Pulmonary Primitive Neuroectodermal Tumor Associated with Digital Clubbing

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Pulmonary Primitive Neuroectodermal Tumor Associated with Digital Clubbing – A Case Report

Sheng-Han Tsai, Han-Yu Chang

Digital clubbing, one of the syndromes of hypertrophic osteoarthropathy, is associated with many types of medical illness, including infectious, inflammatory disease, cyanotic heart disease and neoplasm. Classically, digital clubbing has been thought to be associated with lung cancer. The incidence of clubbing fingers in lung cancer is about 10-29%, and it is more associated with non-small cell lung cancer than small cell lung cancer. We present a rare case of pulmonary primitive neuroectodermal tumor with clubbing fingers. A 56-year-old man had suffered from progressive dyspnea on exertion, accompanied with cough, abdominal fullness and body weight loss of 10 kg in the most recent 5 months. On examination, obvious digital clubbing was found in both hands. Imaging study demonstrated a huge left lung tumor. Sonography-guided biopsy was performed and the pathology report suggested primitive neuroectodermal tumor. The patient received chemotherapy with doxorubicin, decarbazine and ifosfamide, and began gradually feeling less dyspneic after chemotherapy. (Thorac Med 2010; 25: 190-196)

Key words: nail, lung tumor, hypertrophic osteoarthropathy

Introduction especially lung carcinoma [3-4]. The incidence of clubbing fingers in lung cancer is about 10- Digital clubbing is the thickening of the soft 29%, and it is more commonly associated with tissue beneath the proximal nail plate which re- non-small cell lung cancer than small cell lung sults in sponginess and thickening of the distal cancer [5]. Primitive neuroectodermal tumor digit [1]. Clubbing fingers can be an isolated (PNET) is a malignant tumor of neural crest finding or occur as part of the syndrome of hy- origin and arises outside the central nervous pertrophic osteoarthropathy (HOA), which also system. PNET very rarely manifests as primary includes arthralgia and periostitis [2]. Aside lung tumor. Our search of the literature revealed from the rare primary form of HOA, pachyder- that clubbing fingers had never been mentioned moperiostosis, secondary HOA is associated in a patient with pulmonary PNET. Herein, with extrapulmonary or pulmonary disorders, we report the case of a huge pulmonary PNET

Division of Chest Medicine, Department of Internal Medicine, National Cheng-Kung University Medical College and Hospital, Tainan, Taiwan Address reprint requests to: Dr. Han-Yu Chang, Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, No. 138, Sheng-Li Rd., Tainan, 704, Taiwan

Thorac Med 2010. Vol. 25 No. 4 Pulmonary Tumor with Digital Clubbing 191 combined with digital clubbing.

Case Report

The presented case is that of a 56-year-old male patient without a medical history, although he had a smoking history of about 20 years. About 5 months before admission, he suffered from progressive shortness of breath during exercise. The associated symptoms included cough with some sputum, and abdominal distension, especially after intake or during a peri- od when he felt dyspneic. He also reported poor appetite and body weight loss of 10 kg within the most recent 5 months. Both the dyspnea and abdominal distension could be relieved by rest. He denied orthopnea, paroxysmal nocturnal Fig. 2. Chest radiograph shows a left opaque lesion with a midline dyspnea, chest pain or hemoptysis. The symp- structure shift to the right side toms progressed, and finally, he felt dyspneic even when walking. He visited a local hospital showed decreased breathing sounds and dull and abdominal sonography revealed a left up- percussion in the lower half of the left lung. per abdominal mass. Gastric lymphoma was Obvious digital clubbing of both hands (Figure suspected and he was referred to our hospital. 1) and leg edema were also found. Hemogram On admission, no fever was noted and the showed mild normocytic anemia (Hb = 12.8 respiratory rate was 18 per minute, with no re- mg/dl). Biochemistry data revealed normal liver spiratory distress noted. Physical examination function, renal function and electrolytes. Arte- rial blood gas showed metabolic alkalosis with respiratory compensation. The chest radiogra- phy (Figure 2) showed nearly total opacity of the left hemithorax with mediastinum and heart shifting to the right side. Panendoscopy was performed for abdominal discomfort and revealed external compression with posterior wall indentation of the stomach. Chest computed to- mography (CT) scan (Figure 3) showed a huge heterogeneous mass with focal necrosis and pleural effusion in the left thoracic cavity. There was also compression of the mediastinum, liver

Fig. 1. Marked clubbing of the fingers of both hands with a shiny and stomach. Mediastinal lymph node metas- appearance tasis was also suspected. The chest CT favored

胸腔醫學：民國99年25卷4期 192 Sheng-Han Tsai, Han-Yu Chang

(A) (B)

Fig. 3. (A) Chest CT scan shows a tumor in the left lingual and lower lobe with pleural effusion and subcarinal lymphadenopathy. (B) At the lower level, the tumor occupies almost the whole left thoracic cavity with the heart and great vessel deviating to the right side.

an intrapulmonary origin of the tumor. We per- after the treatment and the patient felt less dys- formed intermittent thoracentesis for relief of pneic. the dyspnea. The pleural effusion was reddish and the exudate was lymphocyte-predominant Discussion (54%) in character. Malignant pleural effusion was suspected, but no malignant cells could Digital clubbing, the most ancient sign of be found by effusion cytology. The pathology medicine, was first documented by Hippocrates obtained by sonography-guided biopsy showed about 2500 years ago as “water accumulation” diffuse small blue cells with hyperchromatic in a patient with empyema [6]. Alternatively, it nuclei. In the immunohistochemical study, the is also called Hippocratic finger or drumstick tumor cells were positive for CD99 and synap- fingers. Four grades or stages have been de- tophysin, and negative for cytokeratin, LCA, scribed as follows: fluctuation and softening of S-100, CD34 and TTF-1 (Figure 4). The final nail bed; an increase in the normal 160o angle pathologic diagnosis was PNET. between the nail bed and proximal nailfold; the The pulmonary function test demonstrated a development of a clubbing appearance; shiny severe restrictive ventilatory defect. Bone scan nail and periungual skin and longitudinal ridg- revealed a focal hot spot at the left 11th costo- ing of the nail [7]. Researchers have described vertebral junction and bone involvement was several methods for reaching an accurate diag- considered. Because of advanced disease with nosis, such as the profile sign; modified profile a huge tumor and suspicious metastases to the angle; hyponychial angle; and Schamroth sign lymph node and bone, surgical intervention was [8]. Initially, digital clubbing was considered an not indicated. He then underwent chemotherapy obvious physical sign associated with internal with a regimen of doxorubicin, dacarbazine and illness. With the use of radiologic imaging, it ifosfamide. No obvious side effect was noted was discovered that digital clubbing is usually

Thorac Med 2010. Vol. 25 No. 4 Pulmonary Tumor with Digital Clubbing 193

(A) (B)

Fig. 4. (A) Histological finding shows diffuse small blue cells with areas of tumor necrosis and focal fibrous tissue. (B) Immunohistochemically, the tumor cells show positive staining for CD99 and (C) synaptophysin. (C) accompanied with periosteal proliferation of the and many hypotheses of the pathophysiology tubular bone. The triad of digital clubbing, arth- have been proposed, but no single theory could ralgia, and periostitis comprises HOA. Current- well explain all the disease entities. The most ly, many authors consider that digital clubbing acceptable mechanism has been proposed by and HOA represent different stages of the same Dickinson and Martin [11]. When the normal syndrome [6, 9]. In this case, the clubbing was pulmonary capillary network is disrupted or by- so obvious that at least grade 4 clubbing was passed (such as by chronic lung inflammation, considered. However, the patient did not have carcinoma or intracardiac right-to-left shunt), arthralgia and no evidence of HOA was noted. the megakaryocytes, which escape being nor- Digital clubbing is an ominous sign with mally fragmented in the lung, can enter sys- which we are familiar; however, we appear temic circulation and impact fingertip circula- to know more about it than we really do [10]. tion. These cells release platelet-derived growth There are many reports describing the associa- factor (PDGF), which can promote blood flow, tion between clubbing and numerous diseases, vascular permeability and connective tissue

胸腔醫學：民國99年25卷4期 194 Sheng-Han Tsai, Han-Yu Chang

change, subsequently resulting in the clubbing. sary. Clubbing can be the only or the preceding Recently, observation has suggested that vascu- sign of underlying malignant disease, thus we lar endothelial growth factor (VEGF) may be underscore the importance of a detailed physi- more associated with clubbing [12]. However, cal examination which may lead to the correct the exact mechanism is not fully understood. diagnosis. Clubbing fingers also indicate a poor prognostic sign, as the underlying disease has reached an References advanced stage [6]. Some reports have demonstrated improved clubbing after treatment of the 1. Robert S, Thomas M, Linford S, et al. Nail abnormalities: underlying disease [4, 13]. In the present case, clues to systemic disease. Am Fam Physician 2004; 69: 1417-24. operation was not feasible due to the advanced 2. Gorospe I, Fernandez-Gil MA, Torres I, et al. Misleading stage, so the patient received chemotherapy. lead: inflammatory pseudotumor of the mediastinum with However, the patient did not follow up in our digital clubbing. Med Ped Oncol 2000; 35: 484-7. hospital, so we could not know whether the 3. Pichler G, Eber E, Thalhammer G, et al. Arthralgia and digital clubbing was reversible or not. digital clubbing in a child: hypertrophic osteoarthropathy Peripheral PNET is classified as part of the with inflammatory pseudotumour of the lung. Scand J Ewing’s sarcoma family of tumors which also Rheumatol 2004; 33: 189-91. includes Ewing’s sarcoma of bone, extraosseous 4. Kozak KR, Milne GL, Morrow JD, et al. Hypertrophic osteoarthropathy pathogenesis: a case highlighting the Ewing’s sarcoma, and Askin’s tumor [14]. potential role for cyclo-oxygenase-2-derived prostaglan- They all represent small round cell malignan- din E2. Nat Clin Pract Rheumatol 2006; 8: 452-6. cies of neural crest origin and arise outside the 5. Sridhar KS, Lobo CF, Altman RD. Digital clubbing and central nervous system [15]. PNET can be dis- lung cancer. Chest 1998; 114: 1535-7. tinguished from Ewing’s sarcoma by evidence 6. Martinez-Lavin M. Exploring the cause of the most of neuronal differentiation. Peripheral PNET is ancient clinical sign of medicine: finger clubbing. Semin rare in adults and most cases originate from the Arthritis Rheum 2004; 36: 380-5. chest wall (Askin’s tumor), abdomen, pelvis, 7. Altman RD, Tenenbaum J. Hypertrophic osteoarthropathy. In: Ruddy S, Harris EPJ, Sledge CB, eds. Kelly’s Text- and extremities [16]. To date, there have been book of Rheumatology. 6th ed. Philadelphia: WB Saun- only occasional case reports of primary pulmo- ders, 2001: 1589. nary PNET [15, 17-19]. In these reports, the 8. Kerith E, Joseph C. Clubbing: an update on diagnosis, common presentation included cough, dyspnea, differential diagnosis, pathophysiology, and clinical hemoptysis, and chest pain, and digital clubbing relevance. J Am Acad Dermatol 2005; 52: 1020-8. was never mentioned as a physical sign. PNET 9. Martinez-Lavin M, Vargas A, Rivera-Vinas M. Hypertro- is generally considered to have a poor prognosis phic osteoarthropathy: a palindrome with a pathogenic and needs to be treated with systemic chemo- connotation. Curr Opin Rheumatol 2008; 20: 88-91. 10. Brouwers AAM, Vermeij-Keers C, van Zoelen EJ, et al. therapy. Nevertheless, the mean life expectancy Clubbed fingers: the claws we lost? Medical Hypotheses is less than 1 year. 2004; 62: 321-4. In summary, we have presented a case of 11. Dickinson CJ, Martin JF. Megakaryocytes and platelet pulmonary PNET associated with clubbing clumps as the cause of finger clubbing. Lancet 1987; 2: fingers. Due to its aggressive behavior, early 1434-5. diagnosis and appropriate treatment are neces- 12. Atkinson S, Fox SB. Vascular endothelial growth factor

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(VEGF)-A and platelet-derived growth factor (PDGF) pheral neuroectodermal tumor and its necessary distin- play a central role in the pathogenesis of digital clubbing. ction from Ewing’s sarcoma. Cancer 1991; 68: 2251-9. J Pathol 2004; 203: 721-8. 17. Fritz J, Bassam O, Samuel W. Primitive neuroectodermal 13. Staalman CR, Umans U. Hypertrophic osteoarthropathy tumor of the pulmonary hilum in an adult. Ann Thorac in childhood malignancy. Med Pediatr Oncol 1993; 21: Surg 2001; 72: 285-7. 676-9. 18. Shah ASM, Mohamed Z, Abdullah A, et al. Primitive 14. Carvajal R, Meyers P. Ewing’s sarcoma and primitive neuroectodermal tumor of the lung with pericardial neuroectodermal family of tumors. Hematol Oncol Clin extension: a case report. Cardiovasc Pathol 2007; 16: N Am 2005; 19: 501-25. 351-3. 15. Imamura F, Funakoshi T, Nakamura SI, et al. Primary 19. Mikami Y, Nakajima M, Hashimoto H, et al. Primary primitive neuroectodermal tumor of the lung: report of pulmonary primitive neuroectodermal tumor (PNET): a two cases. Lung Cancer 2000; 27: 55-60. case report. Pathol Res Pract 2001; 197: 113-9. 16. Schmidt D, Herrman C, Jurgens J, et al. Malignant peri-

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肺原始性神經外胚層腫瘤併杵狀指─個案報告

蔡昇翰張漢煜

杵狀指是肥厚性骨頭關節病變的其中一種表徵，並與許多種類的內科疾病包括感染、發炎、發紺性心臟病及腫瘤等有相關。傳統上認為杵狀指與肺癌有相關聯。在肺癌中杵狀指的發生率約10-29%，相較於小細胞癌更容易發生於非小細胞癌。我們在此報告一個罕見的肺部原始性神經外胚層腫瘤合併有杵狀指的個案。一個56歲男性在最近的五個月內發生了漸進的呼吸性氣促，伴隨有咳嗽，腹脹及體重減輕10 公斤。經檢查發現兩手有明顯的杵狀指。影像學檢查顯示了左肺有巨大的腫瘤。經實行超音波導引切片術後病理報告為原始性神經外胚層腫瘤。病人接受了包含Doxorubicin, Decarbazine及Ifosfamide的化學治療。病人在治療後感覺氣促的症狀有漸漸改善。(胸腔醫學 2010; 25: 190-196)

關鍵詞：指甲，肺腫瘤，肥厚性骨頭關節病變

成功大學附設醫院內科部胸腔內科索取抽印本請聯絡：張漢煜醫師，成大醫院內科部胸腔內科，台南市勝利路138號

Thorac Med 2010. Vol. 25 No. 4