By Anonymous
Didactic lectures, original research posters and presentations, and case presentations were conducted at the 5th Biennial Meeting of the Pulmonary Pathology Society June 20 through 22, 2007, at the El Dorado Hotel and Spa in Santa Fe, NM. The meeting drew participants from 10 nations. Fiftytwo faculty members participated in invited lectures and discussions on neoplastic and nonneoplastic lung disease. A discussion on The Utility of Consensus Classifications was organized by Dr JeffreyMyers of the University of Michigan, with opposing views provided by Dr Alain Borczuk of Columbia University and Dr William Travis of Memorial Sloan Kettering Cancer Center. A Techniques Session was organized by Dr Samuel Yousem and moderated by Dr Sanja Dacic, both of the University of Pittsburgh Medical Center. Multidisciplinary sessions were given by Dr Teri Franks and Dr Jeffrey Galvin of the Armed Forces Institute of Pathology, Dr Andrew Churg of the University of British Columbia, and Dr Moises Selman of the Instituto Nacional de Enfermedades Respiratorias. Special presentations were given by Dr Aliya Husain of the University of Chicago and Dr Richard Attanoos of Llandough Hospital, Cardiff, Wales. Dr Douglas Flieder of Fox Chase Cancer Center chaired the Abstract Committee, Dr Andras Khoor of Mayo Clinic Jacksonville chaired the Case Presentations, and Dr Mary Beth Beasley of Mount Sinai School of Medicine, New York, chaired the Mystery Cases. The abstracts from this meeting appear below.
Minute Pulmonary Meningotheliallike Nodule Syndrome
Frank Schneider1 ; Lewis J. Wesselius2 ; Henry D. Tazelaar.2 1Duke University Medical Center; 2Mayo Clinic, Scottsdale, Ariz.
Minute pulmonary meningotheliallike nodules (MPMNs) are small, cellular structures of unknown origin that are frequently identified as incidental findings in lung biopsies. Once thought to be chemodectomas because of their association with vessels, MPMNs’ lack of endocrine granules and nerve fibers helps to dispel this notion. The current designation was prompted by MPMNs’ immunohistochemical and ultrastructural features of meningothelial cells; yet, the histogenesis of MPMNs remains unclear. The presence of more than 3 MPMNs in a patient, as identified by imaging and subsequent histologic examination, has been referred to as MPMNomatosis. Whereas isolated nodules are thought to be of a reactive nature, recent studies suggest that MPMNomatosis might represent the transition between a reactive and neoplastic proliferation. This rare syndrome is usually asymptomatic. We describe a 69yearold woman nonsmoker who had a history of asthma for more than 10 years. She presented with a chronic cough and shortness of breath, which did not improve despite intensification of treatment. Imaging studies showed innumerable bilateral small groundglass opacities in the periphery of the lung. Open biopsies demonstrated multiple MPMNs in each of the 3 lung wedges. In addition, constriction of airways by submucosal fibrosis consistent with obliterative bronchiolitis was found, likely contributing to the patient’s symptoms. After 6 months of steroid treatment, the patient showed neither clinical improvement nor deterioration of her symptoms. It is unclear whether the MPMNs were causally related to the patient’s symptoms or whether they were innocent bystanders.
Metastatic Carcinoma of the Lung to Male Breast or Anterior Chest Wall on FineNeedle Aspiration: A Review of 36 Cases
Monica I. Ruiz1 ; Rodolfo J. Nudelman1 ; Linda K. Green.2 1Baylor College of Medicine, Houston, Tex; 2Veterans Affairs Medical Center & Baylor College of Medicine, Houston, Tex.
Context: Carcinoma of the breast is uncommon in men. When a man presents with a breast or anterior chest mass, a primary tumor must be distinguished from a soft tissue metastases. Lung cancer is the most common tumor metastasizing to soft tissue. It may be difficult to distinguish from a primary tumor. We designed a study to examine the incidence, characteristics and features of primary breast cancer and metastatic lung cancer to the male breast on fineneedle aspiration (FNA).
Design: We reviewed our files dating from 1986 to 2007 for primary and metastatic carcinomas of the male breast diagnosed by FNA. Each case was reviewed for tumor location, cell type, immunohistochemistry, electron microscopy, clinical history, radiographic findings, and clinical course.
Results: There were 36 metastatic lung carcinomas: 12 (33%) adenocarcinomas, 12 (33%) nonsmall cell carcinomas, 8 (22%) squamous cell carcinomas, and 4 (11%) small cell carcinomas. There were 10 primary breast carcinomas. The most important aid in arriving at the correct diagnosis was computed tomography and magnetic resonance imaging of the thorax.
Conclusions: In our patient population, metastatic lung carcinoma to the male breast or chest was much more common than primary breast carcinoma. On FNA, a poorly differentiated carcinoma may be primary or metastatic to the breast. Estrogen and progesterone receptors may be seen in both lung and breast cancer. Immunohistochemistry is variable and may not always distinguish a breast primary from a lung primary. A search for a lung primary should always be considered in a male with a breast or chest mass malignancy.
Metastatic Lung Carcinoma to the Stomach Masquerading as a Primary Gastric Malignancy: A Review of 64 Cases
Rodolfo J. Nudelman1 ; Monica I. Ruiz1 ; Linda K. Green.2 1Baylor College of Medicine, Houston, Tex; 2Veterans Affairs Medical Center & Baylor College of Medicine, Houston, Tex.
Context: Rarely will lung tumors metastasize to the stomach and present as bleeding ulcerated masses. They may be difficult to distinguish from primary gastric malignancies. Differentiation between the two is crucial for therapeutic management.
Design: The files of our institution from the last 40 years were searched for surgical, necropsy, and cytologyproven metastases to the stomach. The tumors proven to be lung in origin by clinical, necropsy, or ancillary tests were selected, and the clinical findings, upper gastrointestinal endoscopy findings, radiographic data, histology, and ancillary tests were reviewed for each case.
Results: There were 123 metastases to the stomach with 64 proven lung cancers. The histopathologic types included the following: 27 (42%) adenocarcinomas, 19 (29%) small cell carcinomas, 12 (19%) squamous cell carcinomas, and 6 (9%) large cell carcinomas. The lesions were often volcano like in appearance. The lack of transformation from the gastric mucosa was a helpful clue. In some cases, immunohistochemistry was valuable.
Conclusions: Lung cancer can present as an ulcerated lesion in the stomach. Lesions with glandular, squamous, and neuroendocrine differentiation all occur in the stomach; therefore, distinction between the two is difficult. If a lesion has an uncharacteristic endoscopic or gross appearance, a metastatic lesion should be entertained. Immunohistochemistry may be helpful (thyroid transcription factor 1 positive), but not in all cases. Clinical and radiographic data is often helpful. To prevent diagnostic errors, it is important to recognize that metastatic carcinomas from the lung may, on rare occasion, present as gastric ulcers or masses.
Superoxide Dismutase Polymorphisms and Expression in Idiopathic Pulmonary Fibrosis
Patrizia Morbini1 ; Simona Inghilleri2 ; Ilaria Campo2 ; Chiara Villa1 ; Tiberio Oggionni2 ; Maurizio Luisetti.1 1Universita` di Pavia; 2 Fondazione IRCCS Policlinico S. Matteo.
Context: Superoxide dismutases (SOD), genetic variants associated with reduced scavenger activity and/or stability, could play a role in the development of pulmonary fibrosis mediated by increased oxidative stress.
Design: The Arg213Gly polymorphism in EcSOD and the Ala16Val polymorphism in MnSOD were investigated in 70 patients with a clinical and instrumental diagnosis of idiopathic pulmonary fibrosis (IPF), in 38 different patients with a confirmed histopathologic diagnosis of usual interstitial pneumonia (UIP) according to ATS/ ERS criteria, and in 295 normal subjects. EcSOD and MnSOD expression were assessed immunohistochemically in UIP samples.
Results: MnSOD Ala16Val polymorphism was significantly more frequent in histologically confirmed UIP cases (heterozygous, 39%; homozygous, 44%) than in control cases (heterozygous, 51%; homozygous, 25%; P
Conclusions: Molecular investigations documented the significant association of a MnSOD genetic variant associated with reduced antioxidant activity in a series of histologically confirmed UIP cases, but not in a series of clinically diagnosed IPF cases. This result stresses the importance of basing molecular association studies of UIP on carefully selected patient series. Negative antioxidant activity in fibroblastic foci, together with the molecular results, suggests that foci can be the site of increased oxidative stress. Glomangiomyopericytoma Arising in a Diffuse and Nodular Myofibromatosislike Process in the Lung With Vascular Endothelial Growth Factor Receptor 3 Expression
Ulrike M. GruberMoesenbacher1 ; Alicia MorresiHauf2 ; Helmut H. Popper. 3 1Teaching Hospital Feldkirch; 2Fachkliniken Asklepios; 3Medical University of Graz.
Tumors of the perivascular system, glomustumor, hemangiopericytoma, and PEComas have been reported in the lung. We present a large tumor arising in a nodular and diffuse growing perivascular process with focal myoid and glomangiopericytoma differentiation for which we propose the term glomangiomyopericytoma. A 46yearold woman presented with a mediastinal mass and pulmonary nodular densities on chest xray, which were interpreted as Langerhans cell histiocytosis. After 5 years, a large lung tumor developed. Both lungs contained nodules composed of small spindle cells with inconspicuous oval nuclei and indistinct borders of the slightly eosinophilic to clear cytoplasm growing around capillaries in a hemangiopericytomalike pattern. The large tumor consisted of spindle and epitheloid cells, increased nuclear polymorphism, some multinucleated giant cells, and no necrosis. Immunohistochemistry of the tumor and diffuse proliferation were negative for pancytokeratin, thyroid transcription factor 1, surfactant apoproteinA, neuronspecific enolase, S100 protein, CD56, leukocyte common antigen, CD68, desmin, estrogen receptor, progesterone receptor, vascular endothelial growth factor (VEGF), CD31, cAMPkinase-alpha, and hamartin, but were positive for vimentin, VEGF receptor 3, endothelkinase Tie2, tuberin, and focally for smooth muscle actin and CD34. Exclusively in the large tumor, PEComalike cells expressed HMB45; 1 to 5% of tumor cells were positive for MIB 1. In the differential diagnosis, lymphangioleiomyomatosis, PEComa, hemangioendothelioma, hemangiopericytoma, histiocytic tumors, and solitary fibrous tumor were considered but could be excluded based on immunohistochemistry. Due to the loss of hamartin, the reticulonodular proliferation clearly belongs to the spectrum of perivascular tuberous sclerosis complexrelated diseases. Hormone therapy with Letrozol and chemotherapy with doxorubicin were unsuccessful. Bevacixumab and Gemcitabine as secondline therapy stopped progression and resulted in shrinkage of the large nodules.
Hodgkin Lymphoma Presenting as Multiple Cavitary Pulmonary Nodules
Shannon Pavlich; Jacqueline K. Trupiano. William Beaumont Hospital.
Context: Hodgkin lymphoma (HL) involving the lung is uncommon. It may present in a variety of radiographic and histologic patterns, including solid, necrotizing, and cavitary lesions with or without associated mediastinal adenopathy. Histologically, it may masquerade as a necrotizing, inflammatory, or granulomatous reaction and may be misdiagnosed as an infectious process. HL should be considered in the differential diagnosis of pulmonary lesions, particularly those associated with adenopathy.
Design: We report a case of an 18yearold man presenting with cough, fever, multiple cavitary pulmonary nodules, pleural effusion, and mediastinal adenopathy.
Results: Bronchoalveolar lavage and pleural fluid cytology revealed neutrophilic inflammation. Initial biopsies of both a mediastinal lymph node and lung nodule showed necrotizing, neutrophilic inflammation consistent with abscess. An infectious etiology was the working diagnosis, and multiple cultures and serologic studies were performed, all of which were negative. The pulmonary nodules increased with enlargement and coalescence. Repeat pulmonary biopsy revealed a marked necrotizing inflammatory reaction with scattered CD30positive ReedSternberg cells and focal areas of fibrosis, consistent with HL, nodular sclerosis type.
Conclustions: HL may involve the lung as a primary process, or more commonly, in association with mediastinal disease. The histology is variable and often masquerades as an inflammatory reaction, which may be misdiagnosed as a presumed infectious process, leading to delay in treatment and progression of disease. HL should be considered in the differential diagnosis of necrotizing, inflammatory, and granulomatous pulmonary lesions.
Expression of Angiostatin Receptor Annexin II in Lung Squamous Cell Carcinoma: A Potential New Therapeutic Target
Kai Zhang; Fan Lin; Jianhui Shi; Ce Zhang. Geisinger Medical Laboratory, Geisinger Health System, Danville, Pa.
We reviewed a total of 44 lung resection cases of lung nonsmall cell carcinoma, including G2, G3 squamous cell carcinoma (SCC) (n = 20) and G2, G3 adenocarcinoma (ACA) (n = 24). Immunostain (IHC) was done using monoclonal antiannexin II (ANX2) antibody. Visible cytoplasmic and/or membranous staining was considered as positive staining. The intensity was graded subjectively as weak, intermediate or strong. The distribution was recorded as negative (no staining), 1+ (75%). Western blotting was done on 1 G2 SCC, 1 G2 ACA, benign lung tissue, and a known positive control. beta Actin was used for checking equal loading. The results were as follows: In all 44 benign lung tissues, no cells were positive for ANX2 by IHC. Positive staining for ANX2 was observed in 19 (95%) of 20 SCCs, and most cases showed strong or moderate staining intensity, with 55% of cases showing 3+ or 4+ staining. In contrast, only 1 case (of 24; 4%) of ACA showed very focal and weak (1+) staining. In addition, the cells located at the basal layers of some of the benign bronchioles near SCCs expressed ANX2, which was not observed in the cases of ACA. Western blotting showed a positive band at 38 kd on SCC and on the positive control sample but not on benign lung tissue and ACA. The Western blotting results support immunohsitochemical findings. In conclusion, the novel findings of expression of ANX2 on lung SCC provide a basis for a potential new therapeutic target, a useful marker for distinction between SCC and ACA, and a potential role in the pathogenesis of lung SCC.
Metastatic Lung Adenocarcinoma of Fetal Type to the Ovaries
Mostafa M. Fraig. Medical University of South Carolina, Charleston.
This case concerns a 37yearold woman with a 5year pack history of smoking who presented with a 7.5cm wellcircumscribed mass in the left lower lobe. Abdominal computed tomography scan performed at the time of presentation revealed no abdominal or pelvic masses. An initial biopsy was reported as carcinoid tumor. A lobectomy was performed, and the tumor was diagnosed as pulmonary blastoma. The woman experienced recurrences in the opposite lung as well as in bone. Six years later, she was found to have a 10cm ovarian mass that was positive for adenocarcinoma. Because of the morphologic similarities between lung adenocarcinoma of fetal type and endometrioid adenocarcinoma, thyroid transcription factor 1 immunostains were performed on both tumors and proved to be positivie in both. The differential diagnosis of both tumors and a review of the literature on the metastatic potential of the welldifferentiarted fetal adenocarcinoma will be presented.
Solitary Intrapulmonary Cystic Lymphangioma
Hiroshi Minato1 ; Sachiko Kaji2 ; Eriko Kinoshita1 ; Nozomu Kurose1 ; Takayuki Nojima.1 1Kanazawa Medical University, Ishikawa, Japan; 2 Chiba Cancer Center, Chiba, Japan.
Context: Intrapulmonary lymphangioma rarely presents as a solitary pulmonary lesion, and the abnormal vessels may be capillary, cavernous, or cystic in type. We experienced a case of solitary cystic lymphangioma of the lung and here present its clinicopathologic findings.
Design: A 2monthold male infant was referred to our hospital because of a persistent cough. Chest radiograph showed a large cyst in the right lung. He was born of a fullterm, normal delivery. No other lesion was observed extrapulmonary or intrapulmonary. Under the preoperative diagnosis of bronchogenic cyst, he underwent right lower lobectomy at the age of 11 months.
Results: A resected specimen contained a septate cystic lesion that measured 5.5 x 5.5 x 4.5 cm. The cyst had a small amount of serous fluid, and the inner surface was smooth. Microscopically, the lesion was composed of a large cystic space and interconnected slitlike spaces surrounding bronchovascular islands. The cysts were lined by a monolayer of flat cells and occasional multinucleated giant cells. Neither significant smooth muscle proliferation nor lymphoid follicles were observed. Immunohistochemically, the lining cells of the cystic lesion were diffusely positive for D240, CD34, and CD31, but were negative for AE1/3 and HMB45. Postoperative course was uneventful. Differential diagnosis of intrapulmonary lymphangioma may include lobar or interstitial emphysema, bronchogenic cyst, congenital cystic adenomatoid malformation, and alveolar adenoma.
Conclusions: Solitary intrapulmonary lymphangioma is a rare, benign, and localized lesion. D240 was useful in differentiating it from other diseases and in determining the extent of the lesion.
Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation in a Patient With Active Wegener Granulomatosis
Lakshmi Puttagunta; Khalida Nasim; Dale C. Lien; Kenneth C. Stewart; Joanne Homik; Steven S. Caldwell; Justin Weinkauf. University of Alberta, Alberta, Canada.
Context: Lung transplantation is a rare indication in patients with Wegener granulomatosis (WG) with failed medical treatment. Ventilator dependence and extracorporeal membrane oxygenation (ECMO) have traditionally been regarded as relative contraindications to lung transplantation. We report on a patient with WG who was maintained on ECMO until the lung allografts became available and were successfully transplanted.
Design: A 17yearold adolescent boy was diagnosed with WG based on clinical history, positive cantineutrophil cytoplasmic antibodies (ANCA), a renal biopsy, and a subsequent lung explant pathology report. Despite rigorous medical treatment with cyclophosphamide,methyl prednisolone, hemodialysis, plasmapheresis, and rituximab, his condition deteriorated, and he developed massive pulmonary hemorrhage and hypoxemic respiratory failure. On day 11 of his admission, the patient was started on venoarterial ECMO along with anticoagulation, but with no improvement in oxygenation. He received bilateral lung allografts on day 15 of his hospitalization and was taken off ECMO intraoperatively. He received standard immunosuppressive therapy and continued with intermittent hemodialysis. He subsequently regained nearly normal renal function and his ANCA titers became negative. He is now 550 days posttransplant and is doing well. Conclusions: To our knowledge, this is the first report of successful use of ECMO as a bridge to lung transplantation.
Diffuse Lymphangiomatosis Mimicking Interstitial Lung Disease
Helmut H. Popper; Jana Polachova. Medical University of Graz.
A 67yearold woman presented having experienced cough and dyspnea for months. From an xray, infection was suspected, and treatment with antibiotics was started. The process worsened. On highresolution computed tomography, ground glass and consolidation areas were seen. Total body irradiation showed organizing pneumonia. Bronchoalveolar lavage diagnosed a lymphocytic, CD4dominated, and mildly granulocytic alveolitis. A videothoracoscopic biopsy was taken. The tissue was processed routinely. Sections were stained with hematoxylineosin and Movat. Serial sections were immunostained for CD31, VEGFC/D, VEGF receptor 3, and podoplanin (D240). On frozen section, a diagnosis of a complex interstitial lung disease was made, composed of organizing pneumonia and focal interstitial fibrosis resembling usual interstitial pneumonia and nonspecific interstitial pneumonia. However, there was also interstitial edema and several foci of an angiomatoid proliferation. These vessels showed a single layer of endothelia, usually flattened, and a thickened wall composed of thickened connective tissue without a muscle layer. In Movatstained sections, adjacent veins and arteries were highlighted by their elastic laminae. The angiomatoid proliferation, however, was devoid of any lamina elastica. Immunohistochemical staining for CD31, VEGFC, podoplanin, and VEGF receptor 3 was performed on the vascular proliferation and were found positive. A diagnosis of diffuse pulmonary lymphangiomatosis was made. Diffuse pulmonary lymphangiomatosis is a rare disorder that usually affects children and young adults. A systemic form (GorhamStout syndrome or vanishing bone disease) can affect lymphatic ducts in bone, mediastinum, soft tissues, and also lungs, liver, and spleen. We present here this rare disease in an adult, combined with complex interstitial pneumonias. No treatment other than transplantation has been successfully applied in isolated pulmonary lymphangiomatosis.
Primary Malignant Melanoma of the Pleura: Report of an Autopsy Case
Toshiaki Kawai1 ; Takayuki Haga2 ; Kuniaki Nakanishi.1 1National Defense Medical College, Tokorozawa, Saitama, Japan; 2National Higashi Saitama Hospital, Hasuda, Saitama, Japan.
Melanoma metastatizing to the lungs is common, but primary pulmonary or pleural melanoma is extremely rare. We present an autopsy case of malignant melanoma of the pleura in a 49yearold man. The patient presented with cough and right back pain. On admission to hospital, 2.5 months before he died, the man was found to have an elastic, hard, subcutaneous mass the size of a thumb in the right chest. The large amount of pleural effusion was bloody and was diagnosed cytologically as negative. From fineneedle aspiration cytology, the right chest mass was diagnosed as spindle cell sarcoma. Autopsy showed that a yellowwhite tumor primarily located in the right visceral pleura had invaded into the right lung and also into the right thoracic wall and had metastatized into the left lung, visceral pleura, thyroid, and left adrenal. No primary site was found (including skin and other mucous membranes). Histologically, the predominantly spindle cell foci exhibited a fascicular growth pattern with elongated to ovoid pleomorphic cells possessing large hyperchromatic nuclei and vague nucleoli, accompanied by areas of a nuclear palisading pattern and extensive necrosis. Some nested and epithelioid foci were seen, intermingled with cartilagelike differentiation. Some finely granular brown pigment was present within tumor cells and macrophages. Most of the pigment was FontanaMasson positive and bleached by potassium permanganate. Immunohistochemical analysis showed the tumor cells to be positive for S100 and focally positive for HMB45, but negative for other markers (including keratin, CAM 5.2, and calretinin). Ultrastructural examination of formalinfixed wet tissue showed the neoplastic cells had a melanosomelike structure.
PlatletDerived Growth Factor Receptor beta, a Potential Target for Molecular Chemotherapy, Is Expressed in Malignant Mesothelioma
Patrizia Morbini1 ; Chiara Villa1 ; Simona Inghilleri2 ; Camillo Porta.2 1University of Pavia; 2Fondazione IRCCS Policlinico S. Matteo.
Context: The synergistic combination of gemcitabine or pemetrexed with tyrosine kinase (TK) inhibitor imatinib mesylate seems to be effective in controlling malignant mesothelioma (MM), both in experimental and in as of yet unpublished clinical settings. Imatinib blocks TKassociated receptors, including cKit/CD117 and platletderived growth factor receptor beta (PDGFRbeta), by inhibiting kinase binding with adenosine triphosphate. PDGF autocrine production seems to be relevant in mesothelioma cell growth. Furthermore, one of the most common genetic abnormalities observed in MM involves chromosome 22q13, where the PDGFRbeta gene is mapped. PDGFRbeta was documented in MM cell cultures, but it has never been investigated in MM tissue samples.
Design: PDGFRbeta (Rb1692, Labvision, Freemont, Calif) and CD117 (A4502, Dako Cytomation, Carpinteria, Calif) expression was investigated immunohistochemically in 138 MM cases and correlated with clinical and tumor data (histological type, patient survival, and type of exposure to asbestos).
Results: One hundred five cases (76%) were moderately or intensely reactive for PDGFRbeta; 33 (24%) showed weak or absent immunoreactivity. Consistent expression of CD117 was observed in 16 cases (11.5%), which were also reactive for PDGFRbeta. CD117 expression was significantly associated with epithelioid histology (P
Conclusions: The present study confirms for the first time in vivo in a large series of MM cases the expression of PDGFRbeta, further supporting the promising therapeutic strategy of combining the TK inhibitor imatinib mesylate with antifolates or gemcitabine.
The Role of cKit (CD117)Positive Mast Cells and Its Ligand (Stem Cell Factor) in Chronic Fibrosing Bronchiolitis Obliterans Including Chemical Exposure: Is There a Potential for Treatment With Imatinib (Gleevec)?
Neil Fuehrer1 ; Alberto Marchevsky2 ; Jaishree Jagirdar.1 1University of Texas Health Science Center, San Antonio; 2Cedar Sinai Medical Center, Los Angeles, Calif.
Context: In many fibrosing lung diseases, it is not clear what leads to the progression of fibrosis following a remote injury. Immunemediated progression may be a reason. cKit (CD117)positive mast cells (M cells) have been associated with chronic fibrosing diseases and carry a potential to be treated with imatinib (Gleevec), a tyrosine kinase inhibitor.We evaluate the role of M cells in fibrosis associated with bronchiolitis obliterans (BO).
Design: Four cases of BO (household cleaner exposure, ammonia exposure, idiopathic, and posttransplant) were compared with asthma/ emphysema. Small and large airways were stained for CD20, CD3, CD4, CD8, CD117, CD34, toluidine blue, hematoxylineosin, trichrome, and stem cell factor (SCF; cKit ligand). CD117stained slides were digitally scanned with Aperio Scanscope, and stained cells were counted within the epithelium and subepithelium of small and large airways (per millimeter of basement membrane).
Results: M cells were concentrated within the involved subepithelium of small airways in BO (122 cells per mm), unlike asthma/emphysema (25 cells per mm). Conversely, there were more M cells in the epithelium in asthma/emphysema than in BO (7 cells permm vs 2 cells per mm, respectively). M cells were significantly increased around involved airways versus uninvolved airways (52 cells per mm vs 14 cells per mm, respectively). Large airways in either group had similar CD117 expression. SCF was not increased. All other stains were similar between the groups.
Conclusions: Mast cells appear to be concentrated in the lesional small airway subepithelium in BO, suggesting that early administration of imatinib may be of value in preventing progression to fibrosis.
Malignant Mesothelioma: Guidelines for Pathologic Diagnosis
Aliya N. Husain1 ; Alain Borczuk2 ; Philip T. Cagle3 ; Andrew Churg4; Thomas V. Colby5 ; Francoise GalateauSalle6 ; Allen R. Gibbs7 ; Allen M. Gown8 ; Samuel P. Hammar9 ; Thomas Krausz1 ; Leslie A. Litzky10 ; Nelson G. Ordonez11 ; Victor L. Roggli12 ; William D. Travis13 ; Mark R.Wick.14 1 University of Chicago Medical Center; 2Columbia University Medical Center; 3The Methodist Hospital; 4University of British Columbia; 5Mayo Clinic College of Medicine; 6Laboratoire d’Anatomie Pathologique; 7 Llandough Hospital; 8PhenoPath Laboratories; 9Diagnostic Specialties Laboratory; 10University of Pennsylvania Medical Center; 11M. D. Anderson Cancer Center; 12Duke University Medical Center; 13Memorial Sloan Kettering Cancer Center; 14University of Virginia Medical Center. A pathology panel was convened in October at the International Mesothelioma Interest Group (IMIG) biennial meeting to discuss guidelines for the pathologic diagnosis of malignant mesothelioma (MM). This resulted in a consensus opinion, which can be divided into the following: (1) distinguishing between benign and malignant mesothelial proliferations (both epithelioid and spindle cell lesions); (2) cytologic diagnosis of MM; (3) key histologic features of pleural and peritoneal MM; (4) use of histochemical and immunohistochemical (IHC) stains; (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, as well as squamous cell and renal cell carcinomas); (6) diagnosing sarcomatoid mesothelioma; (7) use of molecular markers in the differential diagnosis; (8) electron microscopy; (9) what not to use in the diagnosis; and (10) pitfalls in the diagnosis of MM. IHC panels are suggested, the exact makeup of which is dependent on the differential diagnosis, experience of the pathologist, and antibodies available. The panel should contain both positive and negative markers, with at least 60% sensitivity and specificity. Interpretation of positivity generally should take the number of cells staining (>10%) and the localization of the stain (eg, nuclear vs cytoplasmic) into consideration. These guidelines are meant to be a practical reference for the pathologist, rather than a mandate or review of the literature.
Financial discloser: Dr Travis receives financial compensation from plaintiffs and defendants for expert testimony on malignant mesothelioma.
Kiln Burner Pneumoconiosis
Izidor Kern; Katarina Osolnik. University Clinic of Respiratory and Allergic Diseases.
Context: Charcoal can be produced by carbonization of wood in kilns. It is a traditional seasonal job. When the pyrolysis is complete, a kiln burner manually removes the charcoal. While doing this, he is exposed to smoke and charcoal dust. We report a case of socalled kiln burner pneumoconiosis.
Design/Results: A 71yearold man, who was a nonsmoker and farmer, was admitted to the hospital because of bilateral pneumonia. Antibiotic therapy was efficient. Two months after complete resolution of radiologic lung infiltrates and normalization of his laboratory results, pulmonary function testing disclosed a restriction pattern (vital capacity 67% and forced expiratory volume in the first second 75% of predicted values) with diminished diffusion capacity (74% of predicted value). With time, pulmonary function did not improve, and highresolution computed tomography showed a diffuse centrilobular groundglass nodular pattern with subpleural small areas of consolidations. Transbronchial biopsy revealed deposition of black pigment in the bronchiolar interstitium, similar to the histologic appearance of simple coal workers pneumoconiosis, with no signs of fibrosis. A lot of black amorphous material was found in bronchoalveolar lavage. Additional environmental history was taken to elucidate the patient’s lifelong occupation as a kiln burner.
Conclusions: We report a case of lung disease due to inhalation of carbonaceous materials. The patient was exposed to incomplete combustion of wood burning and large amounts of charcoal dust while kiln burning for a long period.
Benign Lymphocytic Angiitis and Granulomatosis
Belinda E. Clarke. Queensland Health Pathology Service.
A 55yearold obese diabetic woman presented with 6 months of fluctuating skin lumps, dry cough, exertional dyspnea, and mild fatigue. No environmental exposures were documented. Serology for infections, connective tissue diseases and vasculitis was negative. Serial computed tomography scanning demonstrated multiple fluctuating pulmonary nodules. Excision of a skin nodule yielded a diagnosis of nodular vasculitis. Videoassisted thoracoscopy lung biopsy revealed an area of infarctlike necrosis associated with lymphocytic and granulomatous vasculitis. There was no atypia of the lymphoid infiltrate, which consisted predominantly of CD4 CD56 T cells. Results of EpsteinBarr virus in situ hybridization (EBVISH) were negative, and polymerase chain reaction for Tcell receptor and immunoglobulin heavy chain rearrangements demonstrated polyclonal DNA. A diagnosis of benign lymphocytic angiitis and granulomatosis (BLAG) was made. The patient was started on chlorambucil with little measurable benefit. Since the original description of 14 cases of BLAG in 1977, controversy has surrounded its existence as an entity distinct from lymphomatoid granulomatosis (LYG). Understanding LYG itself has evolved during that time. Liebow described the classic triad of changes in 1972, but only during the 1980s was it recognized to be an angiocentric lymphoma, thought to be of Tcell origin. Not until 1994 were most shown to be Tcellrich, EBVdriven Bcell lymphomas. Cases of otherwise typical LYG in which the cytologically malignant lymphoid cells mark as T cells and lack evidence of EBV infection are now classified as peripheral Tcell lymphomas. Cases such as that reported here have been designated angiocentric immunoproliferative lesions, grade 1. Some have been shown subsequently to progress to malignant lymphoma.
Primary Epithelioid Angiosarcoma of the Pleura
Kirtee Rishi1 ; Philip T. Cagle1 ; Timothy C. Allen.2 1The Methodist Hospital, Houston; 2University of Texas Health Center at Tyler.
A 61-year-old man presented with shortness of breath and right- sided chest pain. On radiographic studies, he was found to have a large rightsided pleural effusion and a large rightsided pleural mass with adjacent pleural thickening. He underwent thoracotomy, and approximately 750 ml of bloody fluid was drained from his right chest. A hemorrhagic, circumscribed mass was excised from the right pleura. On sectioning, the mass was hemorrhagic and necrotic. Histologic sections showed sheets of epithelioid cells with large, vesicular nuclei and prominent nucleoli. At higher power magnification, similar features with scattered cytoplasmic vacuoles and occasional mitoses were seen. The neoplastic cells were immunopositive for CD31 and factor VIII and focally immunopositive for keratin.
Spontaneous Pleuropulmonary Endometriosis in Baboons: Insights Into Pathogenesis
Jaishree Jagirdar1 ; Jeffrey Christal1 ; Matthew Martin1 ; Gene Hubbard.2 1University of Texas Health Science Center; 2South West Foundation for Biomedical Research.
Context: Endometriosis is a common gynecologic disorder in women. Spontaneous pleuropulmonary endometriosis (PPE) is rare. The pathogenesis of endometriosis, particularly of PPE, remains unclear. Major theories include the following: coelomic metaplasia, embolization from the uterus or pelvis, and retrograde menstruation with transperitonealtransdiaphragmatic migration of endometrium. Although not reported, PPE is common in baboons, which may serve to further our understanding of the pathogenesis and to refine management.
Design: Ten cases of PPE and 4 cases of intraabdominal endometriosis were identified at necropsy in baboons (Papio spp.). Hematoxylineosin stain and immunohistochemistry were performed on sections, using antibodies to estrogen receptor (ER), progesterone receptor (PR), thyroid transcription factor 1 (TTF1), CD10, and the proliferation marker Ki67.
Results: Grossly, clear hemorrhagic, 0.5 to 2mm cystic lesions were noted on the lung surfaces and within the lung parenchyma in the 10 baboons. The cysts were lined by TTF1 , ER/PR columnar/ cuboidal epithelium and cuffed by ER /PR /CD10 stromal cells. Unexpectedly, small deep parenchymal nodular interstitial aggregates of ER /PR / CD10 stromal cells rimmed by TTF epithelial cells were found with variable Ki67 proliferative activity. In contrast, the epithelium and stroma in abdominal endometrioisis was TTF1, ER /PR.
Conclusions: The abdominal endometriosis differs from the PPE in that the latter is lined by TTF1 cells, which suggests that the pathogenesis of PPE is other than what is speculated above. The presence of deep parenchymal interstitial aberrant nodular stromal aggregates suggests that the stroma is the driving force in PPE upon which the lungspecific epithelium condenses and may require a novel approach to therapy.
Tumor Lymphangiogenesis, Lymphatic Invasion, and Micrometastasis in Stage I Lung Cancer Using D240 Immunohistochemistry
Irene CastanedaSanchez1 ; Elizabeth Kurian1 ; Philip T. Cagle2 ; Jaishree Jagirdar.1 1The University of Texas Health Science Center, San Antonio; 2The Methodist Hospital, Houston.
Context: Stage I nonsmall cell lung cancer (NSCLC) carries survival rates of approximately 70% at 5 years, with approximately 30% of patients experiencing poor outcome, despite complete surgical excision. Squamous cell carcinomas (SCCs) fare slightly better. In the search for prognostic markers, this study proposes to evaluate lymphatic invasion, micrometastasis, and lymphangiogenesis in stage I lung cancer, using a specific marker of lymphatic endothelium (D240/podoplanin).
Design: Paraffinembedded tissue sections of tumor and lymph nodes from 60 patients with stage I NSCLC were retrospectively analyzed for lymphatic invasion, micrometastases and lymphatic microvessel density (MVD) using D240. The presence of these pathologic factors were correlated with clinical factors in the search for prognostic markers in early disease. Tumor types included the following: 35 adenocarcinomas (ACAs), 9 bronchoalveolar carcinomas, 10 SCCs, and 7 large cell carcinomas.
Results: Lymphatic invasion, although uncommon, showed a trend toward poor outcome. MVD was uniformly low in SCC. Minimal lymphatic MVD was noted in peritumoral areas in all types of stage I NSCLC. Incidence of increased lymphatic MVD was highest in scar areas (2 to 3 ), particularly in ACAs. Larger scar size correlated with increased lymphatic microvessel density and with a poor prognosis. Conclusions: The increase in lymphatic density in the tumor scar may account for the prognostic significance of scar size in ACAs. The better prognosis of stage I SCCs may be due to low lymphatic MVD and absence of scar. D240 is a valuable marker for lymphatic invasion in stage I lung cancer.
A Case of Pulmonary Epithelioid Hemangioendothelioma With an Unusual Presentation and an Aggressive Clinical Course
Armita Bahrami1 ; Philip T. Cagle2 ; Timothy C. Allen.3 1Baylor College of Medicine, Houston; 2The Methodist Hospital and Weill Medical College of Cornell University, Houston; 3University of Texas Health Center at Tyler.
A 37yearold white man presented with a 1year history of progressively severe posterior chest wall pain. Magnetic resonance imaging of the spine revealed an intrathoracic mass, which on a chest computed tomography scan was described as a 4cm solid left upper lobe lung mass, arising from the left hilum. Initial attempts by bronchoscopic and transthoracic biopsies failed to obtain diagnostic material. The patient underwent thoracotomy and was found to have a locally advanced, surgically unresectable tumor involving the pleura, pericardium, and diaphragm. Bone imaging studies showed loss of periosteum of several ribs in the area where the patient complained of pain. Results of the metastaticworkup were otherwise negative. The patient failed to respond to radiochemotherapy and died 11 months following the diagnosis with large pleural and pericarcdial effusion, tamponade, and metastasis to the skin of the thoracoabdominal wall. Histologically, the tumor had a biphasic (epithelioid and spindled) appearance, suggestive of mesothelioma. The epithelioid cells had roundoval vesicular nuclei, with mild to moderate nuclear pleomorphism without significant mitoses, arranged in nests and strands within a dense hyalinized to chondromyxoid stroma. Immunohistochemically, neoplastic cells expressed endothelial markers CD31, CD34, and FLI1 and were negative for mesothelioma markers. Cytokeratin AE1/AE3 was focally positive. The tumor was diagnosed as epithelioid hemangioendothelioma. Despite lack of unequivocal highgrade histologic features, the tumor had an aggressive biologic behavior. In conclusion, epithelioid hemangioendothelioma is a rare tumor in the lung that can mimic other more common pathologic entities. It should be considered in an approach to unusual pulmonary neoplasms with epithelioid or biphasic morphology.
Angiogenesis in Bronchial Dysplasia and Angiogenic Squamous Dysplasia Is Associated With the Formation of Immature Vasculature
Daniel T. Merrick1 ; Elizabeth S. Buyers2 ; York E. Miller1 ; Robert L. Keith1; Timothy C. Kennedy2 ; Wilbur A. Franklin.2 1Denver Veterans Administration Medical Center; 2University of Colorado Health Sciences Center.
Angiogenic squamous dysplasia (ASD) is a dysplastic lesion of the bronchi of smokers that is distinguished from other dysplasias by virtue of the presence of characteristic vascular morphology with projection of microvessels into the overlying dysplastic epithelium. To date, we have identified ASD in 167 of 721 patients who have undergone LIFE bronchoscopy at the University of Colorado Health Sciences Center: in nonmalignant airways of 37 patients with invasive carcinoma (28 prevalent carcinomas and 9 incident carcinomas) and in 130 patients without carcinoma. ASD can be associated with marked stromal matrix remodeling. These lesions are associated with increased vascular endothelial growth factor expression and high microvessel densities (MVD) in comparison to normal bronchial epithelium. We examined the microvessel maturation index (MMI) (actin+ MVD/CD31+ MVD) of 12 ASD lesions and 4 samples of normal mucosa. The mean MMI for dysplastic lesions was significantly less than that measured for 4 normal bronchial biopsies (MMI, 0.62 vs 1.02, respectively; P = .04). When analyzed independently, the vessels that project into the intraepithelial papillae of ASDs showed the lowest MMI of 0.56. This was not statistically different than the MMI for the dysplasia group as a whole, but was significantly decreased in comparison to normal MMI (P = .71 and .04, respectively). Incomplete vascular maturation is associated with dysplastic change in the bronchi of smokers and is most striking in the vascular structures of ASD. In this respect, ASD is similar to invasive carcinoma. Increased delivery of protumorigenic factors, such as growth promoting factors and mutagenic substances, may be facilitated by immature vascular networks in premalignant airways.
Malignant Solitary Fibrous Tumor of the Pleura
Jerad M. Gardner1 ; Philip T. Cagle1 ; Timothy C. Allen.2 1The Methodist Hospital, Houston; 2University of Texas Health Center at Tyler.
A 65-year-old woman presented with a pleuralbased mass of the right lower lobe. The mass was surgically resected, and the gross specimenwas a 14cm, 858g nodular tumor with a white whorled cut surface. Microscopically, some areas of the tumor were composed of irregularly arranged plump spindle cells with intervening dense collagen and a hemangiopericytoma like vascular pattern. These areas were confluent with areas of highly pleomorphic spindle cells with prominent nucleoli and numerous atypical mitotic figures. Multinucleated tumor giant cells and rhabdoid tumor cells were also seen, as well as focal areas of tumor cell necrosis. The specimen was diagnosed as a malignant solitary fibrous tumor (MSFT). MSFT is a very uncommon lesion. Such tumors may have the architectural characteristics of a benign solitary fibrous tumor but with malignant cytologic features, or they may resemble obvious highgrade sarcoma. Most MSFTs are CD34 positive, but CD34 negativity has been reported. Although there is potential for local recurrence as well as distant metastasis, many patients can be cured of MSFT by complete surgical resection. Interestingly, radiation and chemotherapy may actually decrease survival in patients with this lesion. This case of MSFT is particularly unique because representative areas of both typical solitary fibrous tumor and highgrade MFHlike sarcoma are seen within the same lesion.
Adenoid Cystic Carcinoma of the Trachea
Melissa L. Stanton1 ; Philip T. Cagle.2 1University of Texas at Houston Medical School; 2The Methodist Hospital, Houston.
Primary pulmonary adenoid cystic carcinoma (ACC) is a rare, slowgrowing tumor histologically similar to that found in the salivary glands. Most tumors arise intraluminally within the trachea, main stem, or lobar bronchi. They are generally well circumscribed but can have infiltrative margins along the tracheobronchial wall, extending far beyond the localized mass. Histologically, cribriform, tubular, or solid growth patterns are seen with mucinous and hyalinized basement membranelike material found within the cribriform cylinders or tubules. Local recurrence is common because of the distinctive invasion patterns, and distant metastases have been reported. We report a case of a 61yearold woman who presented with chronic cough and tracheal stenosis. A 1.7cm mass that was attached to and partially filling the tracheal lumen was identified. A segmental tracheal resection was performed, and a diagnosis of ACC was made. ACC comprises less than 1% of all primary lung and bronchial neoplasms. Patients typically present with airway obstructive symptoms, such as dyspnea, cough, chest pain, and hemoptysis. ACC is thought to be an indolent tumor because, in many cases, multiple local recurrences precede the development of distant metastases.
Endobronchial Primary Pulmonary Meningioma
Enrique M. Gomez. University of Texas in Houston.
Primary pulmonary meningioma (PPM) is a very rare entity, with only 33 reported cases in the literature. PPMs are usually benign and located in the peripheral pulmonary parenchyma. None of the previously reported cases had an endobronchial location. To our knowledge, we report the first endobronchial benign PPM case. This case presented in a 34yearold woman who was admitted with symptoms of hemoptysis. Radiographic and bronchoscopic studies revealed an endobronchial mass obstructing the right intermediary bronchus. A right lobectomy was performed. On gross evaluation, a 2.5 x 2.0cm unencapsulate welldemarcated masswas identified, with associated distal pulmonary atelectasis. Histologically, the lesion was composed of whorles and bundles of bland polygonal to fusiform cells with oval to round nuclei and dispersed chromatin. Immunohistochemical studies were performed, supporting a diagnosis of meningioma. Imaging studies did not find evidence of any intracranial or intraspinal meningioma; therefore, this case was diagnosed as a PPM. Although most cases of PPM have no pulmonary symptoms and are discovered as incidental intraparenchimal nodules during routine chest roentenograms, this case presented with symptoms of hemoptysis, probably due to the intrabronchial localization of the disease.
The Concordance of Clinical Asbestosis With Pathological Asbestosis: A 10-Year Survey
Richard Luther Attanoos; Gareth Rowlands; Allen R. Gibbs. Llandough Hospital.
Context: In the United Kingdom, recent governmental guidelines recognize clinical asbestosis without a requirement for supportive pathology. Moreover, diffuse interstitial fibrosis (DIF) without asbestos bodies and/ or low fiber burdens are not considered of value in questioning the clinical diagnosis of asbestosis. This survey was performed to compare the postmortem pathology diagnosis of asbestosis with diagnoses made on clinical grounds.
Design: Of 4800 postmortem examinations from 1997 to 2006, 355 (7.4%) cases were selected for detailed examination on the basis of a history of asbestos exposure and/or DIF. According to established College of American PathologistsNational Institute for Occupational Safety and Health guidelines, lung tissue was sampled and the diagnosis of asbestosis evaluated according to the 1997 Asbestos, Asbestosis, and Cancer report (Scand J Work Environ Health). Asbestos fiber counts were performed by transmission electron microscopy with energydispersive xray analysis. Results: One hundred three cases with an asbestos history had nonneoplastic changes clinically deemed asbestosis. Twentythree (22.3%) cases showed DIF, 73 (71%) cases showed no significant fibrosis, and in 7 (7%) cases, there was insufficient tissue for diagnosis. Of the 23 DIF cases, 5 (21.7%) complied with the Helsinki pathologic criteria for asbestosis, 3 showed fewer than 2 asbestos bodies per square centimeter of lung, and 15 showed no asbestos bodies. After mineralogic analysis, only 1 of 3 and 1 of 15 cases were subsequently diagnosed as asbestosis.
Conclusions: Significant (70%) discordance between the clinical and pathologic diagnoses of asbestosis exists. The validity of basing compensation on clinical asbestosis alone is questionable. There persists a requirement to standardize pathologic and mineralogic criteria for asbestosis. Other causes of DIF recognized pathologically are misdiagnosed clinically.
Financial disclosure: Drs Attanoos and Gibbs receive financial compensation for expert testimony on abestosrelated disease in various countries.
Primary Glomangiosarcoma of the Lung
Munir Shahjahan; Donna M. Coffey; Philip T. Cagle. The Methodist Hospital, Houston.
A 40yearold woman presented with a right lung mass and underwent subsequent lobectomy of the upper lobe. The tumor measured 9 cm in greatest dimension with extension into the adjacent bronchus. Initial clinical impression and gross examination pointed toward a neuroendocrine tumor. Microscopic examination revealed no nuclear atypia or necrosis. However, focal areas with increased mitoses (up to 7 per 10 highpower fields) and features of lymphovascular invasion were identified. Tumor cells were immunopositive for actin, vimentin, collagen type IV, and calponin but negative for chromogranin, synaptophysin, S100, pankeratin, cytokeratin 7, epithelial membrane antigen, desmin, CD99, CD10, inhibin, and progestoreone receptor. Electron microscopic examination showed cells with cytoplasmic bundles of microfilaments, external lamina, and micropinocytotic activity. No desmosomelike junctions and no dense core neurosecretory granules were seen. Presence of lymphovascular invasion with increased focal mitotic activity together with the immunohistochemical staining pattern and ultrastructural findings were characteristic of a malignant glomus tumor. Glomangiosarcomas (malignant glomus tumors) of the lung are extremely rare tumors with only a few cases described to date. Rarity of this tumor and its histologic similarity to more common primary and metastatic neoplasms makes this a very challenging diagnosis. This case emphasizes that clinical, histologic, and immunohistochemical examination are essential in establishing a diagnosis of glomangiosarcoma.
Bronchiolitis and Peribronchiolar Interstitial Disease in 4 Patients Exposed to World Trade Center Smoke and Dust
Maoxin Wu1 ; Maria Padilla2 ; Jacqueline Moline2 ; Robin Herbert2 ; David Mendelson2 ; Virginia Litle2 ; William Travis3 ; Joan Gil.2 1Mount Sinai School of Medicine; 2Mount Sinai Medical Center; 3Memorial SloanKettering Cancer Center.
Persistent respiratory conditions have been described among rescue and recovery workers exposed to smoke and dust from the World Trade Center (WTC) disaster. Sarcoidlike pathologic findings have been reported in some cases. We report findings in 4 patients (ages 4256 years) with WTC exposure commencing on September 11 or 12, 2001, who are being followed at the Mount Sinai WTC Medical Monitoring and Treatment Program. Patients presented with complaints of shortness of breath and nonspecific radiologic findings (diffuse interstitial disease and rarely nodules) and underwent videoassisted thoracoscopic biopsies. The 4 biopsies all revealed generally severe bronchiolitis with variable characteristics. In lessinjured areas, it was associated with peribronchiolar fibrosis with bronchiolar metaplasia; in other fields, the degree of interstitial fibrosis was so extensive that the peribronchiolar origin was less ascertainable. One of the cases was remarkable for areas of honeycombing isolated in an otherwise unremarkable alveolar parenchyma; another case showed eosinophils with very poorly organized granulomas, also present in the lymph nodes. The overall appearance was unusual in that it did not correspond to any of the common interstitial diseases. In none of the cases were classic patterns of usual interstitial pneumonia, nonspecific interstitial pneumonia, or desquamative interstitial pneumonia seen. The lower lobes appeared slightly more affected. We conclude that these findings represent an uncommon pathologic reaction to the inhalation of the smoke and dust generated from the WTC disaster.
This work was supported by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health under contract 20020020038 and grants 5U1O 0H008232, World Trade Center Medical Monitoring and Treatment Program.
New Biomarkers in the Cancerous Stroma: Podoplanin, SPARC, and Galectin9; Tissue Microarray Analysis
Junya Fukuoka; Haruhisa Kitano; Yuta Sakai; Tomonori Tanaka; Kishio Kuroda; Kazuhiro Nomoto; Naoko Kumagai; Takashi Hori. Toyama University Hospital, Toyama, Japan.
In a multiinstitutional collaboration (some antibodies were obtained from National Cancer Institute [Bethesda, Md], Kinki Chuo ChestMedical Center [Sakai, Japan], Kyoto University [Kyoto, Japan], National Institute of Advanced Industrial Science and Technology [Tsukuba, Japan], DAKO [Kyoto, Japan], and Shiga University of Medical Science [Otsu, Japan]), we have dedicated ourselves to archiving a protein expression database of lung cancer using tissue microarray. Of the nearly 100 evaluated markers, we found 3 molecules (podoplanin, SPARC (osteonectin), and galectin9) that are selectively stained in the cancerous stroma, mainly fibroblasts, and significantly associated to cancer progression. Podoplanin is a marker widely used to detect lymphatic endothelial cells. We found that stromal podoplanin expression was significantly associated with nodal metastasis (P
Multinodular Neuroendocrine Carcinoma With Intraepithelial Neoplasia of the Large and Small Airways
Patrizia Morbini; Chiara Villa. Universita di Pavia.
A 64yearold male smoker complaining of cough and fever underwent upper left lobectomy after a computed tomography scan showed concentric stenosis of the upper left lobar bronchus with distal inflammatory opacities and endobronchial biopsydocumented atypical squamous cells. Macroscopic examination showed thickened lobar and segmental bronchial walls and multiple peripheral nodules ranging from 5 to 15 mm in diameter. A histologic examination revealted peripheral nodules consisting of neuroendocrine cell proliferations consistent with atypical carcinoid/ moderately differentiated neuroendocrine carcinoma (NEC) with extensive fibrosis. Distorted airways were observed in the center of some nodules. Stenotic cartilagineous bronchi showed in situ carcinoma, extending to peribronchial glands, and marked fibrosis. The epithelium of many segmental and terminal bronchioli and of some surrounding airspace was also severely atypical. Dysplastic bronchial and bronchiolar epithelia were diffusely immunoreactive for highmolecularweight (HMW) cytokeratins and cytokeratin 7. Focal expression of neuroendocrine markers was also observed. Neoplastic cells invading peribronchial mucous glands expressed neuroendocrine markers and cytokeratin 7, whileHMW cytokeratins were expressed in a small number of cells, mostly negative for neuroendocrine markers. Mixed neuroendocrine and squamous cell carcinoma is a welldocumented entity; however, the coexistence of neuroendocrine and squamous cell markers in intraepithelial bronchial carcinoma extending distally into the bronchial tree, with multiple moderately differentiated NECs, has not been described before. The present case offers many subjects of investigation: Is squamous and neuroendocrine cell proliferation independent? Is endobronchial tumor spread responsible for multinodular dissemination? Could the bronchocentric distribution of neuroendocrine proliferation be related to diffuse idiopathic neuroendocrine cell hyperplasia?
Pulmonary Capillary Hemangiomatosislike Histologic Changes and Severe Clinical Pulmonary Hypertension in Interstitial Lung Diseases: Report of 3 Explant Cases Eunhee S. Yi; Jay H. Ryu. Mayo Clinic, Rochester.
Pulmonary hypertension (PH) has been suggested to play an important role in the prognosis of interstitial lung disease (ILD) in patients. However, it is not clear whether PH in ILD is a reflection of the extent of interstitial remodeling or an independent process. Clinical studies have demonstrated that severe PH in ILDs can occur in the absence of advanced pulmonary dysfunction or hypoxemia. Recent studies reported that there are increased alveolar capillary densities in ILDs. We have also noted that some ILD cases show extraordinary capillary proliferations that mimic an isolated pulmonary capillary hemangiomatosis (PCH) or the PCH associated with pulmonary venoocclusive disease. Herein, we report 3 ILD cases with severe clinical PH for which the patients underwent double lung transplantations. Explanted lungs showed diffuse PCHlike reactions, hemosiderin deposition, muscularized pulmonary arterioles, and occasional occluded pulmonary veins or venules, as well as ILD. The first patient was a 59yearold woman who had a clinical diagnosis of systemic sclerosis. The explanted lungs showed the features of fibrosing nonspecific interstitial pneumonia. Pulmonary artery pressures (PAPs) by right heart catheterization (RHC) measured 75/22/39 mm Hg, in systolic, diastolic, and mean pressure, respectively. The second patient was a 64yearold man with no underlying disease who was diagnosed as having usual interstitial pneumonia (UIP). PAPs by RHC were 62/29/35 mm Hg. The third patient was a 35yearold woman who had the clinical diagnosis of scleroderma, and her explanted lungs showed UIP. Her PAPs were 103/ 42/67 mm Hg. Widespread PCHlike changes in these cases might have caused an increase in pulmonary vascular resistance and severe PH.
Significance of Molecular Alterations in Alveolar Cells in Usual Interstitial Pneumonia With or Without Lung Cancer
Sylvie Lantuejoul1 ; Andrew G. Nicholson2 ; Dimitri Salameire1 ; Christophe Pison1 ; Gilbert Ferretti1 ; Elisabeth Brambilla.1 1CHU A Michallon; 2Royal Brompton Hospital.
Context: Idiopathic pulmonary fibrosis, the most common interstitial lung disease with the worse prognosis, is characterized histologically by a usual interstitial pneumonia (UIP) pattern. Incidence of lung cancer on UIP is higher than that of lung cancer alone. As molecular abnormalities were reported in atypical and/or metaplastic alveolar cells in UIP, we hypothesized that they could characterize carcinoma precursors.
Design: Immunohistochemical expression of proteins involved in proliferation or apoptosis, p53, cyclines D1 and E, p21, Bax, Bcl2 and p16, were scored and compared in 29 UIP cells with cancer, 15 UIP cells without cancer, 11 fibrotic nonspecific interstitial pneumonia (NSIP) cells, and 10 inflammatory lungs. We have analyzed concomitantly the phenotype of tumor cells.
Results: Numerous atypical and/or metaplastic alveolar cells were found in 39% and 43% UIP with and without cancer, respectively, but in 9% of NSIP and in none of the inflammatory cases. p53, cyclin D1, p21 and p16 expression and a Bax:Bcl2 ratio of
Conclusions: Molecular abnormalities in UIP atypical alveolar cells are more frequent but similar to those found in NSIP. However, they are not specifically related to the presence of cancer but are likely a normal DNA damage response to alveolar cell injury leading to apoptosis or G1 arrest for DNA repair.
Three Cases of Diffuse Miliary Lesions in Asymptomatic Human TCell Lymphotrophic Virus Type 1 Carriers
Junya Fukuoka1 ; Kazuya Ichikado2 ; Tomonori Tanaka1 ; Kishio Kuroda1; Moritaka Suga.2 1Toyama University Hospital, Toyama, Japan; 2 Saiseikai Kumamoto Hospital.
Human T-cell lymphotrophic virus type 1 (HTLV1) is a retrovirus that causes adult T-cell leukemia (ATL). Besides that, similar to HIV carriers, those with HTLV1 occasionally can contract other inflammatory disorders, including arthropathy and bronchopneumonopathy. ”HTLV1 Associated BronchioloAlveolar Disease (HABA)” is an immunemediated pulmonary reaction proposed by Kimura et al in 1989. Several additional articles indicate HABA has 2 major morphologic patterns: diffuse panbronchiolitis and lymphocytic interstitial pneumonia. However, the reports are limited in Japan, and the disease entity is not completely established. We have experienced 3 unique cases showing diffuse miliary lesions in HTLV1 carriers. The lung wedge biopsies obtained before treatments showed 1 to 3mm multiple nodules with marked lymphoid infiltration, granuloma, and tissue eosinophilia. Various degrees of organizing pneumonia with airspace fibrin were found inside the nodules in all cases. Two cases showed tiny foci of necrosis in the center of nodules. Most nodules were located around airways, but some were in the periphery of the secondary lobule. No atypical lymphoid cells were identified, and imunohistochemical profile did not show monoclonal proliferation or aberrant expression indicating neoplasm. In situ hybridization against Epstein Barr virus was negative. Genetic analysis done in one case did not show monoclonality, and ATL involvement was found in none of the cases. Examinations, including culture, serum antibodies, and special staining, did not reveal evidence of infection. All patients experienced improvement within a month either by observation alone or with lowdose steroids, and no recurrence was found on followup at 0.5, 4, and 6 years. Those cases may
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