Case 5 -

Malignant Vascular Neoplasm Dani S. Zander Penn State Hershey Medical Center Hershey, PA

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Clinical Summary: The patient is a 36-year-old male with a history of asthma, who noted the onset of hemoptysis about 5 weeks prior to the biopsy. The hemoptysis waxed and waned daily, but could be more than one cup per day. He also experienced a 12 lb. weight loss over the preceding month, with poor appetite, low-grade fevers, and night sweats. Chest CT revealed a solid left hilar mass measuring 4.0 x 2.6 cm, extending into the apical posterior segment of the left upper lobe. Another mass measuring approximately 17 x 13 mm was noted in the right lower lobe, with adjacent smaller masses. Mediastinal lymphadenopathy was also observed. Hemoglobin was 9.4 g/dl, hematocrit was 27.9%. Reticulocyte count was 98.5 K/ul, or 3.06%. ESR was elevated at 125 mm/hr. Serum electrolytes, WBC, platelets, AST, ALT, total and direct bilirubin, alkaline phosphatase, troponin-I, C3, C4, and urinalysis results were within normal limits. Cultures of blood, urine, sputum, and fine needle aspirate of the lung mass yielded no pathogenic bacteria, no viruses, and no fungi. Legionella pneumophila antigen was not detected in the urine. DFA for influenza A and B performed on nasopharyngeal swabs was negative. RF, CCP antibody, ANCA, anti-GBM antibody, ANA, AFP, HCG, and CEA were negative. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The core needle biopsy has a variegated appearance. Portions appear fibrotic, and other areas show necrosis with inflammation and karyorrhectic nuclear fragments. Looking closely at the fibrotic areas, one can see polygonal cells and spindle-shaped cells embedded in the stromal tissue, with focal formation of vascular channels. The nuclei of these cells show mild-moderate nuclear pleomorphism and hyperchromasia. Occasionally nucleoli are visible in these cells. Cytoplasmic vacuolization is also apparent in some of the cells. Mitoses are rare. Immunohistochemical stains for factor VIII and CD31 are positive in the polygonal and spindle-shaped cells. An IHC stain for cytokeratin (AE1/3) is also positive in these cells, but stains for CK7 and CK20 are negative. Case 5 - Slide 1 - Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Figure 1 Round, polygonal and spindle-shaped tumor cells with vacuolated cytoplasm and formation of vascular spaces. Case 5 - Figure 2 Spindle-shaped and round tumor cells in a fibrotic background. Case 5 - Figure 3 Necrosis in a background of fibrotic stroma and scattered tumor cells. Case 5 - Figure 4 CD31+ tumor cells with formation of small caliber vascular spaces. Case 5 - Figure 5 Second biopsy showing tumor cells with more marked cytoatypia than those in the portion of tumor sampled in the first biopsy. Case 5 - Figure 6 Markedly atypical tumor cells with large, pleomorphic nuclei, line irregular vascular spaces (second biopsy). Case 5 - Figure 7 Markedly atypical tumor cells with occasional mitoses (second biopsy). Case 5 - Figure 8 Tumor cells show strong staining for factor VIII (second biopsy). Differential Diagnoses: The histologic differential diagnosis is quite broad and includes vascular neoplasms (angiosarcoma, epithelioid hemangioendothelioma), adenocarcinoma, mesothelioma, sarcomatoid carcinoma, melanoma, and other sarcomas containing epithelioid and spindle cell populations. Inflammatory disorders with prominent granulation tissue and necrosis, which can also be considered in the differential diagnosis, include infarct, Wegener's granulomatosis, mycobacterial and fungal granulomas, necrotizing bacterial and viral pneumonias, and rheumatoid lung disease (rheumatoid nodule). Immunohistochemistry can help to narrow the differential diagnosis list considerably. Final Diagnosis: Malignant vascular neoplasm Additional Evaluation: One week later, a second lung biopsy was performed, revealing sheets of highly atypical polygonal cells with marked nuclear pleomorphism, nucleoli and frequent mitoses, with focal formation of vascular spaces. The neoplastic cells stained for CD31, factor VIII, and AE1/3, but not S100 or TTF1. Mucicarmine stain was negative. Physical examination revealed no evidence of malignancy in other anatomic sites, a CT scan indicated disease limited to the lungs, and a PET scan from the base of the skull to mid-thigh showed no abnormal FDG activity in the abdomen, pelvis, or osseous structures. Final diagnosis: Primary pulmonary angiosarcoma Case Discussion: The primary challenges in this case include recognition of the polygonal and spindle-shaped cell population as neoplastic, classification of the neoplasm, and determination of the site of origin. Given the histology and immunohistochemical staining results, the differential diagnosis should include angiosarcoma, pulmonary or metastatic epithelioid hemangioendothelioma (PEH), and several benign conditions. Immunohistochemical stains for factor VIII and CD31 were valuable for confirming endothelial differentiation and highlighting the infiltrative nature of the tumor. Differentiation between angiosarcoma and PEH depends upon grade, with angiosarcomas demonstrating more cellularity, cytoatypia, and mitoses than PEH, and less matrix than PEH. Intracellular lumens are characteristic of PEH, but can also be observed in angiosarcomas. Angiosarcomas can also show some degree of spindle cell formation, as did this example. Differentiation of primary pulmonary angiosarcoma from metastatic angiosarcoma depends upon a thorough clinical and radiographic workup, which should be performed if angiosarcoma is diagnosed on a lung biopsy [1]. If one was uncertain about the identity of the spaces as vascular, and instead thought they might be glandular spaces, then adenocarcinoma enters into the differential diagnosis. Some of the cells appear to have cytoplasmic vacuoles, which could suggest signet ring cell formation. Although a cytokeratin stain (AE1/3) stain did stain the tumor cells, up to 30% of angiosarcomas stain for cytokeratin. In the event that further confirmation is felt necessary, stains for CEA, berEP4, MOC31, B72.3, leuM1, TTF1, mucicarmine and others could be ordered. Other tumors that could be considered in the histologic differential diagnosis include mesothelioma, sarcomatoid carcinoma, melanoma, and other sarcomas containing epithelioid and spindle cell populations. For mesothelioma, the clinical presentation in the current case is not concordant, nor is the observed vascular marker expression. Had a D2-40 stain been ordered and been positive due to lymphatic differentiation, however, this could have been misleading given the high frequency (up to 96%) of staining of mesotheliomas for D2-40 [2, 3]. Further evaluation with other stains frequently positive in mesotheliomas, such as calretinin, cytokeratin 5/6, and HBME1 would likely have been pursued. Given the positive cytokeratin stain, spindle cell carcinoma could have been considered in the differential diagnosis for the current case, but recognition of the vascular spaces and observation of endothelial marker staining by immunohistochemistry should discourage consideration of this entity. S100 stain was ordered to evaluate for the possibility of melanoma with pseudovascular spaces, but was negative. In light of the negative S100 and positive endothelial stains, melanoma can be excluded. Leiomyosarcoma could also be considered based on morphology, and additional muscle markers ordered, but in this case this additional workup was not deemed necessary. Inflammatory disorders with a prominent component of granulation tissue also form an important part of the differential diagnosis. Granulation tissue behaves as a benign, "invasive" process, whose function lies in wound healing. Endothelial cells and myofibroblasts invade necrotic or inflamed tissues. The endothelial cells form small blood vessels in a proteoglycan-rich matrix, which can undergo collagenization with time. The endothelial cells in granulation tissue can demonstrate mild degrees of atypia, or greater atypia if the area has been subjected to radiation. In this case, however, there was no history of radiation therapy or other types of radiation exposure. Nonetheless, the presence of necrosis and adjacent infiltrative vascular, inflamed and fibrotic tissue in the current case could raise the question of an inflammatory process such as an infarct, Wegener's granulomatosis, mycobacterial and fungal granulomas, necrotizing bacterial and viral pneumonias, or rheumatoid lung disease (rheumatoid nodule), as the primary diagnosis. Clinical laboratory tests for infections, vasculitides, and connective tissue diseases were ordered and did not support a primary role for any of these processes, however. Primary pulmonary angiosarcoma is an extremely rare, aggressive neoplasm occurring in adults [4, 5]. Typical symptoms include pleuritic chest pain, dyspnea, cough, and hemoptysis, which can be severe. The radiographic appearance can be a single mass, multiple masses, or more extensive infiltrates. Grossly, the tumor forms firm gray- tan masses with infiltrative edges, often showing hemorrhage in the mass and sometimes in adjacent lung tissue. Microscopically, as in other anatomic sites, angiosarcomas are cellular tumors with variable tendency to blood vessel formation, cytoatypia, epithelioid characteristics and/or spindle shape, and frequent necrosis [6]. Mitotic counts of 1-2/hpf are common. Myxohyaline or mucoid matrix can be observed, as can tumor growth in alveolar septa. Intracytoplasmic lumens can also occasionally be seen. Immunohistochemical evaluation characteristically reveals expression of endothelial markers (CD31, CD34, factor VIII, Fli1) and vimentin, and cytokeratin expression occurs in up to 30% of cases. Endothelial features which can be observed in tumor cells by electron microscopy include tight junctions, cytofilaments, pinocytotic vesicles, Weibel-Palade bodies, and intracytoplasmic lumens. Basement membrane material can be seen around tumor cells. Unfortunately, the course of primary pulmonary angiosarcoma is aggressive and the prognosis is generally very poor. Metastasis is common early in the course of this tumor. In the current patient, a new left adrenal metastasis, FDG- avid mediastinal lymph node enlargement, subdermal soft tissue nodules, and brain metastases were discovered during the year after the primary diagnosis was determined. Review of the Literature/Treatment Options: If the angiosarcoma is localized when diagnosed, surgical resection is usually performed. Systemic chemotherapy and radiation therapy have also been used for treatment, with variable success [7, 8]. Conclusion(s): In conclusion, this case illustrates some of the challenges involved in distinguishing primary pulmonary angiosarcoma from other types of primary and metastatic neoplasms found in the lung, and from necrotizing and reactive vascular processes. Judicious application of immunohistochemistry can be valuable for assessing differentiation and for highlighting infiltrative populations of neoplastic cells. References: Yousem SA. Angiosarcoma presenting in the lung. Arch Pathol Lab Med 1986; 110:112-115 Chu AY, Litzky LA, Pasha TL, et al. Utility of D2-40, a novel mesothelial marker, in the diagnosis of malignant mesothelioma. Mod Pathol 2005; 18:105-110 Padgett DM, Cathro HP, Wick MR, et al. Podoplanin is a better immunohistochemical marker for sarcomatoid mesothelioma than calretinin. Am J Surg Pathol 2008; 32:123- 127 Murer B, Gruber-Mosenbacher U, Popper HH. Unusual primary malignant lung neoplasms. In: Zander DS, Farver CF, eds. Pulmonary Pathology. Philadelphia: Churchill Livingstone (Elsevier), 2008; 578-621 Travis WD, Tazelaar HD, Miettinen M. Epithelioid haemangioendothelioma/angiosarcoma. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al., eds. Pathology and Genetics. Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press, 2004; 97-98 Weiss SJ, Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. fifth ed. Philadelphia: Mosby (Elsevier), 2008 Maglaras GC, Katsenos S, Kakadelis J, et al. Primary angiosarcoma of the lung and pleura. Monaldi Arch Chest Dis 2004; 61:234-236 Wilson R, Glaros S, Brown RK, et al. Complete radiographic response of primary pulmonary angiosarcomas following gemcitabine and taxotere. Lung Cancer 2008; 61:131-136