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Flashcards in Thirty One Deck (21):
1

What is the most common benign lung tumor? What is it like? What are some other benign lung tumors? What do they consist of?

The most common benign lung tumor is a pulmonary
hamartoma, typically a popcorn-shaped mass of cartilage, fat,
fi brous tissue, and blood vessels (Fig. 31.1). A hamartoma is
a non-neoplastic mass of tissue in a normal anatomic location
but with abnormal architecture. Despite its name, cytogenetic
evidence suggests that the pulmonary hamartoma is neoplastic.
Benign neoplasms of the lung include fi broma (a proliferation
of spindle cells resembling mature fi broblasts), leiomyoma (a
proliferation of spindle cells resembling mature smooth muscle
cells), hemangioma (a proliferation of mature endothelial cells
forming blood vessels of variable size), chondroma (a proliferation
of cells resembling mature chondrocytes admixed with
chondroid extracellular matrix), and infl ammatory pseudotumor
(a myofi broblastic proliferation).

2

What is the most common malignant tumor in the lung? Of the primary malignant neoplasms, how common are bronchogenic carcinoma? What does this mean? How common are other types of tumors? What is referred by the term "lung cancer"?

The most common malignant neoplasm in the lung is a
metastasis. Among primary malignant neoplasms of the lung,
90%-95% of these are derived from bronchial epithelium and
are collectively referred to as bronchogenic carcinoma; the
remaining 5%-10% of primary malignant pulmonary neoplasms
comprise a heterogeneous group of cancers. Unless
otherwise specifi ed, the term “lung cancer” typically refers
to bronchogenic carcinoma rather than metastasis or nonbronchogenic
malignancies.

3

How common is bronchogenic carcinomas among cancers? How big of a contributor to cancer related mortality is it? How does the development proceed? What are some common oncogenes involved with it? Tumor suppressor genes?

Excluding non-melanoma skin cancers (squamous cell carcinoma
of the skin and basal cell carcinoma of the skin),
bronchogenic carcinoma represents the second most common
cancer in the United States (see Fig. 32.1) and the most
common cause of cancer-related death in men and women.
The development of bronchogenic carcinoma is a multistep
process in which numerous specifi c mutations accumulate
in a temporal sequence. Common oncogenes involved in the
pathogenesis of bronchogenic carcinomata include c-MYC,
k-RAS, EGFR, c-MET, and c-KIT. Tumor suppressor genes that are commonly deleted or inactivated in the pathogenesis
of bronchogenic carcinoma include p53, RB, p16, and
unknown genes on the short arm of chromosome 3.

4

How is bronchogenic CA subclassified? What are the four major types? What do they share in common? What percent show a combine pattern and which combos are common?

Bronchogenic carcinoma is further subclassifi ed by
microscopic morphologic criteria. Broadly speaking, there are
four major types of bronchogenic carcinoma, and each can be
further subtyped. All types are associated with cigarette smoking
and are aggressive, locally invasive, and frequently are
already widely metastatic at the time of diagnosis. Furthermore,
all types are associated with paraneoplastic syndromes
(Chap. 32). The four major types of bronchogenic carcinoma
are squamous cell carcinoma (SCCA), adenocarcinoma,
large cell carcinoma, and small cell carcinoma (Fig. 31.2).

Approximately 10% of cases of bronchogenic carcinoma
show a combined pattern, usually of SCCA and adenocarcinoma,
or of SCCA and small cell carcinoma.

5

In whom is Squamous cell carcinoma more common? What part of the lungs does it affect and how? What is it like microscopically when well differentiated and poorly differentiated? What are some variants? What are some genes commonly implicated?

Squamous cell carcinoma is more common in men and
generally is a central disease (Fig. 31.3), often with central
necrosis, cavitation, and hilar lymph node involvement. However,
the incidence of SCCA in more peripheral lung locations
is increasing. Microscopically, SCCA is characterized by
production of keratin and/or by the presence of intercellular
bridges between malignant epithelial cells. In well-differentiated
SCCAs, keratin and/or intercellular bridges may be easily
identifi ed; in more poorly differentiated SCCA, mitotic activity
is typically increased, and keratin and intercellular bridges
are more diffi cult to identify. Variants of SCCA include papillary,
clear cell, small cell (not to be confused with small cell
carcinoma, see below), and basaloid. Common genes implicated
in the pathogenesis of SCCA include p53, RB, p16, and
many others.

6

In whom is adenocarcinoma more common? What part of the lungs does it affect and how? What is it like microscopically when well differentiated and poorly differentiated? What are some variants? Which variant stands out as distinct? What are some genes commonly implicated?

Adenocarcinoma is more common in women and
generally is a peripheral lung disease (Fig. 31.4). It is the
most common primary lung cancer in nonsmokers, and the
most common type of bronchogenic carcinoma in men and
women (previously, SCCA was most common in men).
Microscopically, adenocarcinoma shows mucin production
and/or gland formation, features that are more easily recognized
in well differentiated tumors than in poorly differentiated
tumors. Variants of adenocarcinoma include acinar,
papillary, bronchioloalveolar, and solid. Of the subtypes,
bronchioloalveolar carcinoma stands out as distinct not
only grossly and microscopically but also clinically and is
further discussed below. Common genes implicated in the

7

What is bronchioalveolar adenocarcinoma? Where are how does it grow in the lung? How does its risk differ from the other adenocarcinoma subtypes? How is it further subclassified and how do the subclasses differ?

Bronchioloalveolar adenocarcinoma is typically a peripheral,
multinodular lesion that grows along the preexisting
framework of acini without destruction of its architecture. This
growth pattern is called lepidic, a somewhat colorful term likening
the growth of neoplastic cells to butterfl ies sitting atop a
fence (Fig. 31.5). The bronchioloalveolar subtype of adenocarcinoma,
in contrast to other adenocarcinoma subtypes, shows
no signifi cant association with smoking. Bronchioloalveolar
carcinoma is further subclassifi ed into mucinous and nonmucinous
subtypes, with the latter more likely to show aerogenous
spread and, hence, be multinodular (Fig. 31.6).

8

What are large cell carcinoma like? What do they likely represent? What are some subtypes? What are the carcinomata with neuroendocrine differentiation like?

Large cell carcinoma is an anaplastic carcinoma in which
the large malignant cells are so poorly differentiated as to defy
further classifi cation. Since many show minimal squamous or
glandular differentiation at the ultrastructural level, most large
cell carcinomata likely represent very poorly differentiated
examples of SCCA or adenocarcinoma (Fig. 31.7). However,
neuroendocrine differentiation is present in some examples of
large cell carcinoma with genetic features similar to small cell
carcinoma. Such large cell carcinomata with neuroendocrine differentiation can be thought of as a large cell variant of small
cell carcinoma, a somewhat paradoxic designation. Subtypes
of large cell carcinoma include giant cell carcinoma, clear
cell carcinoma, and spindle cell carcinoma.

9

What part of the lungs does small cell CA affect and how? What is it strong associated with? What is it like microscopically? What patterns of growth does it show? What will immuno-histochemical staining show? What are some genes commonly implicated?

Small cell carcinoma, like SCCA, is generally a central
disease (Fig. 31.8) and is very strongly associated with smoking.
Small cell carcinoma is a neuroendocrine lesion that almost
invariably has metastasized by the time of diagnosis. It is
named for its characteristic malignant cells that are smaller than
malignant cells in other types of bronchogenic carcinoma. The
malignant cells do not show squamous or glandular morphology,
and small cell carcinoma is universally considered
high-grade. Refl ecting their neuroendocrine differentiation,
immuno-histochemical staining will typically be positive for
neural markers, for example, neurofi lament, chromogranin,
synaptophysin, and neuron-specifi c enolase (NSE). Ultrastructural
analysis shows dense-core, membrane-bound neurosecretory
granules. Common genes implicated in the pathogenesis of
small cell carcinoma include p53 and RB.

10

How accurate are the different forms of tumor analysis?

Cytologic analysis of sputum and/or bronchial brushings
(Chaps. 18 and 19) can establish a diagnosis of
bronchogenic carcinoma in 80%-90% of cases, potentially
eliminating the need for diagnostic biopsy. However,
false-positive diagnoses can be made, typically in the
setting of pulmonary infarct, bronchiectasis, fungal/
viral infection, lipid pneumonia, or following irradiation.
With regard to the specifi c subtype of bronchogenic
carcinoma, cytologic diagnosis agreement with histologic
diagnosis (the “gold standard”) is 70%-90%. The best agreement by such assays is for small cell carcinoma and
for well-diff erentiated squamous cell carcinomas and
adenocarcinomas.

11

How does a bronchogenic CA begin? How does it progress? Where does it spread to? How do its metastases spread? Where do they most commonly spread to ?

Bronchogenic carcinoma begins as a focus of epithelial
atypia progressing to a lumpy excrescence that elevates or
erodes the epithelium. As the neoplasm grows, it can extend
into the bronchial lumen to cause obstruction, penetrate the
bronchial wall to invade peribronchial tissue, or grow within
the parenchyma displacing other structures. Depending on the
location within the respiratory tract, bronchogenic carcinoma
can involve the pleural surface and spread through the pleural
cavity or into the pericardium. In addition to metastasis through
pleural fl uid, bronchogenic carcinoma can metastasize via
lymphatic and blood vessels. Most cases of bronchogenic carcinoma
show lymph node metastases at the time of diagnosis;
typical lymph nodes involved include tracheal, bronchial, and
mediastinal. The most common sites of distant metastasis of
bronchogenic carcinoma include the adrenals, liver, brain, and
bone. The presentation of bronchogenic carcinoma is markedly
variable and is discussed, along with staging of disease,
in Chap. 32.

12

What are bronchial carcinoids? What are they composed of? How common are they? In which pts. do they typically appear? What environmental risk factors are there?

Carcinoids (or carcinoid tumors) are neuroendocrine neoplasms
with malignant potential and represent 1%-5% of all
primary pulmonary neoplasms. They show equal incidence in
men and women and typically present in a patient less than 40 years old. The development of bronchial carcinoid tumor
has no known relationship to smoking or to other environmental
factors.

13

What are carcinoids like grossly? Where do they appear? What are they like microscopically? Immunohistochemically?

Grossly, bronchial carcinoids [Fig. 31.9(a)] are typically
in a mainstem bronchus as a polypoid spherical intraluminal
mass or as a mucosal plaque (a “collar button lesion”). They
are typically yellow, in contrast to bronchogenic carcinoma,
which is typically white or off-white unless discolored by
hemorrhage. Microscopically [Fig. 31.9(b)], the neoplastic
cells of carcinoid tumor are monotonous with uniform, round
nuclei and are arranged in nests, cords, and islands separated
by a delicate fi brous stroma. Similar to small cell carcinoma,
cells of bronchial carcinoids contain dense core granules
(typical of neuroendocrine differentiation) that are visible
on electron microscopic analysis. Many of the neuroendocrine
immunohistochemical stains that are positive in small
cell carcinoma are likewise positive in bronchial carcinoids
(Fig. 31.10).

14

What are the subtypes of carcinoids? How do they differ?

Bronchial carcinoids are subdivided into two
subtypes: typical and atypical. Typical carcinoids have no
necrosis, have fewer than two mitotic fi gures per high-power
fi eld, and have 5- and 10-year survival rates of 87%. Atypical
carcinoids show focal necrosis and/or two or more mitotic
fi gures per high-power fi eld and have 5- and 10-year survival
rates of 56% and 35%, respectively.

15

Where else are carcinoid tumors found? What is carcinoid syndrome? How common is it with bronchial carcinoids?

Carcinoid tumors are not unique to the respiratory tract
and occur elsewhere, notably the alimentary tract. Carcinoid
syndrome features intermittent attacks of diarrhea, fl ushing,
and cyanosis when such alimentary tract carcinoid tumors
metastasize to the liver. Patients with bronchial carcinoids
only rarely develop carcinoid syndrome.

16

What are some examples of non-bronchogenic malignancies of the pulmonary tract and what are they composed of?

The most common lung malignancy is a metastasis. Of primary
lung malignancies, approximately 5% are not bronchogenic
carcinoma. Examples include fi brosarcoma (malignant
proliferation of cells resembling fi broblasts), leiomyosarcoma
(malignant proliferation of cells resembling smooth muscle
cells), hemangiopericytoma (malignant proliferation of cells
resembling pericytes), Hodgkin disease (a malignant proliferation
of Reed-Sternberg cells, the original nature of which
is arguably lymphoid or histiocytoid), and non-Hodgkin
lymphoma (malignant proliferation of cells with lymphoid
differentiation). Pseudolymphoma and lymphocytic interstitial
pneumonia are not frank malignancies but likely represent an
early stage of lymphoproliferative disorder and are sometimes
referred to as borderline lesions.

17

What is the most common pleural tumor? Where does it come from? What is it associated with? What is a solitary fibrous tumor like?

The most common pleural tumor is a metastasis. Pleural metastasis
is common among carcinoma of the lung, breast, and ovary
and is often accompanied by pleural effusion (Chaps. 19, 26, and
29) that is typically serous or serosanguineous in composition.
Solitary fi brous tumor (pleural fi broma, benign mesothelioma)
is a localized growth of fi brous connective tissue,
typically attached to the pleura by a pedicle (Fig. 31.12). The
vast majority of solitary fi brous tumors are benign, though
malignant versions exist.

18

Where does malignant mesothelioma usually arise? What are some risk factors?

Malignant mesothelioma usually arises in parietal or
visceral pleura but can occur in the peritoneal cavity. The most
important risk factor for development of malignant mesothelioma
is asbestos exposure (Chap. 23), which increases the
risk >1,000-fold. With heavy asbestos exposure, the lifetime
risk of malignant mesothelioma is 7%-10%. In contrast to the
synergy of asbestos and smoking in development of bronchogenic
carcinoma, smoking does not signifi cantly increase the
risk of malignant mesothelioma.

19

What s malignant mesothelioma like grossly? Microscopically? What are the variants? How can the variants be distinguished?

Grossly, malignant mesothelioma typically ensheathes
the lung and is soft, gelatinous, and variably gray to pink. It is
frequently associated with extensive pleural effusion (Chaps.
19, 26, and 29) and direct invasion of adjacent chest structures
(Fig. 31.13). Microscopically, malignant mesothelioma is subdivided
into a sarcomatoid variant (composed of spindle cells),
an epitheliod variant (with papillary architecture and often
resembling adenocarcinoma), and a biphasic variant showing
features of both. Ultrastructural analysis can be helpful in distinguishing
the epithelioid variant of malignant mesothelioma
from adenocarcinoma: In mesothelioma, the neoplastic cells
will show prominent microvilli. Immunohistochemical staining
has largely replaced ultrastructural analysis in establishing
the diagnosis (see Clinical Correlation 31.3).

20

Why is the setting of a pleural malignancy with epitheliod papillary architecture complicated? What is done to clear things up?

In the setting of a pleural malignancy with epithelioid,
papillary architecture, the pathologist can be faced with
a diagnostic dilemma: is the lesion adenocarcinoma of the lung metastatic to the pleura or a primary pleural
malignant mesothelioma? Making the correct diagnosis is
important for proper clinical management; in the setting
of historical occupational asbestos exposure, the diagnosis
often has signifi cant legal implications. Historically,
ultrastructural analysis was of great value in separating the
two neoplasms (Fig. 31.14).
However, the role of ultrastructural analysis has largely
been replaced by immunohistochemical analysis, for which
the pathologist has a large armamentarium of stains that
can aid diagnostic accuracy.

21

How does malignant mesothelioma present? What is the prognosis?

Clinically, malignant mesothelioma presents with chest
pain, dyspnea, and recurrent pleural effusion. Concurrent
pulmonary asbestosis (Chap. 23) is present in approximately
20% of patients with pleural malignant mesothelioma and approximately one-half of patients with peritoneal malignant
mesothelioma. Malignant mesothelioma is a particularly morbid
disease, with a 1-year survival rate of approximately 50%
and a 2-year survival rate approaching 0%.