Case 3 -

Pulmonary Venous Infarct Secondary to Intravascular Carcinoma Kirk D. Jones, UCSF, San Francisco, CA

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Introduction: 82-year-old woman with abnormal chest x-ray. A CT scan shows two adjacent right upper lobe nodules, both approximately 8 mm in diameter. A right upper lobe wedge resection was performed (9 x 3.5 x 2.8 cm) that showed a 1 cm diameter nodule. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Microscopic description: Sections of the nodule demonstrate a nodule with coagulative central necrosis. There is a surrounding reaction with edematous granulation tissue. Small satellite nodules are noted. An EVG stain supports the finding of coagulative necrosis and reveals that the small satellite nodules show a single layer of peripheral elastica and are consistent with obliterated veins. On higher magnification, the veins show occasional highly pleomorphic cells with large, angular, hyperchromatic nuclei and prominent nucleoli. Immunohistochemical stains show expression of keratin (AE1/AE3/Cam5.2), cytokeratin 5/6, and p63. There is no expression of cytokeratin 7, TTF-1, CD10, estrogen receptor, CD45, or S-100. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 Low power view of pulmonary nodule shows necrotic center with peripheral small satellite nodules (H&E, 20x). Case 3 - Figure 2 Central portion of nodule shows typical coagulative necrosis with ghost-like pulmonary parenchymal structure still visible (H&E, 100x). Case 3 - Figure 3 The periphery of the nodule shows a granulation-tissue like fibrosis, while the smaller nodules have a rounded structure and are reminiscent of thrombosed vessels (H&E, 100x). Case 3 - Figure 4 Higher power view of the peripheral nodules shows atypical cells within the central portion (H&E, 200x). Case 3 - Figure 5 These atypical cells are characterized by enlarged, hyperchromatic, irregular nuclei with prominent nucleoli and scant to moderate amounts of cytoplasm (H&E, 400x). Case 3 - Figure 6 These atypical cells were almost nonexistent on the original H&E slides, but showed up in full force on the recut made for this conference (H&E, 400x). Case 3 - Figure 7 An EVG stain reveals the peripheral nodule to show a single elastic layer, indicative of an obliterated pulmonary vein (Elastic van Gieson, 200x). Case 3 - Figure 8 A p63 stain highlights the nuclei of the atypical cells (p63, 400x). Case 3 - Figure 9 A cytokeratin 5/6 stain shows cytoplasmic staining of the atypical cells (CK5/6, 400x). Differential Diagnoses: Necrotizing granuloma, infectious Pulmonary venous infarct Final Diagnosis: Pulmonary venous infarct secondary to intravascular carcinoma Case Discussion: Carcinoma Within the Pulmonary Vasculature: This case is an unusual example of a pulmonary venous infarct secondary to intravenous carcinoma. There are two issues that I want to address in this discussion: first, how does one recognize pulmonary venous infarct; and two, what are the features of pulmonary tumor thrombotic microangiopathy. Pulmonary Venous Infarct: I missed the first case that I saw of this entity. Luckily it was in a study set. Randy Pausch, the computer scientist, once said, "Good judgment comes from experience, and experience comes from bad judgment." This quote can be applied to pathologic diagnoses and experience. The reason these cases are difficult, is that they so closely resemble a rounded necrotizing infectious granuloma. The textbook examples of "pleural-based, wedge-shaped" infarctions do not apply here. That is the description of pulmonary arterial infarcts (although even PA infarcts often lack this appearance). The pulmonary venous infarct is a more elusive character. It is rarely described in textbooks, and it is uncommon in the literature. Pulmonary venous infarction is rare in clinical practice and is most commonly caused by sclerosing mediastinitis. Other causes include pulmonary veno- occlusive disease, left atrial myxoma or clot, pulmonary venous thrombosis following resection, and carcinoma. Several recent cases have been described following pulmonary venous ablation for treatment of atrial fibrillation. Patients present with variable symptoms including cough, dyspnea, chest pain, and hemoptysis. The histologic appearance of pulmonary venous infarct has several features in common with solitary necrotizing granulomas. Both show a rounded or geographic nodule with central necrosis and peripheral inflammation. The venous infarct almost always shows preservation of the pulmonary parenchyma due to coagulative necrosis, while many forms of infectious granulomas (e.g. tuberculosis, histoplasmosis) will show liquefactive necrosis. In addition, the periphery of the venous infarct will show changes similar to granulation tissue with edematous loose fibrosis, small vessel proliferation, and a sparse chronic inflammatory infiltrate. Infectious granulomas tend to show a proliferation of epithelioid histiocytes admixed with multinucleate giant cells. In addition, solitary necrotizing granulomas often show satellite non-necrotizing "sarcoidal" granulomas in the adjacent lung parenchyma. When a biopsy shows features of coagulative necrosis with peripheral granulation tissue, the etiology of the disease can often be elucidated with clinical and radiologic correlation. It is important to remember other causes of nodular coagulative necrosis including lymphomatoid granulomatosis and infection (e.g. dirofilaria). Pulmonary Tumor Thrombotic Microangiopathy In patients with carcinoma, dyspnea may be the result of multiple thromboemboli (occasionally as a paraneoplastic phenomenon) or from diffuse lymphangitic spread of tumor. A less common cause of dyspnea is diffuse intravascular involvement of the pulmonary arterial tree by carcinoma. While this may present as tumor emboli with minimal inflammatory or coagulation reaction, it occasionally manifests as the clinical entity pulmonary tumor thrombotic microangiopathy (PTTM). In this disease, the tumor cells not only occlude small vessels, but also activate the coagulation cascade, resulting in additional thrombotic occlusion. Patients with PTTM present with dyspnea and symptoms of pulmonary hypertension and right heart failure. The pulmonary clinical examination is usually normal. The chest x-ray is usually normal, and the chest CT can show a variety of changes, and may appear normal, or may show changes suggestive of ground glass opacities. Pulmonary angiogram is often ordered to rule out pulmonary embolism, and is usually negative; however, a ventilation-perfusion scan may show multiple peripheral symmetrical perfusion defects. Laboratory findings include a progressive thrombocytopenia and elevated LDH. The histologic changes of PTTM include intra-arterial microscopic tumor emboli with associated prominent intimal proliferation. The surrounding lung parenchyma is often unremarkable. Many of the reported cases of PTTM are adenocarcinomas. While renal cell carcinoma is often associated with tumor cell emboli, it does not usually result in the marked thrombotic reaction seen in PTTM. PTTM is a rapidly progressive disease, and most patients die within a week of onset of symptoms. There is one reported case (Miyano, et al) of a patient with PTTM secondary to gastric cancer, who was treated with steroids (dexamethasone), anticoagulants (warfarin and aspirin), and chemotherapy (S- 1 and potassium oxonate) and survived. Conclusion(s): The first take-home point of this case is to not jump to conclusions regarding the low-power appearance of a case. When one sees coagulative necrosis in the center of a nodule, it is not enough to order a GMS and AFB stain. One needs to consider other causes of coagulative necrosis including pulmonary venous infarct and lymphomatoid granulomatosis (B-cell lymphoma). The second take-home point is that if a biopsy looks almost normal on first glance, make sure that the small vessels have been adequately examined. Particularly in patients with symptoms suggesting pulmonary tumor thrombotic microangiopathy (i.e. rapidly progressive dyspnea, pulmonary hypertension, and falling platelet counts). References: Gavin MC, et al. Clinical problem-solving. Breathless. N Engl J Med. 2012 Jan 5; 366(1): 75-81. Katzenstein AL, Mazur MT. Pulmonary infarct: an unusual manifestation of fibrosing mediastinitis. Chest. 1980 Apr; 77(4): 521-4. Malani AK, et al. Pulmonary tumor thrombotic microangiopathy from metastatic gallbladder carcinoma: an unusual cause of severe pulmonary hypertension. Dig Dis Sci. 2007 Feb; 52(2): 555-7. McCabe JM, et al. Running from her past: a case of rapidly progressive dyspnea on exertion. Circulation. 2011 Nov 22; 124(21): 2355-61. Miyano S, et al. Pulmonary tumor thrombotic microangiopathy. J Clin Oncol. 2007 Feb 10; 25(5): 597-9. Nomori H, et al. Multiple pulmonary infarctions associated with lung cancer. Jpn J Clin Oncol. 2000 Jan; 30(1): 40-2. Pinckard JK, Wick MR. Tumor-related thrombotic pulmonary microangiopathy: review of pathologic findings and pathophysiologic mechanisms. Ann Diagn Pathol. 2000 Jun; 4(3): 154-7. von Herbay A, Illes A, Waldherr R, Otto HF. Pulmonary tumor thrombotic microangiopathy with pulmonary hypertension. Cancer. 1990 Aug 1; 66(3): 587-92. Williamson WA, et al. Pulmonary venous infarction secondary to squamous cell carcinoma. Chest. 1992 Sep; 102(3): 950-2. Yousem SA. The surgical pathology of pulmonary infarcts: diagnostic confusion with granulomatous disease, vasculitis, and neoplasia. Mod Pathol. 2009 May; 22(5): 679-85.