Heart

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 04, and is pulmonary adenocarcinoma involving the heart.

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.

Sections of the heart show extensive involvement by a tumor with glandular and micropapillary architecture. Tumor necrosis is also present. The neoplastic cells are cytologically ​​​​​​​​atypical, with abundant eosinophilic cytoplasm and prominent nucleoli. Intracytoplasmic vacuoles are present. The tumor is seen predominantly in lymphatic spaces and focally invading the heart muscle. The morphology of the adenocarcinoma in this case is not site-specific, and additional testing is required to identify the primary site. Immunohistochemistry reveals the tumor to express ​​​​​​TTF1 which is a relatively specific marker for pulmonary adenocarcinoma, and CK7. In this case, the morphologic appearance and the immunohistochemical staining pattern are consistent with a diagnosis of primary pulmonary adenocarcinoma.

Lung cancer is the leading cause of cancer-related death globally. As smoking rates have decreased in the US, adenocarcinoma of the lung has overtaken squamous cell carcinoma as the most frequent histologic type of lung cancer. Autopsy studies have demonstrated that different histologic subtypes have different patterns of dissemination, and adenocarcinoma is the most likely to metastasize. For adenocarcinoma, the most common sites of metastases are adrenal gland, liver, bone, and central nervous system. Myocardial involvement is rare overall and is more common for small cell carcinoma than other types. Myocardial involvement is associated with a shorter survival.

The lung is a common site for both primary and metastatic cancer. TTF1 and Napsin A are the two markers for identifying pulmonary origin of an adenocarcinoma, however, TTF1 is preferred due to its nuclear expression. TTF1, is a DNA-binding protein involved in lung development and is expressed in type II pneumocytes and Clara cells. TTF1 stains approximately 75% of lung adenocarcinomas. Napsin A is involved in surfactant production. It is a cytoplasmic stain that stains approximately 75% of lung adenocarcinomas.

The pitfalls with these stains are as ​​​​​​​​​​​​follows:

1. Neither is entirely specific for lung adenocarcinoma. TTF1 stains thyroid tumors and approximately 85% of small cell carcinomas of the lung, 40% of large cell neuroendocrine carcinomas of the lung and extrapulmonary visceral neuroendocrine carcinomas, and fewer than 1% of Merkel cell carcinomas. Napsin A stains a variety of tumors, including most papillary renal cell carcinomas and subsets of clear cell renal cell carcinoma, chromophobe renal cell carcinoma, and ovarian clear cell carcinoma (for which it is diagnostically very useful). A subset of endometrial adenocarcinomas and papillary carcinomas of the thyroid also have been noted to express Napsin ​​​​​​​​​​​​A.
2. TTF1 and Napsin A expression​s​ decrease​ ​with decreasing differentiation of the tumor. Better differentiated adenocarcinomas are more likely to express TTF1 and Napsin A​,​ while poorly differentiated tumors may be negative. Therefore, negative results are inconclusive. As the lung is a common site for metastatic adenocarcinoma, clinical correlation is important​,​ and broadening the panel of antibodies to include lineage specific markers may be useful.
3. Invasive mucinous adenocarcinomas (IMA) of the lung are less common than non-mucinous adenocarcinomas, accounting for 3%–10% of lung adenocarcinomas. IMAs express CK7 and may show focal coexpression of CK20 and/or CDX2 but are usually negative for TTF1 and napsin A. Therefore, separating a primary pulmonary mucinous carcinoma from a metastatic mucinous carcinoma can be difficult or impossible. Co-expression of CK7 and CK20 is often a feature of lung mucinous carcinomas but is also seen in proximal intestinal tumors (foregut tumors). SMAD4 is lost in about 60% of pancreatic ductal adenocarcinomas, which can be a useful finding.
4. Cytokeratin positivity needs to be interpreted with a panel of stains. Cytokeratin expression in some sarcomas can lead to an erroneous assumption that the tumor is a carcinoma.

The WHO classification of lung cancer has now recognized certain morphologic patterns of adenocarcinoma that carry prognostic significance: lepidic (low-grade), acinar and papillary (intermediate-grade), and micropapillary and solid (high-grade). The separation of papillary subtype from micropapillary is important. The papillary subtype is defined as tumor growing in papillary tufts forming florets containing a central fibrovascular core. The micropapillary subtype has papillary tufts that lack central fibrovascular cores. In addition, recent studies have recommended expanding this definition to include tumors that show a filigree histologic pattern characterized by lace-like narrow stacks of tumor cells that are attached to the alveolar walls and lack a central fibrovascular core. Micropapillary features can also be identified in tumors exhibiting stromal invasion. In either setting, the micropapillary and filigree patterns are poor prognostic findings, even when comprising only a small percentage of the tumor.​​

Clear cell renal cell carcinoma (CCRCC) is the most common type of renal cell carcinoma and can be metastatic at presentation. Useful stains to separate CCRCC from non-renal adenocarcinomas include CK7 (unlike most adenocarcinomas, CCRCC is negative for CK7), PAX8 (also a marker for Müllerian, thymic epithelial, and some thyroid tumors), carbonic anhydrase IX (circumferential membranous staining), RCC antigen, and PAX2. ​​​​​

Epithelioid hemangioendothelioma (EHE) is a malignant vascular tumor with myxoid stroma. Intranuclear inclusions and cytologic pleomorphism can be noted. Immunohistochemically, EHE expresses CD31, CD34, FLI, and ERG and is negative for TTF1, calretinin, WT1, and Napsin A. Up to 25% to 30% of EHE can be focally positive for low molecular weight cytokeratin, which is a diagnostic pitfall. The majority of the tumors (90%) harbor a (1;3)(p36.3;q25) translocation creating a WWTR1::CAMTA1 fusion. Immunohistochemically these tumors show nuclear expression of CAMTA1. Approximately 5% of EHE harbor a YAP3::TFE3 fusion. These tumors are more commonly seen in younger patients and are negative for CAMTA1, instead often showing nuclear expression of TFE3.

High-grade serous carcinoma of the ovary (HGSC) is an aggressive tumor that can present with widespread metastases. These tumors morphologically resemble other high-grade adenocarcinomas. Immunostains can help separate HGSC from other high-grade adenocarcinomas. The majority of high-grade serous carcinomas harbor driver mutations in TP53 and show strong and diffuse positive staining for p53. In addition, most HGSC stain with WT1. Along with most adenocarcinomas, HGSC expresses CK7. ​​​​​​​​​​​​PAX8 and ER are also positive in HGSC. TTF1, CK20, CDX2, GATA3, and p63 are negative.

Malignant mesothelioma (MM) is subdivided histologically into epithelioid, sarcomatoid, and mixed forms. Epithelioid MM is the most common subtype and can be difficult to distinguish from adenocarcinoma. It is currently recommended that two mesothelial markers and two adenocarcinoma markers be used to distinguish between epithelioid MM and adenocarcinoma. WT1 (nuclear), calretinin, and CK5/6 are good mesothelial markers, while claudin4, MOC31, BER-EP4, and monoclonal CEA are good markers for adenocarcinoma. Loss of BAP1 staining is also a feature of MM and less likely with adenocarcinomas. One-third to one-half of MM express GATA3, so that is not a useful breast marker. MM would not stain with TTF1.

1. Which statement about the patterns of adenocarcinoma is true?
   
   
   1. Acinar pattern indicate​s​ a poor prognosis.
   2. Cytologic pleomorphism is a component of grading.
   3. Lepidic ​​pattern is considered intermediate histologic grade​.​
   4. Micropapillary pattern consists of papillary tufts lacking fibrovascular cores.
   5. Micropapillary​ pattern​ is only ​prognostically ​significant if comprising 50% or more of the tumor.
2. Which of the following statements best describes mucinous carcinomas of the lung?
   
   
   1. They are more common than non-mucinous lung adenocarcinoma.
   2. They are negative for CDX2.
   3. They are negative for SMAD4.
   4. They co-express CK7 and CK20.
   5. They typically show strong and diffuse expression of TTF1 and Napsin A.
3. Which of the following tumors commonly expresses Napsin A?
   
   
   1. Clear cell carcinoma of the ovary
   2. Colonic adenocarcinoma
   3. Epithelioid hemangioendothelioma
   4. Malignant mesothelioma
   5. Small cell lung carcinoma

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1. Micropapillary pattern consists of papillary tufts lacking fibrovascular cores. (d)
2. They co-express CK7 and CK20. (d)
3. Clear cell carcinoma of the ovary (a)