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Type I Pleuropulmonary Blastoma: A Report From the International Pleuropulmonary Blastoma Registry

John R. Priest, D. Ashley Hill, Gretchen M. Williams, Christopher L. Moertel, Yoav Messinger, Marsha J. Finkelstein, Louis P. Dehner

From the International Pleuropulmonary Blastoma Registry; Department of Pediatric Hematology/Oncology, Children's Hospitals and Clinics of Minnesota, St Paul; Center for Care Innovation and Research, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN; and the Department of Pathology and Immunology, Barnes-Jewish and St Louis Children’s Hospitals at Washington University, St Louis, MO

Address reprint requests to John R. Priest, MD, International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, 345 N Smith Avenue, Mailstop 70-301, St Paul, Minnesota 55102; e-mail: jprst{at}prodigy.net

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: Type I pleuropulmonary blastoma (PPB) is a rare, cystic lung neoplasm in infants characterized by subtle malignant changes and a good prognosis. Recurrences after type I PPB are usually advanced type II or type III neoplasms with a poor prognosis. This article describes the first collection of type I PPB cases, analyzes outcome based on treatments of surgery or surgery plus chemotherapy, and presents type I PPB management recommendations.

PATIENTS AND METHODS: Type I PPB cases from the International PPB Registry and literature were evaluated using standard statistical methods for outcomes based on age at diagnosis, sex, thoracic side, surgical extent, length of follow-up, constitutional/familial disease, pre-existing lung cysts, intrathoracic findings, and treatments (surgery or surgery and chemotherapy).

RESULTS: Thirty-eight type I PPB cases were identified: Registry (n = 30) and literature (n = 8). Twenty children had surgery alone; eight (40%) experienced recurrence; and four died. Eighteen children had surgery and adjuvant chemotherapy; one experienced recurrence and died. All recurrences were type II or III PPB. Recurrence-free survival was higher in the surgery + chemotherapy group (P = .01); overall survival did not differ (P = .18). The improved recurrence-free survival was found only in males. Four of nine children with recurrence survived.

CONCLUSION: Adjuvant chemotherapy appears to benefit type I PPB patients. Benefit limited to males requires broader substantiation. Salvage after types II and III recurrence is poor (four of nine; 44%). A rigorous surveillance schedule after type I PPB diagnosis might detect early recurrence and be an acceptable alternative to adjuvant chemotherapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Pleuropulmonary blastoma (PPB) is an intrathoracic neoplasm occurring almost exclusively in children younger than 5 years. This dysontogenetic neoplasm, an analog to the other unique childhood tumors like Wilms' tumor and neuroblastoma, is classified with the "mesenchymal neoplasms" in the WHO Classification of Lung Tumors.¹

The evolution of the pathologic entity PPB emerged from the observation that the earliest pathologic stage of a solid, morphologically complex, high-grade intrathoracic sarcoma is a cyst of the lung, most often multilocular, which has a primitive mesenchymal-cell proliferation in the stroma beneath a benign epithelial cyst lining.^2,3 The process appears to originate in lung parenchyma and/or visceral pleura. The proliferation may be subtle and often shows rhabdomyoblastic differentiation. This early cystic stage, type I PPB, occurs typically in the first 2 years of life and is often mistaken for a benign congenital cyst, in particular congenital cystic adenomatoid malformation (CCAM). In addition, many type I PPBs are reported in the literature as cystic rhabdomyosarcoma of the lung, rhabdomyosarcoma arising in a congenital lung cyst or CCAM or cystic mesenchymal hamartoma.^4-12

Unique among the developmental neoplasms of childhood is the progression of PPB through a distinctive sequence of pathologic changes, from a purely cystic stage (type I PPB) to the aggressive cystic and solid (type II) and purely solid (type III) neoplasms. The solid components of types II and III PPB are a collage of fibrosarcoma-like, blastemal, cartilaginous, rhabdomyosarcomatous, and anaplastic foci.³ Since the initial description of PPB, additional clinicopathologic studies have supported the relationship of PPB pathologic types and tumor progression.^3,13 The three pathologic types are correlated with both age at diagnosis and clinical outcome. Type I occurs in infants (median diagnosis age, 10 months) in contrast to types II and III (median diagnosis ages, 34 and 44 months, respectively).¹³ Type I PPB has been identified in utero.¹⁴ If PPB recurs in an individual patient, the type has often progressed to more advanced disease. There are also numerous reports of types II or III PPB emerging in children with pre-existing lung cysts that were either observed over time or removed and considered benign.^4,5,15-18 Many of those benign diagnoses we now recognize as type I PPB. Development of a solid component in a previously cystic neoplasm is an ominous sign in PPB. Overall survival in PPB ranges from 80% to 85% for type I to 45% to 50% for type III.¹³ Recent work suggests that the outcome for type III is even less favorable than previously thought, whereas type II prognosis remains intermediate between types I and III.¹⁹

The rarity and subtle malignant features of type I PPB contribute to difficulty in making the correct diagnosis. Patients with type I PPB present with dyspnea from a pneumothorax or large air-filled cyst or with the incidental discovery of a lung cyst. The clinical and radiographic features of type I PPB cannot be distinguished from congenital lung cyst(s) or congenital lobar emphysema (Fig 1A). Because the microscopic presence of the small, primitive, diagnostic tumors cells may be exquisitely localized and relatively inconspicuous, the initial pathologic examination may not suggest a malignant process. Many histologic sections may be required. The diagnosis of type I PPB should be considered for any delicate, translucent, multicystic specimen of peripheral lung from a child younger than age 5 years submitted as a "congenital lung cyst." Multilocular cystic lesions containing a discontinuous layer of rounded to spindle-shaped primitive tumor cells in the subepithelial stroma producing a cambium layer effect or sparsely cellular septa containing nodules of primitive cartilage should suggest a diagnosis of type I PPB.^19,20 (Fig 2).

View larger version (47K): [in this window] [in a new window]   Fig 1. (A) Initial chest radiograph in 9-month-old with mild respiratory distress. No computed tomography (CT) was performed. Cystectomy performed. Diagnosis type I pleuropulmonary blastoma. (B) Chest CT 16 months later. No chemotherapy had been administered. Cyst shown and a smaller cyst (not visible) had been enlarging slightly. Both lesions were resected, and the pathology was benign.

View larger version (104K): [in this window] [in a new window]   Fig 2. (A) Type I PPB in multilocular cyst. Lower septum, primitive tumor cells in condensed (cambium) layer beneath benign epithelium. Upper septum, tumor cells difficult to visualize in septal fibrous tissue. Tumor amount varies widely. (hematoxylin and eosin stained [H&E]; original magnification x200). (B) Cambium layer: several layers of primitive, malignant cells beneath benign epithelium. (H&E; original magnification x400).

In an effort to expand understanding of type I PPB and to clarify some management issues, this article reports clinical, treatment and outcome data for type I PPB patients from the International PPB Registry (www.ppbregistry.org) and literature. We also review the natural history of types II and III PPB arising in pre-existing lung cysts, which we believe may be undiagnosed type I PPB.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The Registry obtains cases of PPB through oncology or pathology consultation, parental enrollment and participation of authors reporting PPB. The Registry has approval from the participating institutions' institutional review boards. The Registry collects data on presentation, family history, radiography, surgery, pathology, treatment, and follow-up. Pathology is centrally reviewed in all Registry cases. Registry and literature cases of type I PPB form the basis of this report. Also included are Registry and literature cases of types II and III PPB occurring in children with known pre-existing lung cysts.

Variables assessed in type I cases were diagnosis age, sex, familial disease, duration of pre-existing cysts when known, pneumothorax, side of lesion, bilaterality, intrathoracic features of disease (exophytic lesion at lung-visceral pleura surface v significant lung deformity; hilar v lateral location; adhesions), surgery extent (cystectomy, segmentectomy, lobectomy), therapy (surgery; surgery and chemotherapy), adjuvant and recurrence chemotherapy regimens, follow-up duration, recurrence, and death.

To evaluate the effect on recurrence and overall survival of adjuvant chemotherapy for type I PPB, all comparisons have been made between patients with and without this treatment. Univariate analysis for categoric data included ², Fisher's exact test and Monte Carlo Simulation applied to ². The latter two exact tests were used when cell entries were not sufficient to meet the requirements of the ² distribution. Univariate analysis for continuous data included the nonparametric Mann-Whitney U test for data that were not normally distributed and the t test for normally distributed data. The Kolmogorov-Smirnov statistic was used to test for normality. The Kaplan-Meier life table was applied to describe both recurrence of the cancer and death. Time for each of the patients was calculated as time from date of diagnosis to an event date (recurrence or death) or to the last follow-up date. The Breslow test was used to compare survival distributions resulting from the early events for the control group, which violated the proportional hazard assumption required by the log-rank test. Survival analysis of other groups used either the Breslow or log-rank test as appropriate. All P values less than .05 were interpreted as significant. All statistical calculations were performed using SPSS for Windows version 11.5 (SPSS Inc, Chicago, IL).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The Registry has enrolled 147 centrally reviewed PPB cases and identified approximately 150 non-Registry cases from the literature. Included in this analysis are 38 type I cases: 30 from the Registry and eight from the literature.^25-29 Thirteen of the Registry cases have been included in previous Registry or primary institution reports.^{4,6,13,15,20,21,24,30-36} All children had intrapulmonary type I PPB without involvement of parietal pleura, diaphragm or mediastinum. Type I PPB was diagnosed after the initial resection in 29 of 38 cases. A CCAM type 4 was revised 4 years later to type I PPB. In eight children diagnosed with type II or III PPB, an earlier cyst resection specimen considered benign was retrospectively diagnosed type I PPB. Patient characteristics are summarized according to two treatment groups in Table 1.

View larger version (15K): [in this window] [in a new window]   Fig 3. (A) Recurrence-free survival in 38 children with type I pleuropulmonary blastoma (PPB) based on initial treatment received. (B) Overall survival in 38 children with type I PPB based on initial treatment received.

Life-table analysis revealed no survival differences associated with any of the other assessed variables.

In addition to 38 type I cases, we identified 28 children (11 Registry, 17 literature) with known lung cysts who later developed type II and III PPB.^{9,10,17,18,37-49} Cysts had been discovered between ages 0 and 48 months (median age, 18 months). In seven cases, cysts were removed and pathologically considered benign. In 21 cases, the cysts were observed. In 28 cases, a PPB diagnosis was made between ages 5 and 144 months, median age, 36 months. The diagnosis was made 2 weeks to 96 months (median, 20.5) after a cyst was first noted.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The results of our study appear to show an advantage to adjuvant chemotherapy compared with surgery alone for type I PPB. One of 18 children who received adjuvant chemotherapy experienced recurrence and died as a result of tumor. In contrast, eight (40%) of 20 children who had surgery alone developed recurrent disease; four died as a result of tumor. All nine recurrences were type II or III PPB. Recurrence-free survival was significantly improved in the surgery plus adjuvant chemotherapy group (P = .01; Fig 3A). Overall survival was not different (P = .18; Fig 3B).

The finding that adjuvant chemotherapy was associated with improved recurrence-free (but not overall) survival in males was unexpected. A sex effect on prognosis in PPB has not been previously observed, and there is no known biologic basis for such a difference. Our data show no sex effect on overall survival in type I PPB. In collections of types I, II, and III PPB, 22 cases from Italy,⁵⁰ 16 cases from Germany,⁵¹ and 50 Registry cases¹³ show no sex differences in overall survival. For now, the type I data suggesting a benefit of adjuvant chemotherapy only in recurrence-free survival and only in males must be interpreted with caution but warrants further attention.

It has been suggested that PPB complicating cystic lung malformations has a better prognosis than de novo PPB.⁵² Our limited type I PPB data suggest the opposite: recurrence-free survival was lower when cysts were known in advance for more than 3 months versus less than 3 months or for more than 6 months versus less than 6 months. The critical debate about cysts preceding PPB is whether they are benign malformations predisposing to cancer or are early manifestations of the cancer itself. In our experience, detailed examination of these cysts rarely reveals typical CCAM. The fact that recently described type 4 CCAM⁵³ shows significant morphologic overlap with type I PPB, and may be followed by solid PPB,^{15,30,31,54,55} raises the question of whether type 4 CCAM is really distinct from type I PPB.

It has also been suggested that "extrapulmonary" involvement in PPB, defined as involvement of "the pleura, diaphragm or mediastinum," indicates a less favorable prognosis.²⁵ It is not clear whether this definition includes both visceral and parietal pleura. We believe type I PPB is limited to pulmonary parenchyma and/or visceral pleura. Involvement of parietal pleura, mediastinum, or diaphragm implies invasive overgrowth of sarcomatous elements, which justify a type II or III PPB designation. Type I PPB may be an exophytic cystic lesion which mostly spares the lung, or it may replace significant pulmonary parenchyma. Type I may arise near the lung hilum or laterally. Even in the absence of prior chest tube placement, there occasionally are adhesions between cysts and visceral or parietal pleura. We found no prognostic importance to these intrathoracic variations. Completeness of cyst removal and status of surgical margins could not be assessed in the patients we report.

Eighteen cases were unilateral/unifocal and 17 were multifocal and/or bilateral, evenly represented in the treatment groups (Table 1). Among those treated with surgery alone, two of eight unilateral/unifocal cases experienced recurrence, whereas five of 10 multifocal/bilateral cases experienced recurrence. This is not significantly different.

The association of PPB with constitutional and/or familial disease has been reported in approximately 25% of PPB cases.^21,24 Reported here are 22 constitutional/familial cases in 24 cases with known family history. Treatments and outcomes were similar to the group of 38 cases (Table 1). This higher incidence of constitutional/familial disease in 38 type I cases is not readily explained.

The data presented here are from the International PPB Registry series and the literature. There are potential problems with retrospective data and data on a malignancy that is rare and difficult to recognize. Case numbers are low. There may be bias in reporting type I patients or in enrolling them with the Registry: Chemotherapy-treated cases or recurrent cases may attract more attention than surgically cured cases. In fact, seven type I cases we report were recognized only retrospectively after type II or III recurrence. As recognition of type I PPB improves, cases cured by surgery may become more numerous. Finally, when a resected cyst is not recognized as type I PPB, further surveillance is probably limited, and children may progress to extensive type II or III disease before returning to medical care.

Because of the observations reported here, the PPB Registry has recommended adjuvant chemotherapy for type I PPB since 2003. An alternative management strategy is rigorous monitoring for early detection of recurrence. Early detection may improve the success of salvage therapy, but this remains to be shown.

The modality, duration, and frequency of an adequate surveillance can be guided by the data reported here. First, a surveillance schedule must address the risk period for recurrence. Eight surgery-only children reported here developed recurrences 3 to 37 months (median interval, 18 months) after the type I diagnosis (Table 1); at recurrence they were 19 to 50 months of age (median, 30 months of age). The chemotherapy-treated child recurred 53 months after diagnosis, at age 76 months. We also report here 28 children with pre-existing lung cysts in whom type II or III PPB emerged at a median age of 36 months. De novo type II and III PPB is diagnosed at ages 34 and 44 months, respectively.¹³ These data suggest that surveillance for detecting recurrence after a type I PPB diagnosis continue for 24 to 36 months after type I diagnosis and to age 48 and perhaps 60 months.

Second, adequate surveillance must recognize that PPB can rapidly progress; solid components of types II and III PPB are capable of rapid growth similar to Wilms' tumor. In two cases reported here, type II or III disease developed 3 and 7 months, respectively, after type I diagnosis. In another case, a large type II recurrence was discovered 6 months after a stable surveillance chest computed tomography (CT) scan. A surveillance scan interval of 6 months will miss the earliest evidence of some recurrences, although it is not proven that more frequent scanning will improve outcomes.

Third, the sensitivity of plain radiographs to detect subtle changes after a type I PPB diagnosis is inadequate. CT is the best modality for chest disease.⁵⁶ Although cumulative radiation from CT in the pediatric age group has risks,⁵⁷ the alternative in type I PPB cases may be poor salvage rates if a solid, high-grade sarcomatous tumor emerges.

Three recent Registry cases, whose outcomes remain to be learned, demonstrate how close surveillance can be used to modulate type I therapy. Seven months after type I diagnosis in a child with multifocal cystic disease, the remaining cysts enlarged, were resected and showed additional sites of type I PPB; chemotherapy was initiated. In another child (Fig 1B), 16 months after type I diagnosis, remaining cysts enlarged and were resected. Pathologic examination did not reveal type I PPB in the residual cysts, and the child continues being observed without chemotherapy. In another child with multifocal cystic disease, adjuvant chemotherapy was initiated after type I diagnosis. After 28 of 48 planned weeks of therapy, remaining cysts enlarged and were resected. Compared with the initial specimen, cyst walls showed hyalinized nodules, hemorrhage, abundant macrophages, and rare cartilage nodules with few nodules of primitive cells, consistent with chemotherapy effect. No residual confluent layers of primitive cells (cambium layer) were seen. On the basis of these findings, the original plan was continued.

The best approach to managing type I PPB remains to be learned. Adjuvant chemotherapy appears beneficial in this small retrospective collection. An alternative active surveillance strategy is reasonable but unproven. Increased recognition of type I PPB and enrollment of new cases in cooperative groups and tumor-specific registries such as the International PPB Registry will allow refinement of these approaches.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: John R. Priest, D. Ashley Hill, Christopher L. Moertel, Yoav Messinger Administrative support: Gretchen M. Williams Provision of study materials or patients: John R. Priest, D. Ashley Hill, Louis P. Dehner Collection and assembly of data: John R. Priest, D. Ashley Hill, Gretchen M. Williams, Christopher L. Moertel, Marsha J. Finkelstein Data analysis and interpretation: John R. Priest, D. Ashley Hill, Gretchen M. Williams, Christopher L. Moertel, Marsha J. Finkelstein, Louis P. Dehner Manuscript writing: John R. Priest, D. Ashley Hill, Marsha J. Finkelstein, Louis P. Dehner Final approval of manuscript: John R. Priest, D. Ashley Hill, Christopher L. Moertel, Yoav Messinger, Marsha J. Finkelstein, Louis P. Dehner

 

	ACKNOWLEDGMENTS

 
Parents who allow their children's illnesses to be shared with the International Registry are essential and are gratefully acknowledged. The Registry also commends many clinicians, pathologists, nurses, and data analysts for providing data. David Slinger, Kris Doyle, Jeannie Doerr, and Nancy Battaglia have provided valuable help.

	NOTES

 
Supported by the Pine Tree Apple Tennis Classic.

Presented in part at the Annual Meeting of the American Society of Pediatric Hematology and Oncology, Orlando, FL, May 14, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted December 16, 2005; accepted July 20, 2006.

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