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A 22-Year-Old Man With Back Pain, Dilated Veins Over Chest, and Mass in Right Atrium

      Case Presentation

      A 22-year-old nonsmoker male, without any previous comorbidity, presented with 4 months’ history of right upper back pain. Pain was constant dull aching type, nonpleuritic, aggravated by lying on the right lateral side and partially relieved on taking analgesics. He then developed progressive dyspnea over 2 months and noticed dilated veins over his neck and front of chest. There was associated unintentional weight loss of 6 kg. There was no history of cough, expectoration, wheeze, or hemoptysis, nor any episodes of night sweats or fever.
      General physical examination revealed a young man not in respiratory distress. His BP was 118/80 mm Hg, a pulse of 84 beats/min, and a respiratory rate of 18 breaths/min. There were engorged, nonpulsatile tortuous veins over the neck and anterior chest extending to the abdomen with flow of blood from above downward (Fig 1A). There was a tender, ill-defined swelling on the right upper back, with overlying peau-d’orange appearance of skin, with no discharge or sinus present. The swelling was firm in consistency and immobile over the underlying fascia (Fig 1B). There were no cervical or axillary lymphadenopathy or clubbing.
      Figure thumbnail gr1
      Figure 1A, Frontal view of chest wall of the patient showing multiple dilated and tortuous veins, seen from neck draining downward and extending to abdomen. B, Posterior chest wall showing localized tender swelling with peau-d’orange appearance of the overlying skin.
      Respiratory system examination showed diminished movement of the right side, a dull note on percussion over the right supra and interscapular areas, where auscultation revealed diminished breath sounds. A clinical diagnosis of right upper lobe mass with chest wall invasion, with features of superior vena cava obstruction was made.
      A frontal chest radiograph (Fig 2) of the patient was performed, which showed a large well-defined opacity with differential density in the right upper zone with broad base toward mediastinum, without silhouetting ascending aorta; displacing the trachea to the left, along with destruction of the right fourth rib with a small right pleural effusion, thereby confirming the clinical diagnosis. The superior margin of the mass was not seen to extend above the level of the clavicle.
      Figure thumbnail gr2
      Figure 2Frontal chest radiograph showing right upper zone mass merging with mediastinum with a differential opacity at its inferior aspect. Associated erosion of posterior end of right fourth rib with faint areas of calcification. There is volume loss of right hemithorax with elevated right hemidiaphragm. The mass is displacing the trachea to the left. There is destruction of the right fourth rib with a small right pleural effusion.
      Further imaging by contrast-enhanced CT of the chest (Fig 3) showed a heterogeneously enhancing mass in the right upper lobe posteriorly, with erosion of the posterior part of the right fourth rib and extrathoracic extension to the chest wall. Additionally, areas of coarse stippled calcification were seen in the mass. There was contiguous extension to the mediastinum, superior vena cava, and right atrium. Mass effect with narrowing of right main bronchus was seen along with right pleural effusion and multiple separate nodules in bilateral lungs suggestive of metastasis. In such a large lesion, the precise localization of the tumor, especially of the origin, is difficult. The combination of doing a pre- and post-contrast CT helps in such cases. The post-contrast CT helped to confirm that calcification was posterior and arising from the rib, rather than from dystrophic calcification in the tumor, and also showed a clear necrosis in the center of this lesion apparent as irregular central low density; confirmed later in pathology. This mass lesion could have originated from lung, pleura, or ribs. Because the epicenter of this lesion is in the mid portion of the posterior lung and not in the rib or chest wall, primary chest wall and pleural tumors are less likely though still possible causes.
      Figure thumbnail gr3
      Figure 3A, Axial noncontrast CT shows large destructive mass epicentered in the mid-portion of the posterior lung with large intrathoracic and small extra-thoracic component in chest wall. Areas of coarse calcification (arrow in A). B and C, seen within the mass posteriorly arising from the rib, rather than from dystrophic calcification in the tumor along with clear necrosis in the center of this lesion apparent as irregular central low-density axial contrast-enhanced CT image shows a contiguous extension to the mediastinum, superior vena cava (solid arrow B), and direct extension into the right atrium (solid arrow, C). Multiple dilated chest wall collateral venous channels seen (dotted arrow, B and C) and right pleural effusion. D, Axial lung window image shows multiple separate nodules in bilateral lungs suggestive of metastasis.
      Thus, the differential diagnosis considered clinico-radiologically for this patient was primary lung malignancy followed by possible lymphoma or hematologic malignancy. Less likely causes included primary or secondary metastatic diseases of the rib and chest wall, with still less likely causes including rhabdomyosarcoma or pleural mesothelioma.
      His baseline blood and urine investigations were unremarkable. Peripheral blood smear did not show any atypical cells or blasts. Ultrasonography of the abdomen and scrotum were normal. Serum alpha fetoprotein, beta human chorionic gonadotropin, and lactate dehydrogenase were within normal limits.
      An echocardiography was performed because the mass lesion showed extension into the right atrium via superior vena cava (Fig 4A). Ultrasound of the chest showed a mixed echogenicity mass in the right posterior aspect of the chest (Fig 4B). Ultrasound of the abdomen was normal.
      Figure thumbnail gr4
      Figure 4A, Apical four-chamber view of transthoracic echocardiogram showing a large echogenic mass nearly filling the right atrial cavity. B, Ultrasound image of the lesion shows mixed echogenic mass.
      A trucut biopsy was performed under ultrasound guidance through the posterior chest wall, which showed (Fig 5A) sheets and lobules of small round tumor cells with scanty cytoplasm in a fibromuscular stroma, with geographic areas of necrosis and occasional areas of spindling. Mitotic activity was high. The immunohistochemistry study was strongly positive for membranous cluster of differentiation (CD)99 (Fig 5B) and friend leukemia integration 1 transcription factor (Fig 5C), and was negative for CD-45, CD-20, CD-3, Cd 79a, E-cadherin, thyroid transcription factor 1, Chromogranin, CD-117, Desmin, and human melanoma black (HMB) 45.
      Figure thumbnail gr5
      Figure 5A, Representative histopathological examination of biopsy material demonstrating sheets of small round blue cells (original magnification, 40×; hematoxylin & eosin); B, Immunohistochemistry photomicrograph showing tumor cells with strong positivity for membranous CD99 (original magnification 40×); C, Immunohistochemistry photomicrograph showing tumor cells with nuclear positivity for FLI-1 (original magnification 10×).
      What is the diagnosis?
      Diagnosis: Ewing sarcoma/primitive neuroectodermal tumor of the right posterior chest wall, involving the lung and mediastinum with malignant thrombus in azygous vein, superior vena cava, extending to right atrium

      Discussion

       Clinical Discussion

      In 1979, Frederic B. Askin et al
      • Askin F.B.
      • Rosai J.
      • Sibley R.K.
      • Dehner L.P.
      • McAlister W.H.
      Malignant small cell tumor of the thoracopulmonary region in childhood: a distinctive clinicopathologic entity of uncertain histogenesis.
      described a unique clinicopathologic entity characterized as a malignant small round cell tumor of the thoracopulmonary region in 20 children and adolescents. The tumor originated in the soft tissues of the chest wall or the peripheral lung, with female predilection (75%), tended to recur locally, and had a median survival of 8 months. This malignant tumor, called askin tumor, is included in the Ewing sarcoma family of tumors because of its histological, immunohistochemical, cytogenetic, and phenotypic similarities, and is therefore better known as Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET). The Ewing sarcoma family of tumors also includes extraosseous Ewing sarcoma, atypical Ewing sarcoma, and primitive neuroectodermal tumors (PNET).
      • Laskar S.
      • Nair C.
      • Mallik S.
      • et al.
      Prognostic factors and outcome in Askin-Rosai tumor: a review of 104 patients.
      Patients usually present in their second or third decade of life, as did this patient, with pain of the chest, back, or shoulder, dyspnea, swelling, neurological symptoms due to vertebral and spinal cord involvement, and systemic manifestations such as fever, weight loss, or symptoms due to metastasis. Because there are no specific symptoms, a possibility of ES/PNET should be kept in mind when young patients, as in our case, present with symptoms such as chest wall swelling, especially if it is increasing in size, which is localized deep to the muscle fascia and are painful. The other possible differential diagnosis includes primary lung malignancy, malignancy involving the bony cage, lymphoma/ hematologic malignancy, malignant germ cell tumor, and rare possibilities such as rhabdomyosarcoma, neuroblastoma, and pleural mesothelioma.
      Standard therapy now includes chemotherapy administered before and after local therapy with surgery or radiation therapy. Current standard chemotherapy includes vincristine, doxorubicin, and cyclophosphamide cycles alternating with cycles of ifosfamide and etoposide. Prognostic factors include disease extent, primary tumor location and size, age, and response to therapy.
      Superior vena cava obstruction due to ES/PNET is an extremely rare manifestation, and this may be the first case report of it extending into the right atrium. Superior vena cava syndrome comprises a constellation of manifestations that develop as a result of obstruction of blood flow through the superior vena cava because of various causes. In malignant etiologies, the plausible causes are direct invasion by the tumor, external compression, or as a manifestation of its hypercoagulable state.

       Radiological Discussion

      ES/PNET presents as a sizeable mass of extrapulmonary origin with chest wall extension.
      • Gladish G.W.
      • Sabloff B.M.
      • Munden R.F.
      • Truong M.T.
      • Erasmus J.J.
      • Chasen M.H.
      Primary thoracic sarcomas.
      CT examination shows extensive mixed attenuation soft tissue mass. ES/PNET may be solitary or may present as multiple masses.
      • Tateishi U.
      • Gladish G.W.
      • Kusumoto M.
      • et al.
      Chest wall tumors: radiologic findings and pathologic correlation: part 2. Malignant tumors.
      Rib destruction is present in 25% to 63% of patients. Tumor calcification is rare. Common location of recurrence is the local chest wall itself or disseminated pulmonary metastases.
      • Saifuddin A.
      • Robertson R.J.
      • Smith S.E.
      The radiology of Askin tumours.

       Pathological Discussion

      The 2002 World Health Organization (WHO) classification listed the askin tumor as Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/PNET) family of tumors because of their common histological features, differentiating from one another by the degree of neuroectodermal differentiation.
      The typical histological features include solidly packed sheets or lobules of strikingly uniform round cells having dark-staining ovoid to round nuclei with distinct nuclear membranes, high nuclear cytoplasmic ratio, indistinct small nucleoli, scanty cytoplasm, and varying rosette formations.
      • Schmidt D.
      • Herrmann C.
      • Jürgens H.
      • Harms D.
      Malignant peripheral neuroectodermal tumor and its necessary distinction from Ewing’s sarcoma: a report from the Kiel Pediatric Tumor Registry.
      They possess a highly vascular stroma and have variable mitotic activity. There may be areas of hemorrhage and necrosis, as was evident in the current case histologically and radiologically. The focal/prominent spindle cell pattern can also be noted as seen in the current case.
      Immunohistochemically, the tumor cells are usually positive for membranous CD99 (MIC2), NKX2.2, Leu7 (CD57), FLI-1 protein, and vimentin.
      • Schmidt D.
      • Herrmann C.
      • Jürgens H.
      • Harms D.
      Malignant peripheral neuroectodermal tumor and its necessary distinction from Ewing’s sarcoma: a report from the Kiel Pediatric Tumor Registry.
      ,
      • Parikh M.
      • Samujh R.
      • Kanojia R.P.
      • Mishra A.K.
      • Sodhi K.S.
      • Bal A.
      Peripheral primitive neuroectodermal tumor of the chest wall in childhood: clinico-pathological significance, management and literature review.
      The MIC2 gene (CD99) gene product is present in 90%of cases, being highly sensitive but nonspecific. Thus it must be complemented with other immunohistochemical markers. Another potentially new (highly sensitive and specific) marker for Ewing family of tumors is NKX2.2, the protein product of the NKX2-2 gene.
      • Yoshida A.
      • Sekine S.
      • Tsuta K.
      • Fukayama M.
      • Furuta K.
      • Tsuda H.
      NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma.
      The tumor cells are negative for S100, LCA (CD45), EMA, HMB45, muscle markers, and vascular markers, helping to differentiate from other histologically similar malignant small blue cell tumors, including lymphoma, small cell osteosarcoma, dedifferentiated synovial sarcoma, desmoplastic small cell tumors, rhabdomyosarcoma, medulloblastoma, neuroendocrine tumors, melanoma, and small cell vascular tumors
      • Yoshida A.
      • Sekine S.
      • Tsuta K.
      • Fukayama M.
      • Furuta K.
      • Tsuda H.
      NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma.
      (Fig 5). In the current case, the tumor cells were positive for membranous CD99 and FLI-1 and negative for CD45, CD20, CD3, CD79a, E-cadherin, thyroid transcription factor 1, chromogranin, CD117, desmin, and HMB45. The immunohistochemical analysis of small round blue cell tumors is given in Table 1.
      Table 1Immunohistochemical Screening for Small Round Cell Tumors
      TumorPan CKS100CD 45DESMINCD99Myog/MyoD1NFPHMB45Nuclear WT1CG(NE)
      EWS/PNETLL--+-L---
      Melanoma-+--L--+-
      NB-M----H-LH
      SmCC+--L---M
      DSRCT+-L+M---+L
      PDSS+V-VHL--
      RMS-L-+L+L---
      Lymphoma--+-V----
      WT+V-+-V+
      Small cell OS-L--L--
      CD = cluster of differentiation; DSRCT = desmoplastic small round cell tumor; (…) = unknown results; EWS/PNET = Ewing sarcoma/primitive neuroectodermal tumor; (H) = high, 60%-90% of tumor—most tumors are positive; HMB = human melanoma black; (L) = low, 10%-40% of tumor—most tumors are negative; (M) = moderate, 40%-60% of tumor—may or may not be positive; (−) = <10% of tumor—almost always negative; NB = neuroblastoma; NFP = neurofilament protein; OS = osteosarcoma; PDSS = poorly differentiated synovial sarcoma; (+) = >90% of tumor—almost always positive; RMS = rhabdomyosarcoma; SmCC = small cell carcinoma; (V) = variable results; WT = Wilms tumor.
      Cytogenetic evaluation is another component of diagnostic and prognostic evaluation of this family of tumors. The defining cytogenetic feature of the ES/PNET family is the presence of nonrandom translocations leading to fusion of the EWS gene on 22q12 with one of the other several members of the ETS family of transcription factors. The most frequent (90%) and having the most favorable prognosis is the translocation t (11;22) (q24; q12) that juxtaposes the proximal portion of the gene EWS (22q12) into the distal portion of the gene FLI-1 (11q24). Regrettably, the chromosomal analysis was not done in the current case, and it was a diagnosis without cytogenetics.

      Take-home Message

      • 1.
        Differential diagnosis of large intrathoracic tumors is wide, and thorough clinical assessment followed by imaging studies and tissue sampling for microbiological and histopathological evaluation is needed to arrive at a specific diagnosis.
      • 2.
        The possibility of ES/PNET should be kept in the differential if the patients present in early adulthood with symptomatic chest wall tumors even if there is no obvious evidence for distant metastasis.
      • 3.
        The importance of early identification of ES/PNET resides in its aggressive behavior and in its high rate of recurrence after treatment.
      • 4.
        Radiologically, ES/PNET presents as heterogenous mass lesion in the thoracopulmonary location, with variable degree of necrosis, calcification, and local tissue displacement or even invasion.
      • 5.
        Prompt imaging studies followed by an attempt to get adequate diagnostic tissue material is essential for extensive pathologic evaluation, which is often required to differentiate ES/PNET from the Ewing sarcoma family of tumors by immunohistochemistry and at times chromosomal analysis and FISH.
      • 6.
        Because the Ewing sarcoma family of tumors is considered as a systemic disease because of its propensity for occult metastasis, systemic chemotherapy is the cornerstone of management, usually administered before and after local therapy with surgery or radiation therapy.
      • 7.
        With the current multidisciplinary treatment, long-term survival can be achieved in almost 75% of patients diagnosed with nonmetastatic disease. Most relapses occur within 2 years of initial diagnosis, and late relapse is also common. Close follow-up of these patients is important.

      Acknowledgments

      Financial/nonfinancial disclosures: None declared.
      Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

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