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A 46-Year-Old Woman With Atelectasis From an Endobronchial TumorA 46-Year-Old Woman With Atelectasis FREE TO VIEW

Takeshi Uenami, MD; Takashi Kijima, MD, PhD; Masahiro Ayata, MD; Yoshitomo Hayama, MD; Naotoshi Tsuruta, MD; Yoshiyuki Saito, MD, PhD; Takashi Niju, MD; Naozumi Higaki, MD; Toshiyuki Ikeda, MD, PhD
Author and Funding Information

From the Department of Respiratory Medicine (Drs Uenami, Hayama, Tsuruta, Saito, Niju, and Ikeda), Department of Pathology (Dr Ayata), and Department of Respiratory Surgery (Dr Higaki), Nishinomiya Municipal Central Hospital, Hyogo; and Department of Respiratory Medicine, Allergy and Rheumatic Diseases (Dr Kijima), Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, Japan.

Correspondence to: Takeshi Uenami, MD, Department of Respiratory Medicine, Nishinomiya Municipal Central Hospital, 8-24 Hayashida-cho, Nishinomiya, Hyogo 663-8014, Japan; e-mail: med31@nishi-hp.jp


Drs Uenami and Kijima contributed equally to this article as first authors.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(4):1170-1173. doi:10.1378/chest.12-1874
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A 46-year-old woman was referred to the surgery department of our hospital for early stage cancer in the left breast. Because a preoperation chest radiograph showed an abnormal shadow, she was referred to our department. She was an ex-smoker with a 22-pack-year history. Past, family, and occupational histories were unremarkable.

Physical Examination Findings

The patient’s vital signs were normal (temperature, 36.8°C; pulse rate, 83/min; BP, 99/66 mm Hg; oxygen saturation as measured by pulse oximetry, 96% on room air). Superficial lymph nodes were not palpable. Chest auscultation was also normal without wheeze and rhonchi.

Diagnostic Findings

Laboratory findings, including functions of major organs and tumor markers, were all within the normal range. Bacterial examination yielded negative results.

An atelectasis of the right lower lobe of the lung was noted on chest radiograph (Fig 1). Chest CT scan revealed a protruding tumor in the right-side intermedius bronchus with diameters of 18 × 16 mm and a complete atelectasis of the right lower lobe (Fig 2A). No findings of invasion, extrabronchial spread, or mediastinal lymphadenopathy were noted. Bronchoscopic examination revealed a soft mass occluding the lumen of the right-side intermedius bronchus, which was immobile and bled easily on contact (Fig 2B).

Figure Jump LinkFigure 1. Chest radiograph showing an atelectasis of the right lower lobe.Grahic Jump Location
Figure Jump LinkFigure 2. A, Chest CT scan showing an endobronchial tumor with diameters of approximately 18×16 mm protruding the truncus intermedius (arrow) and an atelectasis of the right lower lobe. B, Bronchoscopic examination shows a tumor with irregular surface that obstructs the truncus intermedius.Grahic Jump Location

The patient underwent middle and lower lobectomy because the possibility of malignancy could not be excluded. On gross examination, the surgically resected specimen consisted of a well-circumscribed mass obstructing the truncus intermedius. The surface of the cross-section was smooth and yellow (Fig 3A). Histologically, the tumorous lesion contained spindle-shaped and oval cells with varying degrees of inflammatory cell infiltration of predominantly lymphocytes and plasma cells (Fig 3B).

Figure Jump LinkFigure 3. A, The surgically resected specimen shows a well-circumscribed mass obstructing the truncus intermedius. The surface of the cross-section was smooth and yellow, and no hemorrhage or necrosis was observed. B, Microscopic observation reveals that the tumorous lesion comprised spindle-shaped cells associated with infiltrating lymphocytes and plasma cells (hematoxylin and eosin, original magnification ×200).Grahic Jump Location
What is the diagnosis?
Diagnosis: Anaplastic lymphoma kinase-positive endobronchial inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumor (IMT) has been considered a postinflammatory condition rather than a neoplastic process and referred to as inflammatory pseudotumor, plasma cell granuloma, fibroxanthoma, fibrous histiocytoma, pseudosarcomatous myofibroblastic tumor, and invasive fibrous tumor of the tracheobronchial tree. Histologically, it represents a distinct class of neoplasm comprising spindle-shaped myofibroblast-like cells and a prominent infiltration of inflammatory cells, such as lymphocytes, plasma cells, eosinophils, and macrophages. IMT has now come to be distinguishable from other tumors of nonneoplastic entities.

IMT has a tendency to occur in children and adolescents without predominance in either sex, and the most common site of occurrence is in the lung, followed by the mesentery, abdominal organs, head, and extremities. Pulmonary IMT accounts for <1% of all lung tumors. Endobronchial IMT is rare, with a frequency of approximately 12% of those of pulmonary origin. About 40% of patients with endobronchial IMT are asymptomatic, with the condition noticed incidentally. Others show nonspecific symptoms, such as cough, fever, dyspnea, chest pain, hemoptysis, and wheezing. On chest radiograph and CT scan, pulmonary IMT frequently appears as a solitary well-demarcated nodule or mass and sometimes shows pleural indentation or a spicular formation. Some cases have been reported to show high 18F-fluorodeoxyglucose uptake on PET scan. As such, it is difficult to distinguish IMT from primary lung cancer only by diagnostic imaging.

Histologically, IMT is conventionally classified into three patterns: myxoid/vascular, hypocellular fibrous, and compact spindled. Mesenchymal markers vimentin and smooth muscle actin are usually positive, whereas epithelial markers cytokeratin, desmin, CD34, and S-100 are usually negative. Expression of anaplastic lymphoma kinase (ALK) fusion protein has been documented to be positive in approximately 50% of IMT cases, providing further support for the neoplastic nature of these lesions.

To date, ALK fusion partners identified in IMT are ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase), CARS (cysteinyl-tRNA synthetase), TPM3 (tropomyosin 3), TPM4 (tropomyosin 4), CLTC (clathrin heavy chain), RANBP2 (Ran binding protein 2), SEC31L1 (SEC31 homologue A (Saccharomyces cerevisiae), and PPFIBP1 (protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1). Immunohistochemistry (IHC) is simple, cost-effective, and theoretically useful in detecting ALK-positive tumors with any (including unknown) fusion partner. The concern about IHC is the inability of the conventional polymer method to detect the ALK fusion protein because of its low expression level. The intercalated antibody-enhanced polymer (iAEP) method could overcome this issue. Two ALK-negative IMT cases by conventional IHC have been proven to be ALK-positive by the iAEP method and finally revealed to have a new fusion partner, PPFIBP1. Thus, reassessment by highly sensitive IHC is likely to yield more ALK-positive cases in ALK-negative cases defined by conventional IHC. Break-apart fluorescence in situ hybridization (FISH) for ALK is also useful to confirm the separation ALK locus. However, it is inferior to IHC in terms of cost-effectiveness. Therefore, the currently most reliable diagnostic method is to detect ALK-positive IMT by highly sensitive IHC first and then confirm the translocation by break-apart FISH.

Clinical differences between ALK-positive and ALK-negative IMT cases are not well understood. Distant metastasis of IMT occurs in <5% of all cases, and the most common sites of metastasis are the lung and brain followed by the liver and bone. Recent studies suggested that distant metastases occur primarily in ALK-negative IMT, but local recurrence occurs regardless of ALK expression. Because unexpected and poorly expressed ALK fusion may cause ALK-negative IMT cases, these observations should be readdressed after reassessment of ALK-negative IMT by highly sensitive IHC.

As for treatment, the best choice is surgical excision to cure IMT. In endobronchial IMT, there are various approaches, such as bronchial resection with lobectomy, sleeve-resection with bronchoplasty, and bronchoscopic resection, but there is no consensus because of its rarity. A sustained partial response to ALK inhibitor crizotinib was observed in a patient with ALK-positive IMT, whereas no antitumor activity was observed in another patient without ALK translocation. Thus, ALK inhibitors are the most promising therapeutic option for inoperable or postoperative recurrent ALK-positive IMT. Therefore, it is again important to confirm ALK rearrangement.

Clinical Course

The patient’s endobronchial tumor was diagnosed and classified as a compact spindled pattern of IMT. Immunohistochemically, the spindle-shaped cells were positive for ALK by iAEP method using anti-ALK antibody 5A4 (Fig 4A) but negative for α-smooth muscle actin, cytokeratin (AE1/AE3), or CD34. FISH using break-apart probes (Abbott Laboratories) showed the separation of red and green probe signals in 54% of tumor cells, indicating chromosomal split of ALK (Fig 4B). Thus, the final diagnosis was an endobronchial IMT with ALK rearrangement.

Figure Jump LinkFigure 4. A, Immunohistochemistry using the intercalated antibody-enhanced polymer method shows the diffuse cytoplasmic expression of anaplastic lymphoma kinase (ALK) protein in the spindle-shaped cells (original magnification ×200). B, ALK-split fluorescence in situ hybridization shows separate signals of red and green probes, indicating the chromosomal split of ALK locus (original magnification × 400). Nuclei are stained blue with 49,6-diamidino-2-phenylindole. The inset image shows a representative cell that has one ALK-split allele (red and green) and the other normal ALK allele (yellow).Grahic Jump Location

Because the tumor was located in the intermedius bronchus and the lower lobe was not well preserved, a bronchial resection with bilobectomy of the middle and the lower lobes was chosen. Postoperatively, the patient made an uncomplicated recovery and was discharged on the 10th day after operation. She remains asymptomatic and free of recurrent disease as of the 2.5-year follow-up.

  • 1. IMT represents a distinct class of neoplasm comprising spindle-shaped myofibroblast-like cells and a prominent infiltration of inflammatory cells.

  • 2. Surgical resection is the treatment of choice for endobronchial IMT.

  • 3. For directing management of IMT, ALK fusion should be checked by highly sensitive IHC and confirmed by FISH.

  • 4. ALK inhibitor is a promising therapeutic option for ALK-positive IMT.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors obtained patient permission to publish this information. We thank Kengo Takeuchi, MD, PhD, Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan, for carrying out the FISH analysis.

Pettinato G, Manivel JC, De Rosa N, Dehner LP. Inflammatory myofibroblastic tumor (plasma cell granuloma). Clinicopathologic study of 20 cases with immunohistochemical and ultrastructural observations. Am J Clin Pathol. 1990;94(5):538-546. [PubMed]
 
Coffin CM, Patel A, Perkins S, Elenitoba-Johnson KS, Perlman E, Griffin CA. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol. 2001;14(6):569-576. [CrossRef] [PubMed]
 
Travis WD, Elisabeth B, Muller-Hermelink HK, Harris CC., eds. Pathology and Genetics of Tumours of the Lung, Pleural, Thymus and Heart. Lyon, France: IARC Press; 2004.
 
Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol. 2007;31(4):509-520. [CrossRef] [PubMed]
 
Gleason BC, Hornick JL. Inflammatory myofibroblastic tumours: where are we now? J Clin Pathol. 2008;61(4):428-437. [CrossRef] [PubMed]
 
Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res. 2009;15(9):3143-3149. [CrossRef] [PubMed]
 
Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010;363(18):1727-1733. [CrossRef] [PubMed]
 
Dua SG, Purandare N, Pramesh CS, et al. Fluoro-deoxy glucose-avid endobronchial inflammatory myofibroblastic tumor mimicking bronchial malignancy: report of a case. J Cancer Res Ther. 2011;7(3):340-343. [CrossRef] [PubMed]
 
Takeuchi K, Soda M, Togashi Y, et al. Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1-ALK: reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification. Clin Cancer Res. 2011;17(10):3341-3348. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Chest radiograph showing an atelectasis of the right lower lobe.Grahic Jump Location
Figure Jump LinkFigure 2. A, Chest CT scan showing an endobronchial tumor with diameters of approximately 18×16 mm protruding the truncus intermedius (arrow) and an atelectasis of the right lower lobe. B, Bronchoscopic examination shows a tumor with irregular surface that obstructs the truncus intermedius.Grahic Jump Location
Figure Jump LinkFigure 3. A, The surgically resected specimen shows a well-circumscribed mass obstructing the truncus intermedius. The surface of the cross-section was smooth and yellow, and no hemorrhage or necrosis was observed. B, Microscopic observation reveals that the tumorous lesion comprised spindle-shaped cells associated with infiltrating lymphocytes and plasma cells (hematoxylin and eosin, original magnification ×200).Grahic Jump Location
Figure Jump LinkFigure 4. A, Immunohistochemistry using the intercalated antibody-enhanced polymer method shows the diffuse cytoplasmic expression of anaplastic lymphoma kinase (ALK) protein in the spindle-shaped cells (original magnification ×200). B, ALK-split fluorescence in situ hybridization shows separate signals of red and green probes, indicating the chromosomal split of ALK locus (original magnification × 400). Nuclei are stained blue with 49,6-diamidino-2-phenylindole. The inset image shows a representative cell that has one ALK-split allele (red and green) and the other normal ALK allele (yellow).Grahic Jump Location

Tables

Suggested Readings

Pettinato G, Manivel JC, De Rosa N, Dehner LP. Inflammatory myofibroblastic tumor (plasma cell granuloma). Clinicopathologic study of 20 cases with immunohistochemical and ultrastructural observations. Am J Clin Pathol. 1990;94(5):538-546. [PubMed]
 
Coffin CM, Patel A, Perkins S, Elenitoba-Johnson KS, Perlman E, Griffin CA. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol. 2001;14(6):569-576. [CrossRef] [PubMed]
 
Travis WD, Elisabeth B, Muller-Hermelink HK, Harris CC., eds. Pathology and Genetics of Tumours of the Lung, Pleural, Thymus and Heart. Lyon, France: IARC Press; 2004.
 
Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol. 2007;31(4):509-520. [CrossRef] [PubMed]
 
Gleason BC, Hornick JL. Inflammatory myofibroblastic tumours: where are we now? J Clin Pathol. 2008;61(4):428-437. [CrossRef] [PubMed]
 
Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res. 2009;15(9):3143-3149. [CrossRef] [PubMed]
 
Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010;363(18):1727-1733. [CrossRef] [PubMed]
 
Dua SG, Purandare N, Pramesh CS, et al. Fluoro-deoxy glucose-avid endobronchial inflammatory myofibroblastic tumor mimicking bronchial malignancy: report of a case. J Cancer Res Ther. 2011;7(3):340-343. [CrossRef] [PubMed]
 
Takeuchi K, Soda M, Togashi Y, et al. Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1-ALK: reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification. Clin Cancer Res. 2011;17(10):3341-3348. [CrossRef] [PubMed]
 
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