Case 5 -
Lung, Left Upper Lobe; Wedge Biopsy: Miliary Foci of Adenocarcinoma with Micropapillary Pattern; Peribronchiolar Metaplasia; Focal Organizing Pneumonia.
William D. Travis, Memorial Sloan Kettering Cancer Ctr, New York, NY
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77M was diagnosed initially with pneumonia in October 2010. He was treated with antibiotics. PET and
CT showed a RLL hazy infiltrate, but the PET scan was negative. He still had symptoms through the spring
of 2011 with progressive dyspnea and also chest tightness and mucus production. Smoked 1 & ½ pack
per day for 45 years and quit 12 years before. In May of 2011, a new ground glass opacity with
consolidation was found in the left lung. The biopsy revealed the diagnosis.
Case 5 - Slide 1
Lung, left upper lobe; wedge biopsy: Miliary foci of adenocarcinoma with micropapillary pattern; peribronchiolar metaplasia; focal organizing pneumonia.
This case was initially diagnosed as peribronchiolar metaplasia. The challenge in
recognizing that the atypical cells in the alveolar spaces represent adenocarcinoma with an invasive
Worldwide, lung cancer is the most common cause of major cancer mortality in men and the second most
common in women.  Adenocarcinoma is the most common histologic type of lung cancer in most
developed countries.  Recent therapeutic advances have led to a revolution in the lung
cancer field in discovering therapeutically tractable oncogene dependency, that have major implications
for patient evaluation and approach to diagnosis. The recently published IASLC/ATS/ERS Classification of
Lung Adenocarcinoma addresses these issues.  This classification was developed based on an
evidence-based approach by an international multidisciplinary panel including pathologists,
oncologists/respiratory physicians, radiologists, molecular biologists, and thoracic surgeons.
 Multiple new approaches are outlined that will have a major influence on clinical practice
for pathologists as well as the entire multidisciplinary team caring for patients with lung cancer.
Since 70% of patients with lung cancer present with advanced stage disease,  their
diagnosis is usually established based on small biopsies, cytology specimens or both, and the primary
therapy is chemotherapy; the remaining patients usually have resectable lesions and surgery is the
primary treatment. To address all types of patients with lung cancer, there are two major components to
the classification based on the type of specimen: 1) small biopsies and cytology (Table 1) or 2)
resection (Table 2). Because previous WHO classifications did not provide specific criteria and
terminology for pathologic diagnosis of lung cancer in small biopsies and cytology,  this
new classification is more clinically relevant as it addresses these small specimens and addresses
In recent years, three therapeutic advances for advanced NSCLC have made accurate histologic
diagnosis a critical step for developing an individualized approach to management. The first, relates to
tyrosine kinase inhibitors as first line therapy in patients with advanced lung adenocarcinoma with EGFR
mutations.  For this reason, in the new classification EGFR mutation testing is recommended for advanced lung cancer patients with a
histologic diagnosis of adenocarcinoma. Second, patients with adenocarcinoma or NSCLC, not otherwise
specified (NSCLC-NOS) are more responsive to pemetrexed than those squamous cell carcinoma .
Third, squamous cell carcinoma is associated with life threatening hemorrhage in patients treated with
bevacizumab; therefore, this drug is contraindicated in lung cancer patients with this histology .
 So a pathologic diagnosis of adenocarcinoma or squamous cell carcinoma will determine
patient eligibility for EGFR mutation testing and for specific therapies.
In all of these clinical trials the pathologic diagnoses were based on light microscopy with or without
mucin stains but not on the basis of immunohistochemical stains.
Other emerging genetic advances hold future promise for molecular targeted therapies such as 1)
crizotinib which appears to be effective in adenocarcinoma patients with EML4-ALK
and 2) the recent discoveries of FGFR1 amplification and DDR2 mutations in squamous cell carcinoma,
which may render
patients exquisitely sensitive to FGFR inhibition and dasatinib respectively.
New Classification for Resected Specimens
Major changes are also recommended for adenocarcinomas diagnosed in resection specimens (Table
1) the term bronchioloalveolar carcinoma (BAC) should not be used anymore, because
tumors previously classified as BAC are represented by five different tumors in this classification; 2),
for solitary tumors measuring ≤3cm, new concepts of adenocarcinoma in situ
(AIS) and minimally invasive adenocarcinoma (MIA) have been
introduced for lesions that have no invasion or ≤5mm invasion, respectively; these patients should
have 100% or near 100% disease free survival (DFS); 3) for invasive adenocarcinomas, comprehensive
histologic subtyping is recommended for evaluation with classification according to the predominant
subtype; 4) micropapillary adenocarcinoma is proposed as a new subtype with a poor prognosis; 5) the term
lepidic replaces BAC for tumors with a predominant component formerly called non-mucinous BAC, and the
term lepidic predominant adenocarcinoma (LPA) is recommended along with
discontinuing the term "mixed subtype"; and 6) invasive mucinous adenocarcinoma (IMA) is the term used to
replace those formerly classified as mucinous BAC. IMA are strongly correlated with KRAS mutation. EGFR mutations are reported to be
associated with AIS, LPA, papillary and micropapillary patterns and EML4-ALK translocations with acinar,
cribriform and signet ring patterns.
The classification stratifies resected tumors into
prognostically significant histologic subtypes with excellent (AIS and MIA), intermediate (lepidic,
acinar and papillary) and poor prognosis (solid, micropapillary, invasive mucinous and
Points Raised by the Current Case
This case presents an uncommon, but important presentation of lung adenocarcinoma with micropapillary
adenocarcinoma invading alveolar spaces. Since the micropapillary pattern is a poor prognostic subtype
of lung adenocarcinoma, it is particularly important to recognize. This case also illustrates an
important pattern of invasion that is not well appreciated: alveolar space invasion. It is likely this
is an explanation for why the presence of a micropapillary pattern in lung adenocarcinoma is an
independent predictor of recurrence in patients who have had limited resections. 
There are several other patterns of lung adenocarcinoma that can mimic interstitial lung disease.
Colloid adenocarcinomas can resemble mucous plugs or the mucous airspace accumulation in honeycomb
fibrosis. Identification tumor in the form of mucin pools spreading through airspaces in areas that lack
fibrosis is helpful. Clusters of tumor cells within these mucin pools or the presence of foci of other
frankly invasive adenocarcinoma areas are essential to diagnose malignancy. This distinction may be
difficult in a small biopsy, but the presence of mucin pools in the radiographic setting of a lung mass
should raise the differential diagnosis of colloid adenocarcinoma and if the morphology is not completely
benign in appearance, it may indicate the need for additional biopsy material if clinically indicated.
Invasive mucinous adenocarcinomas (IMA), particularly in small biopsies, can be mistaken for benign
glandular epithelium. The presence of columnar goblet cells growing along alveolar walls is not seen in
reactive lesions outside of the setting of type I congenital cystic adenomatoid malformation, where these
mucinous cells may represent precursors to IMA . So in some cases, even small clusters of
goblet cells can be strongly suggestive of IMA.
Rare cases of ciliated adenocarcinomas can be easily mistaken for benign reactive epithelial
proliferations, particularly peribronchiolar metaplasia.
The differential diagnosis also
includes glandular papilloma.
Lepidic patterns of adenocarcinoma also can be confused with interstitial lung disease, particularly
in the setting of multicentric disease. Adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma
(MIA) and lepidic predominant adenocarcinoma (LPA) when they present as a solitary lung nodule they
should not be mistaken for interstitial lung disease. However, when these present in the setting of
multiple nodules or with associated interstitial lesions, this can be a difficult differential diagnosis.
When adenocarcinomas occur in the setting of underlying interstitial lung disease such as
usual interstitial pneumonia or organizing pneumonia, it can also cause challenges in
Key features that favor adenocarcinoma rather than a reactive epithelial
proliferation include: 1) excessive papillary growth, 2) marked cytologic atypia, 3) frank invasive
patterns (e.g. acinar, papillary, solid, micropapillary), 4) invasion of stroma, pleura or blood vessels.
Table 1: IASLC/ATS/ERS Classification for Small Biopsies/cytology
|2004 WHO Classification ||Morphology/Stains ||IASLC/ATS/ERS Terminology|
|Morphologic adenocarcinoma patterns clearly present ||Adenocarcinoma, describe identifiable patterns present (including micropapillary pattern not included in 2004 WHO classification) |
Bronchioloalveolar carcinoma, nonmucinous
Adenocarcinoma with lepidic pattern (if pure, add note: an invasive component cannot be excluded)
Bronchioloalveolar carcinoma, mucinous Mucinous adenocarcinoma (describe patterns present)
|No 2004 WHO counterpart – most will be solid adenocarcinomas ||Morphologic adenocarcinoma patterns not present (supported by special stains, i.e. +TTF-1) ||Non-small cell carcinoma, favor adenocarcinoma|
|SQUAMOUS CELL CARCINOMA ||Morphologic squamous cell patterns clearly present ||Squamous cell carcinoma|
|No 2004 WHO counterpart ||Morphologic squamous cell patterns not present (supported by stains i.e. +p40) ||Non-small cell carcinoma, favor squamous cell carcinoma|
|LARGE CELL CARCINOMA ||No clear adenocarcinoma, squamous or neuroendocrine morphology or staining pattern ||Non-small cell carcinoma, not otherwise specified (NOS)|
Modified from reference 
NSCLC-NOS pattern can be seen not only in large cell carcinomas but also when the solid poorly
differentiated component of adenocarcinomas or squamous cell carcinomas are sampled but do not express
immunohistochemical markers or mucin
Table 2: IASLC/ATS/ERS Classification of Lung Adenocarcinoma in Resection Specimens
Atypical adenomatous hyperplasia
Adenocarcinoma in situ (<3 cm formerly BAC)
- mixed mucinous/non-mucinous
Minimally Invasive Adenocarcinoma
(<3 cm lepidic predominant tumor with <5 mm invasion)
- mixed mucinous/non-mucinous
Lepidic predominant (formerly non-mucinous BAC pattern, with >5 mm invasion)
Solid predominant with mucin production
Variants of Invasive Adenocarcinoma
Invasive mucinous adenocarcinoma (formerly mucinous BAC)
Fetal (low and high grade)
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