Atypical Carcinoid Tumor

Large Cell Neuroendocrine Carcinoma

Age

Adults, peak in the sixth to seventh decades

Adults, peak in the sixth to seventh decades

Location

More than 90% occur in the supraglottis

Most often in supraglottis, followed by subglottis

Symptoms

Hoarseness, dysphagia, sore throat, and hemoptysis

Hoarseness, dysphagia, sore throat, and hemoptysis

Signs

Tan-pink polypoid submucosal masses, often below an ulcerated surface mucosa

Fleshy, ulcerated submucosal mass

Etiology

Closely associated with smoking

Closely associated with smoking

Histology

1. 
   

   Grows in nests, cords, sheets, and trabeculae (Fig. 7.1.1)

   
   
2. 
   

   Gland-like structures, rosettes, or cell spindling may be seen (Fig. 7.1.1)

   
   
3. 
   

   Tumor cells with ample amphophilic to eosinophilic granular cytoplasm (Fig. 7.1.2)

   
   
4. 
   

   Nuclei with finely stippled chromatin and mild to moderate pleomorphism (Fig. 7.1.2)

   
   
5. 
   

   Defining features are necrosis and/or 2-10 mitoses per 2 mm2 or 10 high-power fields (Fig. 7.1.2)

   
   
6. 
   

   No component of squamous cell carcinoma

1. 
   

   Grows as organoid nests, rosettes, and/or trabeculae (Figs. 7.1.4 and 7.1.5)

   
   
2. 
   

   Gland-like structures, rosettes, or cell spindling may be seen (Fig. 7.1.5)

   
   
3. 
   

   Medium-to-large-sized cells with abundant cytoplasm (Fig. 7.1.5)

   
   
4. 
   

   Nuclei have coarse chromatin, sometimes with a speckled, “salt-and-pepper” quality, and usually display a single prominent nucleolus (Fig. 7.1.5)

   
   
5. 
   

   Comedonecrosis and >10 mitoses per 2 mm2 or 10 high-power fields (Figs. 7.1.4 and 7.1.5)

   
   
6. 
   

   Occasionally harbor a component of squamous cell carcinoma either within the invasive tumor or within the overlying mucosa (Fig. 7.1.6)

Special studies

Positive for cytokeratins and at least one neuroendocrine marker (e.g., synaptophysin, chromogranin, and CD56) (Fig. 7.1.3). TTF-1 is variably expressed

Positive for cytokeratins and at least one neuroendocrine marker (e.g., synaptophysin, chromogranin, and CD56) (Fig. 7.1.7). TTF-1 is variably expressed

Treatment

Surgical resection with or without neck dissection

Chemoradiation, with or without surgical resection

Prognosis

Fair. Thirty percent of patients present with advanced disease, with a recurrence rate of approximately 60% and a 5-year survival of 50%

Poor. High rates of regional and distant metastasis, with approximately 70% of patients presenting with advanced disease and 5-year survivals from 5% to 20%

Atypical Carcinoid Tumor

Medullary Thyroid Carcinoma

Age

Adults, peak in the sixth to seventh decades, male predominance

Sporadic cases present in middle-aged adults (peak in fifth to sixth decades), with slight female predominance. Familial cases (especially MEN2B) present younger, including in children

Location

More than 90% occur in the supraglottic larynx. This differential diagnosis is most difficult when presenting with cervical lymph node metastasis and the primary source is unknown

Thyroid gland. This differential diagnosis is most difficult when presenting with cervical lymph node metastasis and the primary source is unknown (Fig. 7.2.6)

Symptoms

Hoarseness, dysphagia, sore throat, and hemoptysis

Painless thyroid nodule, hoarseness, and dysphagia

Signs

Tan-pink polypoid submucosal masses, often below an ulcerated surface mucosa. Serum calcitonin is not elevated

Fleshy thyroid nodule. Serum calcitonin is almost always elevated

Etiology

Closely associated with smoking

Approximately 25% present in the setting of a familial syndrome (MEN2A or MEN2B, familial medullary carcinoma) due to RET germline mutations

Histology

1. 
   

   Grows in nests, cords, sheets, and trabeculae (Fig. 7.2.1)

   
   
2. 
   

   Gland-like structures, rosettes, or cell spindling may be seen (Fig. 7.2.2)

   
   
3. 
   

   Tumor cells with abundant amphophilic to eosinophilic granular cytoplasm, often eccentric creating a plasmacytoid appearance (Fig. 7.2.3)

   
   
4. 
   

   Nuclei with finely stippled chromatin and mild to moderate pleomorphism (Fig. 7.2.3)

   
   
5. 
   

   Defining features are necrosis and/or 2-10 mitoses per 2 mm2 or 10 high-power fields (Fig. 7.2.3)

   
   
6. 
   

   Amyloid deposition may be seen

1. 
   

   Grows in nests, cords, sheets, and trabeculae (Fig. 7.2.7)

   
   
2. 
   

   Gland-like structures, rosettes, or cell spindling may be seen

   
   
3. 
   

   Tumor cells with abundant amphophilic to eosinophilic granular cytoplasm, often eccentric creating a plasmacytoid appearance

   
   
4. 
   

   Nuclei with finely stippled chromatin and mild to moderate pleomorphism (Fig. 7.2.7)

   
   
5. 
   

   Necrosis is uncommon, and the mitotic rate is variable

   
   
6. 
   

   Amyloid deposition is often seen (Fig. 7.2.8)

Special studies

Positive for cytokeratins and at least one neuroendocrine marker (e.g., synaptophysin, chromogranin, and CD56) (Fig. 7.2.4). Calcitonin is usually positive, and CEA and TTF-1 may be positive or negative (Fig. 7.2.5)

Positive for cytokeratins, neuroendocrine markers, calcitonin, and CEA. TTF-1 is usually positive (Fig. 7.2.9)

Treatment

Surgical resection with or without neck dissection

Total thyroidectomy, cervical lymph node dissection, and sometimes also lateral neck lymph node dissection. Tyrosine kinase inhibitors may be used for advanced disease

Prognosis

Fair. Thirty percent of patients present with advanced disease, with a recurrence rate of approximately 60% and a 5-year survival rate of 50%

Good. Five-year survival rates range from 65% to 89%

Squamous Cell Carcinoma In Situ Extending into Ducts

Conventional squamous Cell Carcinoma

Age

Adults, peak sixth to seventh decades

Adults, peak sixth to seventh decades

Location

Anywhere in the larynx

In the larynx, most common in glottis followed by supraglottis and subglottis

Symptoms

Hoarseness, dysphonia, and cough

Hoarseness, dysphonia, dysphagia, and pain

Signs

White patch (leukoplakia) and/or red patch (erythroplakia)

Variably exophytic or endophytic mass, often ulcerated

Etiology

Associated with smoking

Associated with smoking. Only rare cases harbor high-risk HPV

Histology

1. 
   

   Full-thickness atypical cellular and architectural changes of the surface squamous epithelium

   
   
2. 
   

   Squamous cell carcinoma in situ may colonize preexisting excretory ducts in a downward fashion, mimicking invasion (Fig. 7.3.1)

   
   
3. 
   

   Other, unaffected ducts are often seen in the background (Fig. 7.3.2)

   
   
4. 
   

   The colonized ducts maintain a smooth, rounded border and an intact basement membrane (Fig. 7.3.3)

   
   
5. 
   

   The colonized ducts are often only partially involved, with a residual component of ductal and/or mucinous cells (Fig. 7.3.3)

1. 
   

   An in situ component of the surface epithelium may be seen

   
   
2. 
   

   Invading nests are characterized by irregular, jagged edges (Fig. 7.3.4)

   
   
3. 
   

   Invasive nests are usually accompanied by a tissue reaction: stromal desmoplasia or a giant cell inflammatory reaction (Fig. 7.3.4)

   
   
4. 
   

   Invasive nests often show paradoxical maturation—an increase in glassy pink cytoplasm—in contrast to more basaloid squamous cell carcinoma in situ (Fig. 7.3.4)

   
   
5. 
   

   Invasion of local structures (e.g., nerves or vessels) is confirmatory (Fig. 7.3.5)

Special studies

None useful in this differential diagnosis

None useful in this differential diagnosis

Treatment

Conservative excision (e.g., laser surgery or mucosal stripping)

Surgical resection or radiation for low-stage tumors and multimodality therapy for highstage tumors

Prognosis

By itself, carcinoma in situ is cured by excision but has a high association with progression to invasive carcinoma

Dependent on location and stage. Five-year survival 80%-85% for glottic tumors, 65%-75% for supraglottic tumors, and 40% for subglottic

Squamous Cell Carcinoma In Situ

Squamous Metaplasia of the Larynx

Age

Adults, peak sixth to seventh decades All ages Location Anywhere in the larynx, most often vocal cords

Transitional epithelial area between the ciliated respiratory epithelial lining of the supraglottis and subglottis and the squamous epithelial lining of glottis

Symptoms

Hoarseness, dysphonia, and cough Depends on the inciting agent Signs White patch (leukoplakia) and/or red patch (erythroplakia)

Depends on the inciting agent

Etiology

Associated with smoking

Often a reactive change induced by various forms of irritation or trauma (e.g., reflux, intubation, smoking)

Histology

1. 
   

   Composed of squamous cells with increased nuclear: cytoplasmic ratios (Figs. 7.4.1 and 7.4.2)

   
   
2. 
   

   Lack of maturation with disorganization and hypercellularity (Figs. 7.4.1 and 7.4.2)

   
   
3. 
   

   Usually thickened with irregularly shaped rete (Figs. 7.4.1 and 7.4.2)

   
   
4. 
   

   May exhibit hyperkeratosis and parakeratosis

   
   
5. 
   

   Marked nuclear hyperchromasia and pleomorphism and irregular nuclear contours (Figs. 7.4.1 and 7.4.2)

   
   
6. 
   

   Mitotic activity at all epithelial levels (Figs. 7.4.1 and 7.4.2)

1. 
   

   Composed of squamous cells with increased nuclear:cytoplasmic ratios (Fig. 7.4.3)

   
   
2. 
   

   Lack of maturation with disorganization and hypercellularity (Fig. 7.4.3)

   
   
3. 
   

   Thin epithelium, with no rete (Fig. 7.4.3)

   
   
4. 
   

   No hyperkeratosis or parakeratosis (Fig. 7.4.3)

   
   
5. 
   

   Uniform nuclei with open chromatin, prominent nucleoli, and smooth nuclear contours (Fig. 7.4.3)

   
   
6. 
   

   Mitotic activity limited to basal layer (Fig. 7.4.3)

   
   
7. 
   

   Particularly challenging on frozen section, where cells artifactually appear more atypical (Fig. 7.4.4)

Special studies

None useful in this differential diagnosis

None useful in this differential diagnosis

Treatment

Conservative excision (e.g., laser surgery or mucosal stripping)

Eliminate source of irritation

Prognosis

By itself, carcinoma in situ is cured by excision but has a high association with progression to invasive carcinoma

By itself, squamous metaplasia is not a premalignant condition

Granular Cell Tumor

Rhabdomyoma (Adult Type)

Age

Wide age range, most often third to fifth decades

Adults, median in sixth decade

Location

Most frequently larynx and oral cavity (especially tongue)

Head and neck, including larynx, pharynx, parapharyngeal space, paratracheal soft tissue, and oral cavity

Symptoms

In larynx, hoarseness. Elsewhere, painless nodule

In larynx, hoarseness. Elsewhere, painless nodule

Signs

Small, nontender, circumscribed nodule

Small, nontender, circumscribed nodule

Etiology

Unknown. Granular cell tumor is of nerve sheath origin

Unknown

Histology

1. 
   

   Unencapsulated sheetlike proliferation of large polygonal cells with pale, granular amphophilic to eosinophilic cytoplasm (Figs. 7.5.1 and 7.5.2)

   
   
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. 7.5.3)

   
   
3. 
   

   No cytoplasmic cross-striations or crystals

   
   
4. 
   

   No significant nuclear atypia, mitoses, or necrosis

1. 
   

   Unencapsulated sheetlike proliferation of large polygonal cells with granular brightly eosinophilic cytoplasm (Fig. 7.5.5)

   
   
2. 
   

   Cross-striations or cytoplasmic crystals can be seen

   
   
3. 
   

   Some cells demonstrate cytoplasmic vacuolization resulting in the appearance of fibrillar processes (so-called spider cells) (Figs. 7.5.5 and 7.5.6)

   
   
4. 
   

   No significant nuclear atypia, mitoses, or necrosis

   
   
5. 
   

   No associated pseudoepitheliomatous hyperplasia

Special studies

Diffusely positive for S100, SOX10, inhibin. Negative for desmin and myogenin (Fig. 7.5.4)

Positive for desmin (which highlights the crossstriations), typically negative for myogenin (Fig. 7.5.7). Sometimes positive for S100 but negative for inhibin and SOX10

Treatment

Surgical excision only

Surgical excision only

Prognosis

Excellent. Low risk of recurrence

Excellent. Low risk of recurrence

Inflammatory Myofibroblastic Tumor

Sarcomatoid Carcinoma (Spindle Cell Variant of Squamous Cell Carcinoma)

Age

Wide age range, including children and adolescents

Elderly patients (peak in seventh decade), male predominance

Location

Can arise in almost any head and neck site, most often larynx. In the larynx, the glottis is most commonly affected

In the head and neck, the larynx (especially glottis) is the most common site

Symptoms

In the larynx, airway obstruction and/or hoarseness

In the larynx, airway obstruction and/or hoarseness

Signs

Polypoid mass protruding into the airway, sometimes ulcerated. Unlike visceral inflammatory myofibroblastic tumors, head and neck cases are not associated with anemia, thrombocytopenia, or elevated sedimentation rate

Polypoid mass protruding into the airway, often with an ulcerated surface mucosa

Etiology

Unknown

Linked to cigarette smoking and alcohol consumption. A subset may be radiation induced

Histology

1. 
   

   Exophytic mass with or without an ulcerated surface (Fig. 7.6.1)

   
   
2. 
   

   Loosely fascicular or storiform proliferation of spindled cells (Fig. 7.6.2)

   
   
3. 
   

   No heterologous differentiation

   
   
4. 
   

   No foci of squamous cell carcinoma or foci of squamous dysplasia/carcinoma in situ of the non-ulcerated surface epithelium

   
   
5. 
   

   Variably intense infiltrate of chronic inflammatory cells (Figs. 7.6.2 and 7.6.3)

   
   
6. 
   

   Tumor cells are spindled, stellate, or epithelioid with fibrillar projections (tissue culture appearance) and have nuclei with open chromatin, mild pleomorphism, and prominent nucleoli (Fig. 7.6.3)

   
   
7. 
   

   Mitotic activity may be seen, but no atypical mitoses (Fig. 7.6.3)

1. 
   

   Exophytic mass with a predominantly ulcerated surface (Fig. 7.6.5)

   
   
2. 
   

   Haphazard proliferation of spindled cells with no obvious architectural pattern (Fig. 7.6.6)

   
   
3. 
   

   A small subset shows heterologous differentiation (malignant bone, cartilage, or skeletal muscle)

   
   
4. 
   

   Most have areas of squamous cell carcinoma in the invasive tumor or foci of squamous dysplasia/carcinoma in situ of the residual surface epithelium (Fig. 7.6.6)

   
   
5. 
   

   Inflammatory infiltrate may be present (Fig. 7.6.6)

   
   
6. 
   

   Most are overtly malignant, with hypercellularity, necrosis, atypical mitotic figures, and hyperchromatic nuclei showing marked nuclear pleomorphism (Fig. 7.6.7)

Special studies

• 
  

  ALK immunohistochemistry is very specific, but only 30%-60% sensitive (Fig. 7.6.4)

  
  
• 
  

  Up to 70% harbor ALK gene rearrangements

  
  
• 
  

  Positive for actin and occasionally positive for desmin or cytokeratins. Negative for p63 and p40

  
  
• 
  

  P53 focal or negative in the tumor and surface epithelium

• 
  

  Some are positive for at least one epithelial marker (e.g., p40, p63, cytokeratins, EMA) but a significant subset is negative. P40 is the most specific of these markers (Fig. 7.6.8)

  
  
• 
  

  Negative for ALK

  
  
• 
  

  P53 can be useful if diffusely positive in the tumor as well as atypical surface epithelium

Treatment

Surgical resection

Surgical resection, with or without adjuvant chemoradiation

Prognosis

Good. May rarely recur

Stage-for-stage, has a prognosis similar to conventional squamous cell carcinoma