Lung

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 08, and is sclerosing pneumocytoma of the lung.

The information provided in this case was accurate and correct at the time of publication in 2021. Any changes in terminology since the time of publication may not be reflected in this case.

Microscopic evaluation shows a well-circumscribed heterogeneous lesion with solid, papillary, sclerotic, and hemorrhagic architectural patterns. Two cell types are noted: cuboidal surface cells and round stromal cells. Cytologic atypia, mitos​e​s, and necrosis are ​absent or ​minimal. A background of variable amounts of chronic inflammatory cells, eosinophils, mast cells, and hemosiderin deposits can be seen throughout the tumor. The clinicopathologic findings in this case are characteristic of sclerosing pneumocytoma.

Sclerosing pneumocytoma (SP) is a rare tumor that was first classified as an adenoma in the 2015 World Health Organization (WHO) Classification of Lung Tumors. Most patients present around the fifth decade of life, are predominantly Asian​,​ and are non-smokers. There is a female predilection, with a female-to-male ratio of 5:1. Most cases are incidentally found, but some individuals present with hemoptysis, cough, chest pain, and dyspnea. Imaging usually shows a unilateral solitary peripheral mass. On gross examination, the tumor is well-circumscribed, ranges from 0.3 – 7.0 cm, is gray to tan-yellow and hemorrhagic, and may show cystic areas. SP is considered benign and while rare lymph node metastases have been reported, those cases still behave in an indolent fashion. Limited surgical resection is considered curative without additional treatment. 

Formerly, this tumor was called sclerosing hemangioma because of its morphologic resemblance to a vascular tumor. However, the tumor was renamed sclerosing pneumocytoma on the principle that the tumor cells originate from primitive respiratory epithelial cells. Both the surface cells and round stromal cells stain positive for thyroid transcription factor 1 (TTF1) and epithelial membrane antigen (EMA) and are negative for neuroendocrine ​and vascular ​markers. The surface cells also stain positive for pancytokeratin, surfactant proteins, and Clara cell antigens, while the round stromal cells are negative and stain for ER and PR. AKT1 mutation is the genetic hallmark of SP.

SP usually shows a combination of four primary growth patterns:

1. Papillary pattern: characterized by fronds with a sclerotic center, cuboidal to hobnail lining cells​,​ and round cells sometimes seen in the stalk. The lining cells covering the fronds may exhibit mild pleomorphism and variation in nuclear size, and they may contain intranuclear inclusions. The overall papillary pattern may appear complex and mimic an adenocarcinoma with lepidic growth pattern; however, the cytologic atypia and mitoses are usually minimal. The papillae lack true fibrovascular cores, differentiating them from those of papillary carcinoma. 
2. Solid pattern: shows sheets of round stromal cells. Overall, the round cells appear monotonous with pale ill-defined cytoplasm and bland nuclei. Often, the cytoplasm can be clear and on frozen section may resemble signet-ring cells with eccentrically placed nuclei. A pancytokeratin immunostain can emphasize irregular spaces lined by trapped pneumocytes within the solid sheets of round cells. 
3. Sclerotic pattern: can have dense fibrosis with foci of hyalinization. The sclerosis can be seen in the stalks of the papillae, within the solid pattern, and around hemorrhagic areas. Small blood-filled spaces can be formed from split fibrocollagen within sclerotic areas. 
4. Hemorrhagic pattern: ​v​ariably sized blood-filled cystic spaces creating “blood lakes."
   

Carcinoid tumor is a neuroendocrine neoplasm that appears on imaging as a slow-growing, round, centrally located lesion, although it can be peripherally located in rare cases. Gross examination shows a well-defined, smooth, white cut surface. Microscopically, there is a trabecular and/or organoid growth pattern composed of uniform cells with eosinophilic cytoplasm, round nuclei, and salt-and-pepper chromatin. Peripherally located tumors are more likely to be composed of uniform spindle cells. The solid growth pattern of SP can mimic the appearance of a spindle cell carcinoid. Immunohistochemistry (IHC) for neuroendocrine markers like chromogranin and synaptophysin favor a carcinoid tumor.

Hemangiomas of the lung are rare. They may present with cough and hemoptysis or as incidental, slow-growing solitary peripheral lesions in the lower lobes in children and are associated with indolent behavior. They are composed of thin-walled “capillary” type anastomosing vascular spaces lined by bland endothelial cells in thickened alveolar septae. No atypia or mitoses are seen. The vessels are CD31, CD34, factor 8 positive, and TTF1 negative. Pulmonary hemangiomas are most commonly associated with congenital dysplasia, pulmonary arterio-venous fistula, and congenital telangiectasia.

Well-differentiated invasive pulmonary adenocarcinoma is a common pitfall in the diagnosis of sclerosing pneumocytoma. Differentiating the two entities can be a diagnostic challenge on cytology, small biopsies, and frozen section. Moreover, IHC is not ​very ​helpful because both of the tumors show TTF1, EMA, and Napsin A positivity. Adenocarcinoma usually appears as a spiculated mass on imaging and would have a faster growth rate. Microscopic examination shows indistinct borders, contrary to the well-defined pushing borders of SP​ ​Although SP can show mild atypia and intranuclear pseudoinclusions, the cells of adenocarcinoma typically are more crowded, show frequent and higher-degree atypia, and lack the dual cell population.

Non-mucinous adenocarcinoma in situ classically presents as an incidental ground glass lesion found on imaging. Gross findings show an ill-defined, pale tan nodule or may appear inconspicuous. The lesion is composed of a monomorphic population of bland cuboidal-to-columnar epithelial cells lining slightly widened fibrous septa. This lesion lacks the heterogeneous architecture and biphasic cell population found in SP.

Papillary adenoma is an uncommon solitary, well-defined, intraparenchymal neoplasm with a gray-to-brown cut surface. The overall architecture ​shows​ a papillary growth pattern composed of fibrovascular cores lined by bland cuboidal-to-columnar cells with nuclear grooves. On microscopic examination, the lesion can be differentiated from SP ​​​​​​​​by a single architectural growth pattern, large ectatic spaces without blood, and lack of TTF1-positive stromal round cells.

Solitary fibrous tumor (SFT) is usually pleura-based​ in location​ and well-circumscribed, which on imaging can be confused for a sclerotic SP. However, on microscopic evaluation, SFT shows a patternless architecture composed of alternating hypercellular areas of bland spindled cells and hypocellular areas of hyalinized ropy collagen with dilated, branching blood vessels (hemangiopericytoma-like/staghorn appearance). IHC stains are helpful in confirming the diagnosis of SFT. The tumor cells are positive for CD34 and negative for cytokeratin. A specific diagnostic marker for SFT is STAT6, which reflects the presence of the NAB2-STAT6 gene fusion.

1. Stromal and lining cells of sclerosing ​pneumocytoma ​stain diffusely with which of the following markers?
   
   
   1. CD34
   2. Pancytokeratin
   3. STAT6
   4. Synaptophysin and chromogranin
   5. TTF-1
2. Which of the following best differentiates sclerosing pneumocytoma from invasive well-differentiated pulmonary adenocarcinoma?
   
   
   1. Bland tumor cells
   2. Intranuclear pseudoinclusions
   3. Papillary architecture
   4. TTF1 positivity
   5. ​​​​​Well-defined pushing border
3. Which of the following is most characteristic of sclerosing ​pneumocytoma​?
   
   
   1. Associated with a history of smoking
   2. Benign clinical outcome
   3. Central location
   4. Male predominance
   5. Spiculated mass on imaging

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2. Guseva NV, Tanas MR, Stence AA, et al. The NAB2-STAT6 gene fusion in solitary fibrous tumor can be reliably detected by anchored multiplexed PCR for targeted next-generation sequencing. Cancer Genet. 2016;209(7-8):303-312.
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4. Leslie KO, Wick MR. Practical Pulmonary Pathology: A Diagnostic Approach. 3rd ed. Elsevier; 2018.
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7. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG, eds. WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart. IARC press; 2015. 
8. Wang SE, Nieberg RK. Fine needle aspiration cytology of sclerosing hemangioma of the lung, a mimicker of bronchioloalveolar carcinoma. Acta Cytol 1986;30(1):51–54.

1. TTF-1 (e)
2. Well-defined pushing border (e)
3. Benign clinical outcome (b)