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Ann Thorac Surg 2005;79:426-432
© 2005 The Society of Thoracic Surgeons
a Department of Thoracic Surgery
b Department of Pathology, Scientific Institute H San Raffaele
c Department of Thoracic Surgery, Niguarda Ca' Granda Hospital, Milan, Italy
d Department of Pathology, Niguarda Ca' Granda Hospital, Milan, Italy
Accepted for publication July 23, 2004.
* Address reprint requests to Dr Melloni, Unità Operativa di Chirurgia Toracica, Ospedale San Raffaele, Via Olgettina, 60, 20132, Milan, Italy (E-mail: giulio.melloni{at}hsr.it).
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Abstract |
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METHODS: We retrospectively investigated the clinicopathologic features of 18 patients with inflammatory pseudotumor of the lung observed between 1992 and 2002.
RESULTS: There were 13 men and 5 women. Median age was 57 years. Eight patients (44%) were symptomatic. Computed tomographic scan showed a solitary nodule (
3 cm) in 12 patients, bilateral nodules in 1, and a mass in 5. Two patients had undergone prior incomplete resections. Lobectomy was performed in 5 patients, bilobectomy in 1, segmentectomy in 1, and wedge resection in 11. Complete resection was achieved in 13 patients (72%). There was no operative mortality. Follow-up was complete in all patients (range, 13 to 134 months; median, 63 months). Overall 3-year and 5-year survival rates were 82% and 74%, respectively. Thirteen patients are currently alive with no evidence of disease, 1 is alive with disease, 1 died of unrelated causes, and 3 had a relapse and died. Completeness of resection and lesion size less than or equal to 3 cm were associated with a better survival (p < 0.001 and p = 0.007, respectively). Multivariate Cox analysis confirmed the association between completeness of resection and better survival, which is independent of other clinicopathologic variables (p = 0.02).
CONCLUSIONS: This series shows that a significant number of patients with inflammatory pseudotumor of the lung have a poor prognosis and confirms the need for radical resection in the treatment of this unusual entity.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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To contribute to a better understanding of the clinical significance of inflammatory pseudotumors of the lung and of the criteria for treating them, we retrospectively analyzed 18 cases of inflammatory pseudotumor of the lung to ascertain their clinical, imaging, histopathologic, and evolutive features.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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3 cm in diameter) or masses (>3 cm in diameter). Follow-up data were obtained from the patients' hospital visit or telephone interview. Operative mortality was defined as any death during hospitalization or within 30 days from surgery. Late mortality was defined as any subsequent death.
Differences between patients who died and those who did not were tested for significance with the 
2 or Fisher's exact tests for discrete variables, and with the Student's t test for continuous variables. Survival rates of patients grouped according to selected variables were compared by log-rank statistics. Survival plots were reconstructed according to the Kaplan-Meier method. Potential predictors of outcome were identified by 2 analysis of selected dichotomous variables. Simple Cox regression analysis was used to estimate the odds ratios for the variables evaluated at baseline. On the basis of the univariate analysis, multivariable Cox regression analyses were performed to adjust for potential confounders using a forward stepwise method to introduce significant covariates into the model. Reported p values are two-sided. Results of analyses were considered significant at a level of p less than 0.05. All confidence intervals were calculated at the 95% level.
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Results |
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3 cm) in 11 patients, a nodule with invasion of the mediastinal pleura in 1, bilateral nodules in 1, a pulmonary mass (>3 cm) in 2, a mass with bilateral nodules in 1, a mass with chest wall invasion in 1, and a mass with invasion of the mediastinal pleura in 1 (Fig 1). No patients had enlarged (short axis > 1 cm) mediastinal lymph nodes at CT scan. The location of the lesions at CT scan was right upper lobe in 2 patients, left upper lobe in 3, right lower lobe in 3, left lower lobe in 5, medium lobe in 3, and bilateral in 2. Bronchoscopy, performed preoperatively in 13 patients and intraoperatively in the remaining 5, was always negative for bronchial lesions. Transthoracic fine-needle aspiration under CT guidance, performed in 6 patients, was invariably not diagnostic. A complete study of bone, brain, and abdomen was performed in 12 patients to assess the stage of a presumed bronchogenic carcinoma, and no extrapulmonary involvement was noted. Two patients (11%) had had prior incomplete pulmonary resections elsewhere and underwent repeat resection because of growth of residual inflammatory pseudotumor. Surgery was always carried out to obtain a diagnosis and achieve cure. Lobectomy was performed in 4 patients, lobectomy with chest wall resection in 1, bilobectomy in 1, segmentectomy in 1, and wedge resection in 11. Resection of the lesion was complete in 13 patients (72%). In the remaining 5 patients who had an incomplete resection, residual tumor was left on the mediastinum (2 patients), on the chest wall (1 patient), and on the lungs (2 patients with bilateral disease who underwent resection for diagnostic purposes). The mean diameter of the resected lesions was 3 cm (range, 0.5 to 8 cm). The histologic types according to the criteria of Matsubara and associates [11] were organizing pneumonia in 1 patient, fibrous histiocytic in 13, and lymphoplasmacytic in 4. The histologic types according to the World Health Organization criteria were compact spindle cells pattern in 16 patients and hypocellular fibrous pattern in 2. All cases (100%) were immunoreactive for CD68 and vimentin, 14 (78%) expressed smooth muscle actin, and 5 (28%) were positive for epithelial membrane antigen. No patients were immunoreactive for CD34, desmin, and ALK-1. There was no operative mortality. Complications occurred in 3 patients and included atrial fibrillation in 2 and persistent air leak in 1. Median hospital stay was 8 days (range, 4 to 21 days).
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3 cm) and incompleteness versus completeness of the resection identified groups with a more than sevenfold higher mortality rate. We also observed a trend toward increased mortality for symptomatic patients (Table 1). Patients with a nodule showed a better survival rate than patients with a mass (3-year rates, 91% versus 50%; p = 0.006; Fig 2, top), as did patients who underwent complete resection versus those who did not (3-year rates, 91% versus 25%; p = 0.007; Fig 2, bottom). Univariate analysis showed that mass versus nodule and complete versus incomplete resection predicted mortality (p = 0.03, p = 0.01, respectively; Fig 3). The other variables analyzed were not significant predictors of mortality (male sex, p = 0.43; presence of symptoms, p = 0.32; previous respiratory infection, p = 0.30; comorbidities, p = 0.44; invasiveness on CT scan, p = 0.27; Fig 3). Multivariate Cox regression analysis showed that incomplete versus complete resection was significantly associated with mortality, with a hazard ratio of 13.8 (p = 0.028; Fig 3).
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Comment |
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Inflammatory pseudotumor of the lung is rare, although its exact incidence is unknown. The number of inflammatory pseudotumor–related pulmonary resections reported in the literature varies considerably. Mitsudomi and colleagues [15] performed 9 resections of inflammatory pseudotumor of the lung from a total of 721 pulmonary resections (1.2%) during a period of 15 years. At the Mayo Clinic, 56,400 thoracic procedures were performed during more than 47 years, of which 23 (0.04%) were for an inflammatory pseudotumor of the lung [4]. At the San Raffaele University Hospital of Milan we performed 13 resections of inflammatory pseudotumor of the lung (0.3%) from a total of 4,120 thoracic procedures in more than 11 years. This variability is likely to depend on both the difficulty in diagnosis and the percentage of pediatric patients. Inflammatory pseudotumors are difficult for the pathologist to diagnose. Even though transthoracic fine-needle aspiration has been proposed as a diagnostic method, specimens are aspecific and it is often not possible to identify the disease [11, 12]. As a consequence, final diagnosis is generally obtained on the resected specimen. However, even in such cases, it can be difficult to recognize the disease and to differentiate it from other lesions such as sarcoma, lymphoma, malignant fibrous histiocytoma, and malignant plasmacytoma [4, 12]. Furthermore, although rare, inflammatory pseudotumor represents the most frequent primary tumor of the lung in children younger than 16 years of age [13]. The different percentages of pediatric patients included in the various studies would therefore partly explain the variability in the number of pulmonary resections performed for inflammatory pseudotumor.
Inflammatory pseudotumor of the lung is not sex related, and it spans all ages from childhood to the eighth decade of life, with a prevalence (60%) of patients younger than 40 years of age [5, 13]. All the patients in our series were adults and only 3 (16%) were younger than 40 years.
A history of upper respiratory tract infections or pneumonia is reported in approximately 30% of patients [11], an association we found in 28% of our patients. Occasional cases of inflammatory pseudotumor of the lung are reported in which bacteria and fungi could be isolated [5]. The human herpesvirus-8 has recently been assumed to play a role in the pathogenesis of inflammatory pseudotumors [16]. In a minority of patients inflammatory pseudotumor of the lung is associated with inflammation symptoms, such as fever and erythrocyte sedimentation rate increase [6]. Although these reports seem to suggest that inflammatory pseudotumors are inflammatory type lesions, the majority of authors currently consider inflammatory pseudotumors as tumors [5]. The lesion may in some cases feature local aggressiveness, with infiltration of the pulmonary vessels, heart, chest wall, diaphragm, and vertebrae; it can relapse, be multifocal, and give distant metastases [1–4, 6–10]. Further evidence of its neoplastic origin has been the finding of rearrangements of the anaplastic lymphoma kinase gene on chromosome 2p23, resulting in the expression of the ALK-1 protein, in a subgroup of patients with inflammatory pseudotumor of the lung [17–20]. Recently Malam and associates [21] described a case of inflammatory pseudotumor of the lung associated with a paraneoplastic syndrome (dermatomyositis).
From a clinical point of view, the percentage of asymptomatic inflammatory pseudotumors of the lung ranges between 30% and 70% of cases [12, 13]. Symptoms are strictly related to lesion location: parenchymal, mediastinal, or endobronchial. In our series, approximately 50% of patients were asymptomatic at diagnosis. All lesions were located in the lung, and there were no mediastinal or endobronchial inflammatory pseudotumors. Extrapulmonary endothoracic inflammatory pseudotumors are, however, rare [6].
The radiologic features of inflammatory pseudotumors of the lung have been analyzed by Agrons and coworkers [3]. Computed tomographic scan shows a nodule or a mass in approximately 90% of patients and multiple nodules in 5%. Secondary infiltration of hilum, mediastinum, and airways is proven in 16% of patients. In our series, CT scan revealed well-circumscribed parenchymal lesions (nodules or masses) without signs of infiltration in 15 patients, whereas 3 patients (16%) presented with an infiltration of the adjacent pleura. Computed tomographic scan did not enable us to identify any specific features of inflammatory pseudotumors of the lung, and all our patients underwent surgery with suspected lung cancer or carcinoid as the diagnosis.
As already stated, inflammatory pseudotumors are difficult to diagnose. Fine-needle aspiration shows a mixture of inflammatory cells, including plasma cells, fibroblasts, and pneumocytes. Such specimens are thus aspecific, given that inflammatory lesions of different origin can present the same picture. Moreover, inflammation and fibrosis can sometimes represent a reaction around a malignant tumor [11]. Surgical excision of the lesion therefore remains the most accurate diagnostic method [4]. Even though not universally accepted, the most widely used histologic classification is that of Matsubara and associates [11]. It presents organizing pneumonia (44%), fibrous histiocytic (44%), and lymphoplasmacytic (12%) as three overlapping histologic types, none of which is free from the features of the others. This can explain the different percentages found in our series, in which fibrous histiocytoma was the most frequent type (69%), followed by lymphoplasmacytic (25%) and organizing pneumonia (6%). More recently the World Health Organization [14] devised a new classification that recognizes three main histologic patterns: myxoid vascular, compact spindle cell, and hypocellular fibrous patterns. Within any one lesion, the three patterns may be equally represented with one blending into another, or one or two patterns may predominate [14]. However, our experience confirms that neither the classification of Matsubara and coworkers [11] nor the World Health Organization classification [14] seem to have a prognostic value.
The diagnosis of all inflammatory pseudotumors of the lung presented in this series was always supported not only by their morphologic features but also by their immunophenotypic features. In the vast majority of cases, immunohistochemical techniques enable inflammatory pseudotumors to be clearly identified and are indispensable in the diagnostic workup of these lesions. Immunohistochemical investigations [7, 14, 22], as confirmed by our series, show universally negative results for CD34, universally positive results for vimentin, and generally positive staining for smooth muscle actin, CD68, and epithelial membrane antigen.
The treatment of choice of inflammatory pseudotumor of the lung is surgery [4, 8, 12, 13]. Wedge resection, if radical, is suitable for curative purposes whether it is performed with video-assisted thoracoscopic surgery techniques or as an open procedure. When wedge resection is not technically feasible, the lesion is removed with major resection (lobectomy or pneumonectomy). In some cases, neighboring anatomic structures (chest wall, diaphragm) also need to be excised. The use of corticosteroids has been proposed for functionally inoperable patients, those with unresectable lesions and with disease relapse [8]. However, the results of corticosteroid treatment are extremely variable. The literature reports its inefficacy as well as its occasional ability to reduce lesion size and lead to complete regression [6, 8]. Even the efficacy of radiotherapy and chemotherapy as alternatives to surgery is controversial [6].
The prognosis of patients who undergo radical resection is excellent [4, 5]. Nevertheless, relapse can occur even many years after resection, and disease-related deaths are reported [4, 8]. In recent years, inflammatory pseudotumor of the lung with considerable biologic aggressiveness and unfavorable evolution have been described with increasing frequency [23, 24]. Death is secondary to both local relapse with infiltration of the mediastinal organs and distant metastases.
The study carried out by Cerfolio and colleagues [4] includes the most numerous surgical series (23 patients) reported in the literature up to now. Complete resection was possible in 18 cases (78%), and overall survival at 5 years was 91%. Nineteen patients were alive, and the remaining 4 died as a result of reasons not related to the tumor. Three of the 5 patients who underwent incomplete resection had a relapse: of these, 2 later underwent complete resection with no evidence of relapse after 8 and 9 years from surgery. The authors conclude that inflammatory pseudotumor of the lung is often locally invasive and complete resection can lead to excellent survival rates. In our series, complete resection was achieved in 13 patients (72%). Overall 5-year survival was 74%. Fourteen patients are currently alive: of these, 13 with no evidence of the disease and 1 with the disease. One patient died of unrelated causes, and the remaining 3 patients died as a result of local tumor relapse with distant metastases. In 1 of these 3 patients a fine-needle aspiration under CT guidance performed after the appearance of a mediastinal mass in the follow-up was compatible with sarcoma.
Sarcomatous transformation is described in the literature and can occur with both pulmonary and extrapulmonary inflammatory pseudotumors. Spencer and coworkers [25] reported a sarcomatous transformation of two inflammatory pseudotumors of the lung of the 27 observed. Coffin and colleagues [22] reported a sarcomatous transformation in 2 of 84 extrapulmonary inflammatory pseudotumors. Donner and associates [26] reported one case of inflammatory pseudotumor arising in the soft tissue of the forearm and progressing into sarcoma after five recurrences. The possibility of a sarcomatous transformation should therefore be taken into account in inflammatory pseudotumor patients. Caution is needed, however, because inflammatory pseudotumors may resemble low-grade sarcomas from a histologic point of view. Our diagnosis of sarcomatous transformation, even though extremely likely, cannot be taken as certain because it was based only on cytology.
It is difficult to establish whether the other two deaths can also be attributed to transformation into sarcomas as no workup was performed after inflammatory pseudotumor relapse. According to the literature, some inflammatory pseudotumors of the lung exhibit features of biologic aggressiveness independently of their evolution into sarcomas or other malignant lesions. Some authors [2] consider inflammatory pseudotumor as being not a single histologic entity but rather a lesion including a wide range of different diseases, ranging from benign fibrohistiocytoma to fibrohistiocytic lesions of borderline malignant appearance to malignant fibrous histiocytoma.
In our study, statistical analysis demonstrated a relation between lesion size and survival. Patients with a lesion diameter greater than 3 cm showed a significantly lower survival rate than those with solitary nodules. Moreover, patients who died had lesions with a significantly larger diameter than those of patients who are alive (56 mm versus 29 mm). In addition, the radicality of the resection was also a prognostic factor, and all the deaths because of the tumor occurred in patients who underwent incomplete resection.
In conclusion, in this study inflammatory pseudotumor of the lung had similar clinical characteristics to those of a true tumor. The series showed that a considerable percentage of patients with inflammatory pseudotumor of the lung can suffer local relapse with metastases and can die as a result of the disease. Although this is a very important clinical issue, it is not extensively reported in the literature. The possibility that some of these lesions can have a poor prognosis has so far been stated only by a few authors without reference to clinical series [6], or occasionally mentioned in case reports [9, 23, 24]. According to our data, it is not possible to establish whether the prognosis is mainly influenced by early diagnosis, presence of biologically aggressive variants, or variants prone to convert into malignant neoplasms. Our experience confirms that surgery is the treatment of choice for inflammatory pseudotumors of the lung, although the effectiveness of nonsurgical treatments is not demonstrated. The search for radicality, even by means of extended resections, is the primary goal of surgery, which should be pursued, if technically feasible, even for relapsed inflammatory pseudotumors. Patients with large lesions at surgical observation should, however, be considered at risk for relapse, especially if resection has not been radical, and should always undergo stringent and prolonged follow-up.
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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