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malignant progression from type A to type C (81,82). On the basis of these findings, type A and B
adenocarcinomas with an extremely favorable prognosis are candidates for limited surgery such as wedge
resection or segmentectomy, or careful observation alone.

Figure 26.35. Five-year survival rate of each type of small-sized adenocarcinoma

(Noguchi's classification). Type A and B adenocarcinoma shows 100% 5-year survival
rate but is decreased to 75% for type C. And even if the size is less than 2 cm, 5-
year survival rate is only 50%.
VARIANTS OF ADENOCARCINOMA.

The variants include five subtypes. Well-differentiated fetal adenocarcinoma (WDFA) or PET (8, 9, 10) is rare.
The average age of incidence is in the fifth decade. Grossly, the tumor is nonencapsulated but well defined,
and it is not related to visible bronchi. Histologically, the tumor grows expansively, and is composed of
irregular tubular structures consisting of columnar epithelial cells with irregularly dispersed oval nuclei and
clear cytoplasm, which are continuous with morular structures composed of polygonal cells with scant
cytoplasm (Fig. 26.37). The nuclei in morulae are often optically clear or they resemble ground glass, and
they are rich in biotin (87), whereas cytoplasm in some morular cells is argyrophilic, often containing
chromogranin A, synaptophysin, and N-CAM. The stroma is fibrous with no cellular atypia. The prognosis is
much better than that of biphasic blastoma. Mutations in the p53 gene were not seen in any of nine WDFAs,
but they were seen in 5 of 12 biphasic blastomas (88). The subtype that had been referred to as
adenocarcinoma of the fetal lung type (Fig. 26.38) (89,90), although it is very rare, is different from WDFA or
PET (8). The difference is the absence of morular structures, even though the glandular structures with clear

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cytoplasm resemble those seen in pulmonary blastoma and WDFA. This subtype is now classified as clear-cell
adenocarcinoma in the revised classification.
Mucinous adenocarcinoma, mucinous cystadenocarcinoma, and signet ring adenocarcinoma resemble the
tumors of the same name in the gastrointestinal tract. Signet ring carcinoma is a special form of bronchial
gland-type adenocarcinoma, as was previously described (Fig. 26.26) (68,69). Adenocarcinomas with spindle
cell or giant-cell components (or both) are categorized as pleomorphic carcinoma under carcinomas with
pleomorphic, sarcomatoid, or sarcomatous elements (21,22).

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Figure 26.36. Correlation between histolopathologic feature and CT appearance.

Noguchi's type C adenocarcinoma. Replacement growth (lepidic growth) of type C
adenocarcinoma corresponds to ground-glass opacity (GGO) in CT. (A) CT. (B)
Histologic section. (C) Bronchioloalveolar carcinoma (BAC). (D) Invasive lesion.

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Figure 26.37. Pulmonary endodermal tumor resembling fetal lung (well-

differentiated fetal adenocarcinoma, WDFA). Columnar epithelial cells forming
irregular tubules are continuous with morulae consisting of polygonal cells with
occasional clear nuclei.

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Figure 26.38. Histology of clear-cell adenocarcinoma. Tall columnar cells with

clear cytoplasm are arranged in a papillary fashion. Nuclei are apically situated.
Similar papillotubular structures are also seen in pulmonary blastoma and in well-
differentiated fetal adenocarcinoma (WDFA).
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BIOPSY INTERPRETATION.

Because most adenocarcinomas arise in the periphery of the lung, tissue or cells from those tumors must be
obtained by either a transbronchial or a percutaneous route. Therefore, the size of tissue or the number of
cells obtained is often extremely small, and this can make interpretation difficult, particularly when cell
atypia is mild. This means that sometimes a decision cannot be made on whether the specimen represents
atypical adenomatous hyperplasia (3,4,9, 10, 11, 12, 13) or quite well-differentiated papillary or
bronchioloalveolar carcinoma when the specimen is obtained from the periphery of a tumor. If tissue is
obtained from the central portion of a tumor, the fibrous tissue may contain scant or no epithelial
components. When peripheral adenocarcinoma invades proximal bronchi, tumor cell nests are frequently
seen in the subepithelial layer or in the lymphatics, and these rarely spread intraepithelially.
Adenocarcinomas arising in cartilage-bearing bronchi are of either surface epithelial or bronchial gland cell

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type. In the latter case, the biopsy specimen may disclose only bronchial mucosa with or without hyperplastic
or metaplastic changes because carcinoma tends to grow beneath the bronchial epithelium.

DIFFERENTIATION FROM MESOTHELIOMA OF THE MONOPHASIC

EPITHELIAL TYPE.

Peripheral-type adenocarcinoma may spread diffusely into, as well as obliterate, the pleural cavity, in which
the subpleural primary focus remains small and inconspicuous at times. Such an adenocarcinoma simulates
epithelialtype mesothelioma, both grossly and microscopically.
If the tumor cells do not produce mucin, as in the case of the Clara cell or type II alveolar epithelial cell
types, differentiation from mesothelioma may become extremely difficult. Even in such instances,
conventional approaches (i.e., gross features, histology, and histochemistry of mucosubstances) are of prime
importance. However, electron microscopy also may be of great help. The microvilli are often long and
slender in mesothelioma, with the ratio of length to diameter often exceeding 10 (91). IHC, using antibodies
to carcinoembryonic antigen (CEA), vimentin, and adenocarcinoma cells, is also useful for the differential
diagnosis (92). In other words, expression of CEA, surfactant apoprotein, and thyroid transcription factor-1
(TTF-1) is absent or weaker in mesothelioma (93, 94, 95, 96); also, some monoclonal antibodies are
unreactive with mesothelioma but are reactive with adenocarcinoma (97,98). Mesothelioma-binding
antibodies such as thrombomodulin, calretinin, and WT1 are also useful (99, 100, 101, 102). For additional
discussion, see Chapter 27, The Pleura, and the review article by Ordoez and Mackay (103), who stated that
although no method is consistently reliable, a carefully selected and cautiously interpreted group of
immunostains often strongly indicate one tumor or the other.

DIFFERENTIATION FROM METASTATIC ADENOCARCINOMAS IN THE LUNG.

The cytologic features and histologic arrangement of tumor cells of the Clara cell and/or type II alveolar
epithelial cell types are so characteristic that diagnosis of primary lung cancer can be established with ease
in most well-differentiated or moderately differentiated tumors. However, adenocarcinoma metastatic from
organs with myoepithelial cells, such as the breast and salivary gland, may be very similar to some
adenocarcinomas of the bronchial gland cell type, and, although rare, some primary lung adenocarcinomas
resemble colonic and endometrial adenocarcinomas. If such tumors are solitary in the lung, treating the
tumor as a primary adenocarcinoma (unless proved otherwise) is advisable. Adenocarcinoma of the pancreas
and endocervix may spread like bronchioloalveolar carcinoma of the goblet cell type, but the presence of
coagulation necrosis in the tumor suggests a metastatic, rather than a primary, lesion.
A monoclonal antibody against surfactant apoprotein is useful for the differential diagnosis of primary versus

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metastatic adenocarcinoma because positive immunostaining almost definitely indicates primary lung origin
(77,104). TTF-1 has been found to be valuable in distinguishing between primary lung adenocarcinoma and
metastatic carcinoma from other sites, excluding the thyroid gland (95,96). Cytokeratin 7 (CK7), CK20, and
villin IHC profiles are useful in the differential diagnosis of primary versus metastatic adenocarcinoma
because the primary adenocarcinoma reveals a unique profile of CK7 positivity (98%), CK20 negativity (86%),
and villin positivity (without a brush-border pattern; 68%) (see Immunohistochemistry of Malignant Lung
Tumors) (105, 106, 107).

BIOLOGIC BEHAVIOR AND PROGNOSTIC FACTORS.

In lung cancers, as in other cancers, the three most important factors affecting the prognosis of patients are
distant organ metastasis, lymph node metastasis, and pleural involvementthat is, the TNM factors. Other
than the TNM factors, histopathologic findings such as lymphatic and vascular invasion, mitotic index, cell
atypia, micropapillary structures, the proportion of bronchioloalveolar carcinoma at the largest cut surface,
and Noguchi's classification are associated with poor prognosis of adenocarcinoma (7,108).
Many molecules have been reported as IHC prognostic markers, including CEA, Cox2, EGFR, pEGFR, p27, p53,
TTF-1, and H2AX (109, 110, 111, 112, 113, 114, 115, 116). Among these, however, only CEA expression has
been shown to be a statistically significant prognostic marker for small-sized adenocarcinomas.

FUNCTION.

Besides the production of mucin and surfactant, about 9% of adenocarcinomas are said to contain
immunoreactive peptide hormones, such as calcitonin and GRP (117). Some adenocarcinomas are also
immunohistochemically positive for NCAM, chromogranin A, and/or synaptophysin, which are markers for
small-cell carcinoma. An ectopic function more specific for adenocarcinoma is the production of salivary
gland-type amylase (118,119). The incidences of hypertrophic osteoarthropathy and estrogen production are
said to be higher in adenocarcinoma cases in comparison with other forms of lung cancer (21).

Large-Cell Carcinoma

The histologic diagnosis of large-cell carcinoma is made after the exclusion of squamous cell carcinoma,
small-cell carcinoma, adenocarcinoma, and other lung cancers of specific type. The male-to-female ratio in
affected cases is 4 or 5:1, which lies between the ratios of squamous cell carcinoma and adenocarcinoma.

GROSS FEATURES.

Large-cell carcinoma arises more frequently in the periphery of the lung, and it may invade the
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thoracic wall if it is untreated. Typical undifferentiated large-cell carcinoma forms a spherical tumor with
well-defined borders, and it has a bulging, fleshy, homogeneous, rather sarcomatous cut surface. Anthracotic
pigments are not seen because of compressive growth. However, some large-cell carcinomas resemble poorly
differentiated adenocarcinoma or squamous cell carcinoma grossly.

HISTOLOGIC FEATURES.

Most large-cell carcinomas are composed of solid nests of polygonal cells with vesicular nuclei, prominent
nucleoli, moderately abundant cytoplasm, well-defined cell borders, and rather scant fibrovascular stroma
(Fig. 26.39). Carcinomas with frequent mucin-producing cells are classified as adenocarcinoma according to
the WHO criteria, but those with occasional or a few mucin-producing cells are placed in the large-cell
category. Large-cell carcinomas are either cytocohesive or incohesive. In the latter case, marked infiltration
of inflammatory cells, which consist of both lymphoid cells and polymorphonuclear leukocytes, is present.
The WHO has defined five histological variants of large-cell carcinoma: large-cell neuroendocrine carcinoma
(LCNEC); basaloid carcinoma; lymphoepithelioma-like carcinoma; clear-cell carcinoma; and large-cell
carcinoma with a rhabdoid phenotype (Table 26.2) (21,22). Variants other than LCNEC are rare. Basaloid
carcinoma is similar to basaloid squamous cell carcinoma but lacks squamous cell characteristics (39).
Lymphoepithelioma-like carcinoma is histologically similar to carcinoma of the same name in the epipharynx
and thymus, has shown a geographic distribution similar to epipharyngeal lymphoepithelioma, and has the
Epstein-Barr virus genome by in situ hybridization (120). Large-cell carcinoma with the rhabdoid phenotype is
made up of large cells containing eosinophilic globular cytoplasmic inclusions, which are vimentin-positive
(121). Rhabdoid cells may also be present in poorly differentiated adenocarcinomas.
Giant-cell carcinoma, which was a variant of large-cell carcinoma in the second edition of the WHO
classification, is now classified in the category of carcinomas with pleomorphic, sarcomatoid, or sarcomatous
elements (21,22).

ULTRASTRUCTURAL AND IMMUNOHISTOCHEMICAL CHARACTERISTICS.

Ultrastructurally, many large-cell carcinomas can be classified as adenocarcinoma (roughly 50%),

adenosquamous carcinoma (15%), and squamous cell carcinoma (11%) (27). The incidence of undifferentiated
carcinoma (19%) would probably decrease if more samples were examined electron microscopically.
Differentiation toward neuroendocrine cells with neurosecretory-type granules has been observed in one case
of 27, although it appears to be more frequent in Western countries (26).

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Figure 26.39. Large-cell carcinoma. Large polygonal cells with vesicular nuclei,
prominent nucleoli, and rich cytoplasm show diffuse growth accompanied by scant
fibrovascular stroma.
Immunohistochemically, some tumors (37%) react positively with DAKO cytokeratin antibody, and other
tumors (33%) possess an immunoreactive secretory component (DAKO). A tumor with neuroendocrine-type
granules was shown to be positive for calcitonin (27).

INTERPRETATION OF BRONCHIAL BIOPSY SPECIMENS.

Because large-cell carcinomas are generally considered poorly differentiated forms of adenocarcinoma,
squamous cell carcinoma, or neuroendocrine carcinoma, and all major histologic types of lung cancers may
contain foci with features of large-cell carcinoma, a diagnosis of large-cell carcinoma cannot be made from
small bronchial biopsy specimens. The same can be said concerning metastatic tumors in lymph nodes. In
those instances, the diagnosis must be poorly differentiated carcinoma consisting of large-cell components.

CLINICAL ASPECTS AND BIOLOGIC BEHAVIOR.

The 5-year survival rate of patients with large-cell carcinoma is quite close to that for adenocarcinoma.

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Therefore, a discrepancy in the diagnosis of large-cell carcinoma and poorly differentiated adenocarcinoma
does not mean much from a practical viewpoint. The diagnosis of large-cell carcinoma from small biopsy
specimens indicates that the tumor is large-cell carcinoma, poorly differentiated squamous cell carcinoma, or
adenocarcinoma with large-cell components. The incidence of large-cell carcinoma varies from one
institution to another, partly because of variations in the details of histologic examination. Its incidence in
autopsy materials is generally higher than that in surgical materials because postmortem changes may
obscure the glandular structures. Furthermore, the responses to antitumor agents and radiation may also be
similar and fairly good in these tumors.
A sign occasionally noted in cases of large-cell carcinoma and poorly differentiated carcinoma with a
predominant large-cell component is leukocytosis in the absence of infection. The white blood cell count may
exceed 100,000 cells per mm3. This results from the production of colony-stimulating factor by the tumor
(122). The xenotransplantation of such tumors into athymic nude mice induces leukocytosis, in which the
white blood cell count returns to a normal level within a week after removal of the transplanted tumor (123).
Patients with large (giant)-cell carcinoma also may develop hepatosplenomegaly without metastasis, which
also regresses after the removal of the primary tumor. This phenomenon is probably the result of
hypervolemia. In rare instances, this tumor produces human chorionic gonadotropin, and gynecomastia may
occur (139).

Large-Cell Neuroendocrine Carcinoma

The revised WHO classification of lung and pleural tumors recommended inclusion of large-cell
neuroendocrine carcinoma (LCNEC) in the category of large-cell carcinoma (21,22). LCNEC is defined as a
large-cell carcinoma showing histologic

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features such as organoid nesting, trabeculae, and rosette-like and palisading patterns that suggest
neuroendocrine differentiation and in which the latter can be confirmed by IHC or electron microscopy. The
tumor cells are generally large with moderate to abundant cytoplasm, vesicular to finely granular nuclei,
and, often, prominent nucleoli (Fig. 26.40). In distinguishing large-cell neuroendocrine carcinoma from
atypical carcinoid, in addition to histology, the mitotic count is useful (21,22), with 2 to 10 mitotic figures per
10 high-power fields in atypical carcinoids and a larger number in LCNEC.

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Figure 26.40. Large-cell neuroendocrine carcinoma. (A) Histology of a large-cell

neuroendocrine carcinoma with a rosettelike structure is shown. (B) The cell
membrane of large tumor cells is positive for neural cell adhesion molecule
(immunostaining).
Various terms proposed for non-small-cell lung cancers with neuroendocrine properties are encountered
occasionally, including neuroendocrine carcinoma of intermediate cell type, non-small-cell carcinoma with
neuroendocrine features, and large-cell neuroendocrine carcinoma (26,125, 126, 127). The marker
substances used for determination of neuroendocrine properties vary among investigators, and include
chromogranin A, N-CAM (CD56), synaptophysin, GRP, neurofilament, NSE, and Leu-7, as well as
neurosecretory granules. Expression of TTF-1 and BCL-2 protein is reported to be closely associated with
neuroendocrine differentiation in both small-cell carcinoma and large-cell neuroendocrine carcinoma
(128,129). NSE and Leu-7 may be positive in nonneuroendocrine cells, and these should be excluded as
neuroendocrine markers. The WHO has recommended that CD56, chromogranin A, and synaptophysin be used
to confirm the diagnosis of LCNEC immunohistochemically. Interpretation of granules at the ultrastructural
level must also be performed cautiously; not only the structure but also the location should be examined
carefully. On the basis of these data, together with those of others (130,131), it can be concluded that many
large-cell carcinomas are, in fact, poorly differentiated squamous cell carcinomas, adenocarcinomas, or
neuroendocrine carcinomas.
Together with LCNEC, neuroendocrine (NE) tumors of the lung include four histological subtypes: LCNEC,
typical carcinoid, atypical carcinoid, and small-cell carcinoma. The clinicopathologic differences among these
four tumor types are still not fully characterized. However, Asamura et al. examined 366 NE tumors in
Japanese patients clinicopathologically, and reported that the 5-year survival rate was 96.2% for those with
typical carcinoid, 77.8% for atypical carcinoid, 40.3% for LCNEC, and 35.7% for small-cell carcinoma ( 8).
LCNEC and small-cell carcinoma are the two most highly malignant NE tumors and show no significant

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difference in prognosis. However, the question of whether large-cell neuroendocrine carcinoma should be
treated similarly to small-cell carcinoma remains to be decided until further cases have been accumulated.

Adenosquamous Carcinoma

Adenosquamous carcinoma, a mixture of adenocarcinoma and squamous cell carcinoma ( Fig. 26.41),
comprises about 3.5% of surgically resected lung cancers. It arises both in the hilar region (major bronchi) and
in the periphery of the lung. Theoretically, the following four types exist: (a) collision of adenocarcinoma and
squamous cell carcinoma, in which the gross features and serial chest radiographs, if available, may be of
great help; (b) adenocarcinoma showing squamous metaplasia in areas; (c) tumors composed of bipotential
cells showing glandular cell differentiation in some areas and squamous cell differentiation in others; and (d)
mucoepidermoid tumor with marked cell atypia or of a less differentiated form. Tumors of types (a)

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through (c) supposedly originate in bronchial or bronchioloalveolar cells, but a tumor of type (d) is of
bronchial gland origin, and it should therefore not be included in the category of adenosquamous carcinoma.

Figure 26.41. Adenosquamous carcinoma. At the upper left, a focus of metaplastic

squamous cell change is evident in a neoplastic gland.

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TABLE 26.5 Histology of Metastases in Lymph Nodes in Cases of

Adenosquamous Carcinoma, According to the Amount of Each

Component

Total No. Cases with Lymph Node Metastases by Histology

Number of

Area (%) Cases

Occupied (Male:Fem

by ale) Subtotal Ad Sq Adsq Undiff

Ad > 80, 20 5 (3:2) 3 2 1 0 0

> Sq

80 > Ad > 9 (6:3) 6 4 1 0 1

50, 50 > Sq

> 20

Ad > Sq 9 (9:0) 7 4 1 1 1

50 > Ad > 10 (6:4) 2 2 0 0 0

20, 80 > Sq

> 50

20 > Ad, Sq 16 (13:3) 11 1 6 3 0

> 80

Ad > Undiff 3 (3:0) 3 1 0 1 1

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> Sq

Total 52 32 14 9 5 3

Ad, adenocarcinoma; Adsq, adenosquamous carcinoma; Sq, squamous cell

carcinoma; Undiff, undifferentiated carcinoma.

In any of those instances, both components should be recognized without difficulty and should lead to a
diagnosis of adenosquamous carcinoma, with each comprising at least 10% of the whole tumor according to
the revised WHO classification (21,22). If either adenocarcinoma or squamous cell carcinoma is the minor
component of the tumor, the histologic diagnosis is made on the basis of the histologic characteristics of the
major component, and the presence of the minor component is merely described. In our series, about 90% of
cases were peripheral in origin. The histology of lymph node metastasis cannot always be predicted from the
histology of the primary focus, as Table 26.5 shows. However, the adenocarcinomatous component tends to
metastasize more frequently, unless the squamous cell carcinoma component is predominant in the primary
tumor. Analyses of 56 cases of surgically resected adenosquamous carcinomas revealed that the outcome was
significantly poorer than that of adenocarcinomas and squamous cell carcinomas, particularly in stages I and
II, and that the amount of the adenocarcinoma component did not affect the survival rate (132). The finding
that the histologic subtype of adenosquamous carcinoma is one of the independent prognostic determinants
may be explained by the general observation that adenosquamous carcinoma of the lung is almost always
composed of tumor cells with moderate to severe nuclear atypia.

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