuclear enlargement, hyperchromasia, pleomorphism, frequent mitotic figures, and atypical mitotic figures (Figs. 5.1.6 and 5.1.7)

Special studies

• 
  

  The tumor—including the pseudovascular spaces—is diffusely positive for squamous markers p63, p40, and CK5/6 (Fig. 5.1.4)

  
  
• 
  

  Negative for vascular markers CD31, CD34, and ERG

• 
  

  Positive for vascular markers CD31, CD34, and ERG (Fig. 5.1.8)

  
  
• 
  

  May be positive for cytokeratins (epithelioid angiosarcoma) but typically negative for squamous markers p63, p40, and CK5/6

Treatment

Similar to mucosal squamous cell carcinoma: surgical excision usually with adjuvant radiation and chemotherapy

Resection, external beam radiation therapy, and/or chemotherapy

Prognosis

Does not seem to have a prognosis that differs from conventional squamous cell carcinoma

Poor, with 5-year survival of approximately 30%-50%. Recurrences and metastases (lymph node and lung) are common

Adenosquamous Carcinoma

Acantholytic Variant of Squamous Cell Carcinoma

Age

Adults, peak in seventh and eighth decades

Typically elderly adults

Location

Almost always mucosal sites, especially the larynx, oral cavity, and oropharynx

Most common in the skin. In the upper aerodigestive tract, most commonly affects the oral cavity, particularly the vermillion border of the lip

Symptoms

Dependent on site. In the oral cavity, a mass, often with associated pain

Dependent on site. In the oral cavity, a mass, often with associated pain

Signs

Irregular fleshy mass, often large and exophytic

Irregular fleshy mass, often large and exophytic

Etiology

Glandular component could represent divergent differentiation from squamous cell carcinoma or perhaps a component that arose from seromucinous glands. A subset of oropharyngeal and nasal cases harbor highrisk HPV

Disruption of intercellular connections in the nests of invasive carcinoma. Tumors of the vermillion border often seen in association with chronic sun exposure. An HPV-related form has not been described

Histology

1. 
   

   Highly infiltrative, unencapsulated proliferation of squamous nests and tumor glands

   
   
2. 
   

   Squamous and glandular components are typically separate and distinct, with the glandular component often in the deeper portions of the tumor (Fig. 5.2.1)

   
   
3. 
   

   Glandular component consists of punched-out ductal structures and/or scattered mucinous cells (Fig. 5.2.2)

   
   
4. 
   

   Marked cellular atypia, with frequent mitotic figures in both squamous and glandular components (Fig. 5.2.2)

1. 
   

   Highly infiltrative, unencapsulated proliferation of gland-like structures that merge with other foci of recognizable squamous cell carcinoma (Fig. 5.2.5)

   
   
2. 
   

   The pseudoglandular spaces represent foci of dyscohesion in the squamous carcinoma and not true glands (Fig. 5.2.6)

   
   
3. 
   

   Pseudoglandular spaces are ragged and usually contain cellular debris or dyskeratotic cells within the false lumen (Figs. 5.2.6 and 5.2.7)

   
   
4. 
   

   Mucinous cells are absent

   
   
5. 
   

   Marked cellular atypia, with frequent mitotic figures

Special studies

• 
  

  The squamous component is diffusely positive for squamous markers p63, p40, and CK5/6

  
  
• 
  

  Glandular component is negative for p63, p40, CK5/6, and positive for CK7 (Fig. 5.2.3)

  
  
• 
  

  Mucin stains are positive in scattered mucinous cells in the glandular component (Fig. 5.2.4)

  
  
• 
  

  A subset of oropharyngeal and nasal cases harbor high-risk HPV

• 
  

  The tumor—including the pseudoglandular spaces—is diffusely positive for squamous markers p63, p40, and CK5/6 (Fig. 5.2.7)

  
  
• 
  

  Negative for CK7 and mucin (Fig. 5.2.8)

  
  
• 
  

  An HPV-related form has not been described

Treatment

Similar to mucosal squamous cell carcinoma: surgical excision usually with adjuvant radiation and chemotherapy

Similar to mucosal squamous cell carcinoma: surgical excision usually with adjuvant radiation and chemotherapy

Prognosis

Poor, with 5-year survivals of 20%-40%

Does not seem to have a prognosis that differs from conventional squamous cell carcinoma

Oral Candidiasis

Squamous dysplasia

Age

Young infants and elderly patients most commonly affected

Adults, peak in sixth to eighth decades

Location

Anywhere in the oral cavity, most commonly buccal mucosa, oropharynx, and lateral tongue

Most commonly the tongue, floor of the mouth, and palate

Symptoms

Burning sensation, tenderness, and dysphagia

Usually asymptomatic

Signs

Four clinical forms in order of frequency: (1) pseudomembranous (thrush), (2) erythematous, (3) hyperplastic, and (4) angular cheilitis

White (leukoplakia), red (erythroplakia), or mixed (speckled leukoplakia) plaques in the oral cavity

Etiology

Candida spp., most commonly C. albicans. Patients often immunocompromised (HIV/AIDS, chronic steroid therapy, diabetes, undergoing chemotherapy)

Accumulation of genetic alterations including p53 mutations, usually secondary to smoking. Rare examples of bowenoid dysplasia harbor high-risk HPV

Histology

1. 
   

   Varying degrees of squamous hyperplasia with hyperkeratosis and parakeratosis, increasing with the chronicity of infection (Fig. 5.3.1)

   
   
2. 
   

   Presence of a neutrophilic infiltrate and/or microabscesses in the squamous epithelium is an important clue (Fig. 5.3.1). The more acute the infection is, the more inflammation is seen

   
   
3. 
   

   Some reactive cellular and architectural atypia typically present in the form of bulbous rete, enlarged nuclei, and elevated mitotic rate, but the severity is usually mild (Fig. 5.3.2)

   
   
4. 
   

   Variable numbers of fungal hyphae in the superficial epithelial layers, particularly in foci of parakeratosis (Fig. 5.3.3)

   
   
5. 
   

   Fungal elements usually visible by routine histology, consisting of refractile elements, often arranged perpendicularly to the surface (Fig. 5.3.3)

1. 
   

   Combination of cytologic and architectural atypical features

   
   
2. 
   

   Atypical cytologic features include nuclear enlargement, nuclear hyperchromasia, prominent nucleoli, and abnormal mitotic figures

   
   
3. 
   

   Atypical architectural features include dropshaped rete ridges, basal layer hyperplasia, mitotic figures above the basal layer, irregular stratification, deep keratin pearls, and dyskeratotic cells

   
   
4. 
   

   Graded as mild, moderate, or severe based largely on how much of the epithelium is involved (lower one-third for mild, midthird for moderate, upper-third for severe) (Figs. 5.3.5, 5.3.6 and 5.3.7)

   
   
5. 
   

   Candida organisms not typically seen. If present, the degree of atypia must be beyond what can be accounted for by candidiasis

Special studies

Special stains for fungi (GMS or PAS) highlight the fungal organisms (Fig. 5.3.4)

Special stains for fungi (GMS or PAS) typically negative for the fungal organisms

Treatment

Antifungal agents (either topical or systemic) and attention to any underlying disease process

Mild dysplasia: excision or close follow-up. Mild/severe: surgical excision

Prognosis

Benign process. When predisposing conditions present, recurrence is common

Rate of malignant transformation is low overall (5%-20%); risk rises with increasing severity

Granular Cell Tumor

Congenital Epulis

Age

Wide age range, most often third to fifth decades

Newborn infants, usually girls

Location

Most frequently larynx and oral cavity (especially tongue)

Usually anterior maxillary alveolus

Symptoms

In the larynx, hoarseness. Elsewhere, painless nodule

May interfere with breathing or feeding

Signs

Small, nontender, circumscribed nodule

Pedunculated fleshy gingival mass

Etiology

Unknown. Granular cell tumor is of nerve sheath origin

Unknown

Histology

1. 
   

   Unencapsulated sheet-like proliferation of large polygonal cells with pale, granular amphophilic to eosinophilic cytoplasm (Fig. 5.4.1)

   
   
2. 
   

   Often associated with a striking pseudoepitheliomatous hyperplasia of the overlying surface epithelium that can mimic squamous cell carcinoma and obscure the granular cell tumor (Fig. 5.4.2)

   
   
3. 
   

   No significant nuclear atypia, mitoses, or necrosis

1. 
   

   Unencapsulated sheet-like proliferation of large polygonal cells with pale, granular amphophilic to eosinophilic cytoplasm (Figs. 5.4.4 and 5.4.5)

   
   
2. 
   

   No pseudoepitheliomatous hyperplasia. In fact, in some cases, the overlying epithelium is atrophic

   
   
3. 
   

   No significant nuclear atypia, mitoses, or necrosis (Fig. 5.4.5)

Special studies

Diffusely positive for S100, SOX10, and inhibin (Fig. 5.4.3). Negative for desmin and myogenin

Negative for S100, SOX10, and inhibin

Treatment

Surgical excision

Surgical excision or observation

Prognosis

Excellent. Low risk of recurrence

Excellent. Some tumors may regress spontaneously

Heck Disease (Focal Epithelial Hyperplasia)

Squamous Dysplasia

Age

Can affect any age, but most commonly children and young adults. Often American Indians or Inuits, but not restricted to these populations

Adults, peak in sixth to eighth decades

Location

Labial, lingual, or buccal mucosa

Most commonly the tongue, floor of the mouth, and palate

Symptoms

Usually none

Usually asymptomatic

Signs

Multiple small, clustered fleshy papules or nodules

White (leukoplakia), red (erythroplakia), or mixed (speckled leukoplakia) plaques in the oral cavity

Etiology

Human papillomavirus types 13 or 32

Accumulation of genetic alterations including p53 mutations, usually secondary to smoking. Rare examples of bowenoid dysplasia harbor high-risk HPV

Histology

1. 
   

   Squamous hyperplasia with expansion and fusion of rete ridges (Fig. 5.5.1)

   
   
2. 
   

   Koilocytes—squamous cells with hyperchromatic, wrinkled appearing nuclei, and paranuclear haloes—may be seen (Fig. 5.5.2)

   
   
3. 
   

   Mitosoid body—squamous cell with peculiar fragmentation of chromatin, resembling an atypical mitotic figure—haphazardly distributed throughout squamous epithelium (Fig. 5.5.3)

   
   
4. 
   

   No other significant cytologic or architectural atypia

1. 
   

   Combination of cytologic and architectural atypical features

   
   
2. 
   

   Atypical cytologic features include nuclear enlargement, hyperchromasia, prominent nucleoli, and abnormal mitotic figures

   
   
3. 
   

   Atypical architectural features include dropshaped rete ridges, basal layer hyperplasia, mitotic figures above the basal layer, irregular stratification, deep keratin pearls, and dyskeratotic cells (Fig. 5.5.4)

   
   
4. 
   

   Graded as mild, moderate, or severe based largely on how much of the epithelium is involved (lower one-third for mild, mid-third for moderate, upper-third for severe)

Special studies

HPV in situ hybridization for HPV types 13 and 32

Negative for HPV types 13 and 32

Treatment

None or simple excision

Mild dysplasia: excision or close follow-up. Mild/severe: surgical excision

Prognosis

Excellent. Some cases spontaneously regress

Rate of malignant transformation is low overall (5%-20%); risk rises with increasing severity

Injected Cosmetic Material

Atypical Lipomatous Tumor (Well-Differentiated Liposarcoma)

Age

Adults, ranging from 21 to 81, with mean 50 years. Women more common than man

Adults ranging from 25 to 83, mean age approximately 50

Location

Upper and/or lower lip, nasolabial fold, and buccal mucosa

Can rarely involve virtually any head and neck site, most often oral cavity and larynx. In areas like oral cavity that are accessible for complete excision, the term “atypical lipomatous tumor” is used, while identical tumors that are deep-seated tumors are referred to as welldifferentiated liposarcoma

Symptoms

None or pain

Painless, slow-growing mass

Signs

Nodule(s) or swelling

Circumscribed mass, yellow on cut section

Etiology

Cosmetic injection of various biomaterials (silicone, collagen, hyaluronic acid, and others)

Unknown

Histology

1. 
   

   Permeation of soft tissues by clusters, sheets and individual histiocytes (Figs. 5.6.1 and 5.6.2)

   
   
2. 
   

   The histiocytes often exhibit clear cytoplasmic vacuoles that indent the nucleus, closely mimicking lipoblasts (Fig. 5.6.3)

   
   
3. 
   

   No cells with large, hyperchromatic nuclei

1. 
   

   Variably circumscribed proliferation of mature-appearing fat divided into lobules by fibrous septa (Fig. 5.6.5)

   
   
2. 
   

   Diagnostic cells are large, hyperchromatic spindled cells scattered among the matureappearing lipocytes, often in the fibrous septa (Fig. 5.6.6)

   
   
3. 
   

   Lipoblasts—fatty cells with fat vacuoles that crisply indent the tumor cell nucleus—are scant and often not seen at all (Fig. 5.6.7)

Special studies

Positive for CD68, negative for MDM2 (Fig. 5.6.4)

Positive for MDM2, negative for CD68 (Fig. 5.6.8)

Treatment

Excision and/or steroids (intralesional or systemic)

Wide local excision

Prognosis

Benign, but can be a disfiguring process

Good. Low risk of recurrence when completely excised