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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Clinical History 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 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Figure 1 Case 5 - Figure 2 Case 5 - Figure 3 Case 5 - Figure 4 Case 5 - Figure 5 Case 5 - Figure 6 Case 5 - Figure 7 Case 5 - Figure 8 Case 5 - Figure 9 Case Diagnosis Lung, left upper lobe; wedge biopsy: Miliary foci of adenocarcinoma with micropapillary pattern; peribronchiolar metaplasia; focal organizing pneumonia. Comment: 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 pattern. Introduction Worldwide, lung cancer is the most common cause of major cancer mortality in men and the second most common in women. [1] Adenocarcinoma is the most common histologic type of lung cancer in most developed countries. [2] 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. [3] 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. [3] 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, [3] 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, [3] this new classification is more clinically relevant as it addresses these small specimens and addresses molecular testing. 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. [4] 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 . [5] 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 . [6] 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. [4, 5, 6] 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 translocations [7] and 2) the recent discoveries of FGFR1 amplification and DDR2 mutations in squamous cell carcinoma, [8, 9] 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 2): [3] 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. [3, 10] 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 colloid). [11, 12, 13] 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. [14] 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 [15]. 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. [16, 17, 18] The differential diagnosis also includes glandular papilloma. [16, 17, 18] 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 diagnosis. [19, 20] 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 ADENOCARCINOMA Mixed subtype Acinar Papillary Solid 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 [3] ‡ 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† Preinvasive Lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ (<3 cm formerly BAC) nonmucinous mucinous mixed mucinous/non-mucinous Minimally Invasive Adenocarcinoma (<3 cm lepidic predominant tumor with <5 mm invasion) nonmucinous mucinous mixed mucinous/non-mucinous Invasive Adenocarcinoma Lepidic predominant (formerly non-mucinous BAC pattern, with >5 mm invasion) Acinar predominant Papillary predominant Micropapillary predominant Solid predominant with mucin production Variants of Invasive Adenocarcinoma Invasive mucinous adenocarcinoma (formerly mucinous BAC) Colloid Fetal (low and high grade) Enteric †From reference [3] Reference List Jemal A, Center MM, DeSantis C, Ward EM. 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