Pleuropulmonary Involvement in Pseudomyxoma Peritonei ...

Anatomic Pathology / THORACIC PSEUDOMYXOMA

Pleuropulmonary Involvement in Pseudomyxoma Peritonei Morphologic Assessment and Literature Review Kim R. Geisinger, MD,1 Edward A. Levine, MD,2 Perry Shen, MD,2 and Robert F. Bradley, MD1 Key Words: Pseudomyxoma peritonei; Lung; Pleura DOI: 10.1309/601K2L2T7CR5U7G1

Abstract Intrathoracic spread in patients with pseudomyxoma peritonei (PP) is rare. We reviewed 101 patients uniformly treated at our institution for PP of appendiceal origin. In that study, we suggested mucinous carcinoma peritonei (MCP) as the pathologic terminology for all cases of PP. Four patients had pathologically documented pleuropulmonary involvement. We subsequently examined another patient with pleural invasion. Of 5 patients, 3 had low-grade histologic features in the peritoneum; these showed variably proliferative, bland-appearing neoplastic cells arising from low-grade appendiceal mucinous neoplasms. In 2 cases, 1 or more pulmonary parenchymal metastases of low histologic grade developed. The lack of pleural involvement argued against transdiaphragmatic tumor extension. The third patient with low-grade MCP had direct extension through the left diaphragm involving the left pleural and pericardial spaces without pulmonary parenchymal involvement. In the 2 patients with high-grade MCP, right-sided pleural effusions developed. Neither patient had documented injury to the diaphragm. Pleural cytologic examination revealed high-grade adenocarcinoma cells singly, in small clusters, and in large spheres. The smear backgrounds contained wispy mucin. None of the 5 patients developed thoracic lymph nodal metastases. Although rare, mucinous neoplasms from PP may involve the thorax.

Pseudomyxoma peritonei (PP) is the clinical syndrome of diffuse gelatinous or mucinous ascites associated with peritoneal implants of mucin-producing neoplasms. The definitions and concepts revolving about the origin and the biologic nature of the associated neoplasms have been controversial for decades.1 For many years, it was thought that most cases of PP were due to mucinous neoplasms arising in the ovary. However, within the last 15 years, it has become clear that most of this syndrome is related to primary tumors of the appendix.1-12 Benign vs malignant nature of the primary neoplasms has been debated.1,13-15 Although the peritoneal disease in most patients closely resembles the histologically bland appendiceal precursors, the data from our clinicopathologic correlations suggest that all neoplasms that produce PP are best classified as carcinoma.15 More specifically, we believe that the peritoneal neoplastic processes can be divided into low- and high-grade mucinous carcinomas in relation to their associated prognoses. Extension of PP into the thorax is unusual. Although published accounts of pleural effusions or pulmonary parenchymal metastases exist, unfortunately, they are generally lacking in microscopic detail.15-23 In a series of 101 patients with PP secondary to appendiceal neoplasms, 4 had supradiaphragmatic involvement by PP; 3 additional patients had radiographic evidence of pulmonary metastases but no confirmatory pathology and thus, are not included in the present study.15 Data on a subsequent fifth patient are also included herein. Three patients had cytologically malignant pleural effusions, 2 of whom had high-grade mucinous carcinomas. The third with pleural disease had a low-grade mucinous carcinoma. The fourth and fifth patients each had metastases to the parenchyma of the lung; the latter masses were, in part, Am J Clin Pathol 2007;127:135-143

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surgically resected. All 5 patients had abdominal disease that we characterize as mucinous carcinoma peritonei (MCP).15 None had hepatic or splenic parenchymal metastases. Both with pulmonary parenchymal metastases had low-grade MCP that could have been categorized as adenomucinosis or lowgrade mucinous neoplasm according to earlier terminology.11,14 The purpose of this report is to detail the histologic and cytomorphologic features of the malignant pleural effusions and the histopathologic findings of the resected metastases in the context of an extensive literature review.

Materials and Methods We examined a large series of patients with PP secondary to primary neoplasms of the appendix.15 At varying times after the initial diagnosis of PP, 4 patients in our initial investigation had pathologically confirmed thoracic disease related to their appendiceal tumors. A fifth patient with resected thoracic disease was encountered later. In our initial series, we searched the clinical records for evidence of chest involvement in other patients. Three other patients, all with high-grade MCP, had radiographic evidence of pulmonary parenchymal metastases without pathologic confirmation (lung, liver, spleen parenchymal metastases in one; lung, liver in another; lung only in third). Slides from all previous pathologic material were reviewed for each patient. Pleural fluid samples from cases 1 and 2 were obtained by conventional thoracentesis. Aliquots were centrifuged, and the sediment was used to create direct smears. The specimens were fixed in 95% ethanol and stained with the Papanicolaou technique; in 1 case, the rapid Romanowsky stain was also applied. A cell block was also prepared from each of the sediments and processed in paraffin to yield H&E-stained sections. Resected lung and pleural tissues from cases 3, 4, and 5 were fixed in formalin and processed by routine histologic techniques to yield H&E-stained sections.

Results Clinical Case Histories Case 1 A 45-year-old man was referred to our institution with a primary signet-ring cell adenocarcinoma of the appendix associated with PP in October 2001. Cytologic examination of the ascitic fluid demonstrated signet-ring cell adenocarcinoma suspended within mucin. A computed tomography (CT) scan of the chest was negative. The patient underwent cytoreductive surgery with intraperitoneal hyperthermic chemotherapy (IPHC) with mitomycin. The operative note did not mention 136 136

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injury to or defect in the diaphragm. Fourteen months later, chest radiograph and CT scan revealed a moderately sized right pleural effusion and a small nodule that appeared to be tumor along the right pericardium. Thoracentesis yielded fluid that was examined cytologically. Case 2 A 38-year-old man sought care because of increasing abdominal girth and bloating. The patient had ascites, underwent exploration, and had an omental biopsy that demonstrated well-differentiated mucinous adenocarcinoma. He underwent resection of the ascending and transverse colon, distal ileum, appendix, gallbladder, spleen, and part of the pancreas. A primary mucinous adenocarcinoma was detected in the appendix. The other findings were consistent with high-grade MCP. The patient then received IPHC with mitomycin. A right-sided pleural effusion associated with respiratory distress developed. Therapeutic thoracentesis yielded a large volume of fluid that was examined cytologically. Case 3 A 36-year-old man complained of vague abdominal pain before having definitive therapy at our institution. His initial workup included a CT scan that demonstrated peritoneal carcinomatosis. He underwent a needle core biopsy of the appendix and an omental mass. Our review of the histologic features was consistent with low-grade MCP secondary to adenocarcinoma of the appendix. A few months before his definitive therapy, he was admitted to our institution for the first time. The physical examination was unremarkable with the major exceptions of a minimal fullness of the abdomen, especially on the right side, and an umbilical mass consistent with a Sister Mary Joseph nodule. Radiologic studies manifested prominent soft tissue masses involving the omentum, the right lower and right upper quadrants of the peritoneal cavity, the left and right sides of the diaphragm, the right side of the large intestine, and the splenic surface. In addition, the CT scan demonstrated a mass in the appendix and disease involving the full thickness of the left side of the diaphragm and the lower half of the left pleural space. He underwent IPHC. A portion of the left side of the diaphragm was removed, along with the lower portion of the left pleural cavity, left lower pulmonary lobe, and soft tissue in the pericardial region. Case 4 A 41-year-old woman initially underwent treatment at another institution for PP and a neoplasm involving the left ovary. The initial histologic diagnosis of this ovarian tumor was mucinous borderline tumor. Later, a routine chest radiograph revealed a solitary mass lesion in the upper lobe of the right lung not associated with the pleura. This mass was resected and diagnosed as a metastasis from the ovarian neoplasm. Two © American Society for Clinical Pathology

Anatomic Pathology / ORIGINAL ARTICLE

Case 5 A 61-year-old man was first diagnosed with PP associated with a well-differentiated mucinous adenocarcinoma primary tumor in the appendix (low-grade MCP). Three years later, he had a solitary nodule in the right lower lung. This mass was removed by wedge resection. He was referred to our institution for further evaluation and underwent cytoreductive surgery with IPHC using mitomycin. There was no documentation of injury to the diaphragm. A subsequent CT scan of the chest demonstrated a new 1-cm nodule in the lower lobe of the left lung. This nodule was removed by wedge resection. Later, a CT scan of the chest demonstrated multiple nodules in the lower and middle right lobes and a new nodule in the left lower lobe, all suggestive of metastases.

aggregates ❚Image 1❚. In both cases, the smear background contained wispy to striated mucin. Cellular contours varied from round to low columnar. Nuclei were eccentric and hyperchromatic with small nucleoli. Collectively, the nuclear/cytoplasmic (N/C) ratios were low due to obvious cytoplasmic mucin, often in solitary round vacuoles compressing the nucleus into a crescent shape. The cell-block sections in cases 1 and 2 showed clusters of signet-ring cells identical to those noted in the abdominal histologic samples ❚Image 2❚ and ❚Image 3❚. Grossly and microscopically, the gelatinous tumor in case 3 dissected through the left side of the diaphragm to involve directly the left pleural space ❚Image 4❚. The resected pleural space was markedly distended grossly by gelatinous material (pseudomyxoma “pleurii”). Microscopically, the tumor was consistent with low-grade MCP ❚Image 5A❚. The tumor consisted of abundant extracellular mucin containing scattered neoplastic cell clusters, generally arrayed in single layers interfacing fibrous connective tissue. The tumor cells were tall, columnar, glandular elements with ample cytoplasm and small, bland, basally oriented nuclei. There was no evidence of invasion of the parenchyma of the lung. The pericardial tumor histologically was indistinguishable from that involving the left pleural cavity and the abdomen. Vascular invasion by tumor cells was present in a section from the left side of the diaphragm, in direct continuity with the malignant pleural disease ❚Image 5B❚. The appendix manifested primary low-grade adenocarcinoma that invaded and perforated the appendiceal wall.

Pleural Pathology The cytologic smears in cases 1 and 2 were quite similar. Both were moderately cellular with occasional single cells, and most of the tumor cells were in small cohesive 3-dimensional

Pathology of Lung Metastases In case 4, grossly, the pulmonary neoplasm formed a wellcircumscribed subpleural sphere with a tenacious, glistening, gray cut surface. Microscopic features resembled the typical

years later, she was referred to our institution for additional evaluation. The chest CT scan demonstrated no evidence of parenchymal disease, mediastinal lymphadenopathy, or effusions. She underwent cytoreductive surgery and IPHC with mitomycin. There was no documentation of injury to the diaphragm. In addition to low-grade MCP involving much of the abdominal cavity, the appendix was resected and contained a low-grade mucinous neoplasm. Subsequently, we evaluated the ovarian tumor by immunohistochemical analysis. The neoplastic cells were positive for cytokeratin 20 and negative for cytokeratin 7, supporting a lower gastrointestinal origin.8 The pulmonary nodule was also reevaluated and deemed consistent with a low-grade appendiceal metastasis.

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❚Image 1❚ A and B, Pleural cytology from patient 2 showing mucinous carcinoma (Papanicolaou stain, ×400).

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❚Image 2❚ Patient 1. A, Histologic section from peritoneum with high-grade mucinous carcinoma (H&E, ×400). B, Cell block from pleural fluid with identical cells (H&E, ×400).

lesions of low-grade MCP ❚Image 6❚. At the interface between tumor and parenchyma, hypocellular fibrous connective tissue trabeculae were focally dissected by acellular mucin. The neoplastic cells were often arranged in single layers between the extracellular mucin and the trabeculae, with mild pseudostratification and well-maintained polarity. The cells were tall and columnar with minimally enlarged hyperchromatic nuclei. Mitotic figures were not seen, and nucleoli were inconspicuous. In case 5, grossly, both nodules were spherical masses that had a dominant gelatinous, glistening surface. In the scanning lens view, the circumscribed, spherical tumors consisted of extracellular mucin in which neoplastic cells were present singly,

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in linear strips with micropapillae, spheres, and glands ❚Image 7❚. Nuclei were moderately enlarged with thick and irregular membranes, hyperchromatic chromatin, distinct nucleoli, and scattered mitotic figures. The N/C ratios were mostly low. The tumor-parenchymal interface was relatively sharply demarcated without any sclerotic connective tissue, capsule-like structure.

Discussion Despite evolving controversy regarding nomenclature, most current clinical, histologic, molecular, and genetic data strongly support the notion that the vast majority of cases of

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❚Image 3❚ Patient 2. A, Histologic section from peritoneum with high-grade mucinous carcinoma (H&E, ×400). B, Cell block from pleural fluid with identical cells (H&E, ×400).

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PP result from primary mucinous neoplasms of the appendix or large intestine with extension of the tumor cells and their extracellular mucinous material to the peritoneal cavity and often to the ovaries or other abdominal organs.1-15 In their 1995 study, Ronnett et al5 divided the histopathology of the peritoneal lesions into prognostically significant categories. There were 2 major groups: disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). Bradley et al15 recently examined a series of 101 patients with PP due to primary neoplasms restricted to the appendix. All patients were uniformly managed in the same institution with cytoreductive surgery and IPHC with mitomycin. By using the histologic criteria of Ronnett et al,5 Bradley et al15 found the 1-, 3-, and 5-year survival rates for patients with DPAM and the well-differentiated subset of PMCA to be identical. Thus, they suggested combining these 2 groups into a single clinicopathologic entity, namely, low-grade MCP.15 In that series, patients with low-grade MCP had significantly better survival than patients with high-grade MCP. One important difference in the classification of well-differentiated (intermediate) PMCA between Ronnett et al5 and Bradley et al15 was that the latter authors considered patients to have a poorly differentiated carcinoma (high-grade MCP) if there was any signet-ring differentiation by the neoplasm. With no difference in 5-year survival or distribution of organ invasion between the most bland histology and the cases that have otherwise been classified as well-differentiated carcinomas without controversy, we now consider all cases low- or high-grade MCP. Thus, we believe that once an appendiceal tumor, regardless of its original histology, reaches beyond the right

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❚Image 4❚ Patient 3. Gross photograph from lung wedge resection with gelatinous tumor encasing lung. Note portion of diaphragm on the left.

lower quadrant into the peritoneal cavity and results in PP, it is clinically and pathologically malignant. Although most unusual, thoracic involvement by the PP process has been well documented as pleural effusions or pulmonary metastases (the case reported by Lee et al20 had effusions and metastases).15-19,21-23 However, most publications dealing with this subject do not provide detail on the morphologic features of the thoracic disease. Including the 3 cases in our report, a total of 30 cases have been reported to have pleural effusions due directly to

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❚Image 5❚ Patient 3. A, Histologic section showing pleural invasion by low-grade mucinous carcinoma (H&E, ×40). B, Histologic section showing vascular invasion in section from ipsilateral hemidiaphragm (H&E, ×100).

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❚Image 6❚ Patient 4. A, Peritoneal histologic section showing low-grade mucinous carcinoma peritonei (H&E, ×100). B, Pulmonary metastasis with identical morphology (H&E, ×100).

tumor in patients with PP ❚Table 1❚. Patient ages ranged from 34 to 79 years at the time of initial diagnosis of PP. The interval between the initial diagnosis of PP and the discovery of thoracic disease related to this syndrome has ranged from less than 1 year to nearly 15 years.20 However, in most patients, the interval is between 2 and 6 years. Of these 30 patients, 17 were men and 13 were women. Right-sided effusions were reported in 15 cases, whereas in 12 cases, the disease was on the left side; in 3 cases, pleural effusions were bilateral. Pleural fluid in cytologic specimens had been examined previously in only 2 cases.17,23 In both, the smears showed only extracellular mucinous material without neoplastic cells.

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Pleural biopsies were obtained in 14 cases. In the case reported by Lee et al,20 the biopsy sample contained only mucin without associated malignant cells. Of the cases reported by Pestieau et al,19 13 had pleural biopsy specimens that were said to confirm the presence of neoplasm. However, the authors did not describe the histologic features of the thoracic disease or of the primary neoplasm.19 Of these 13 cases, 1 was also separately reported by Pestieau et al24 in a single case report; in this communication, the histologic features of the pleural disease were said to resemble DPAM in a woman whose primary neoplasm was a cystadenoma of the appendix.

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❚Image 7❚ Patient 5. A, Peritoneal section showing low-grade mucinous carcinoma peritonei (H&E, ×100). B, Pulmonary metastasis with identical morphology (H&E, ×100).

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❚Table 1❚ Reported Cases of Pleural Effusions Due to Pseudomyxoma Peritonei Reference

No. of Cases

Mets et al16 Radosavljevic et al17 Peek and Beets18 Pestieau et al19 Lee et al20 Present study * Ages

Sex/Age (y)

1 1 1 23 1 3

Laterality of Effusion

M/47 M/41 M/38 F, 13; M, 10/34-79* M/60 M/36, 45, 38

Right Left Bilateral Right, 12; left, 9; bilateral, 2 Left Right, 2; left, 1

were not described separately for men and women.

Several mechanisms have been proposed to explain the means by which neoplastic cells spread from the peritoneal cavity to the pleural space.19,20 Only a minority with positive pleural effusions had thoracic disease before abdominal surgery. Several workers believe that iatrogenic damage to the diaphragm occurs with some frequency when a subdiaphragmatic peritonectomy is performed.19,20 In some reported cases, the surgeon recognized at operation that the pleural space had been entered. In other cases, unrecognized minor injuries of the diaphragm may occur during operation. In a small proportion of cases, patients may have congenital or acquired pleuroperitoneal communications that allow neoplastic cells to reach the pleural spaces.24 As in our case 3, it has been suggested that tumor may directly pass through an intact diaphragm, via lymphovascular spaces or, more likely, via direct invasion.19 In a significant minority of cases, the mechanism remains idiopathic.19 The histopathologic features in patients with PP and pulmonary parenchymal metastases have been better documented (8 cases, including our 2) ❚Table 2❚.20-23 Although it is difficult to be sure from the descriptions by some authors exactly how the pulmonary neoplasia would be classified, most patients seem to have had low-grade mucinous neoplasms at both sites, as seen in our 2 cases. In the 3 cases reported by Mortman and colleagues,23 the authors stated that the histologic features of the metastasis completely resembled the primary appendiceal neoplasm. In their case 1, the tumor was classified as a low-grade mucinous

tumor. From their description, it would seem that the primary appendiceal neoplasm was an adenoma. In their case 2, the neoplasm in the lung was characterized as a well-differentiated mucinous adenocarcinoma. The pathology of the primary lesion in their patient was not described. Although the case reported by Lee et al20 was classified as a well-differentiated mucinous adenocarcinoma primary tumor in the appendix, from their description and published photomicrograph, it would likely otherwise be considered a primary “adenoma causing DPAM,” if the criteria of Ronnett et al5 were used. The patient described by Kreissig et al22 was said to have a borderline mucinous cystadenoma primary tumor in the appendix with the histologic features of the pulmonary metastasis resembling it. In the case reported by Berge,21 the primary appendiceal lesion was classified as a mucocele. From the description and published photomicrographs, the primary tumor seems to be a bland low-grade neoplasm with a DPAM-like lesion involving the pulmonary parenchyma.20-23 All patients’ neoplasms were primary in the appendix. If the classification of Bradley et al15 were used, all cases would be considered low-grade MCP due to well-differentiated appendiceal carcinomas. In all patients with pleuropulmonary involvement, the diagnosis of PP was made at some point earlier in the patient’s clinical history. With this information, the differential diagnosis of cytologic and histologic material from the thorax should not pose major challenges. Access to previous morphologic material, both peritoneal cytologic samples (spontaneous

❚Table 2❚ Reported Cases of Pulmonary Metastases of Pseudomyxoma Peritonei Reference

No. of Cases

Sex/Age (y)

Solitary or Multiple

Laterality

Berge21 Kreissig et al22 Mortman et al23

1 1 3

Lee et al20 Present study

1 2

M/59 M/39 F/47 M/48 M/41 M/60 M/61 F/45

Multiple Multiple Multiple Solitary Multiple Multiple Multiple Solitary

Bilateral Bilateral Right Left Right Left Bilateral Right

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ascitic fluids or washings) and histologic resection specimens, is paramount because these should demonstrate essentially the same picture on both sides of the diaphragm. In patients with obviously malignant primary epithelial neoplasms of the appendix, the cytologic smears will contain similar cells, often having a signet-ring configuration. The presence of intracytoplasmic and extracellular mucin in the background should readily lead one to the correct diagnosis. Such a picture in a pleural effusion would be most exceptional from a primary pulmonary adenocarcinoma. In patients whose primary appendiceal neoplasm was low-grade, obviously malignant cells would not be expected in a pleural fluid examination. Rather, one would expect it to resemble morphologically the peritoneal washings from such cases as detailed by Jackson and colleagues.12 In this situation, mucinous material is often abundant in the smear background. The neoplastic cells are characterized by well-maintained intercellular cohesion and polarity. Thus, the vast majority of tumor cells are present in relatively large flat sheets with sharply defined smooth edges. The tumor cells have small round dark nuclei, often without obvious nucleoli. The nuclei are surrounded by moderate volumes of mucin, and, thus, the N/C ratios are low. One characteristically sees a honeycomb arrangement of the nuclei in epithelial sheets. At times, the columnar configuration of the cells is more apparent if one examines carefully the edges of the sheet where the orientation of the cells may be perpendicular to the majority of the neoplastic elements present in the sheet.12 Based purely on the morphologic features, several primary pulmonary neoplasms fall into the differential diagnosis.25,26 From a histologic viewpoint, the entities with the greatest overlap with parenchymal involvement by PP are primary mucinous cystic neoplasms and colloid carcinomas of the lung. The finding of a progressive spectrum from bland and benign through varying degrees of atypia to obviously malignant in the same specimen would strongly favor a primary tumor, as such features are much less obvious in the vast majority of cases of MCP. Obviously, clinical history is paramount. We are unaware of any documented cases of cytologically positive pleural effusions in patients with mucinous cystic neoplasms of the lung. The histologic distinction between mucinous bronchioalveolar carcinoma and MCP may be much more readily achieved. In the former, one would expect to see malignant cells growing in a lepidic pattern along preexisting alveolar septa. Cytomorphologically, a positive pleural effusion related to a primary mucinous adenocarcinoma might be indistinguishable from pleural involvement by MCP. Although immunocytochemical studies might be useful in the differential diagnosis, the antigenic overlap of these 2 entities may be striking. One must also consider the possibility of a well-differentiated mucoepidermoid carcinoma. Histologically and cytologically, these neoplasms manifest cells with some 142 142


degree of squamous differentiation, which would not be expected in morphologic samples from thoracic involvement by MCP. As is always the case, metastases from elsewhere in the body must also be considered in the differential diagnosis. In all cases, an accurate clinical history is crucial. It is worthwhile mentioning a unique case report published by Smith et al.27 These authors described a 44-year-old man who underwent 3 sequential insertions of peritonealvenous shunts to decompress PP, which was due to a well-differentiated mucinous adenocarcinoma. The third of these, a Denver shunt, was inserted into the right saphenous vein at the authors’ institution. The patient went into almost immediate respiratory distress with increased pulmonary arterial pressures. He died 3 days later. At autopsy, the appendix was obliterated by what was termed mucosal hyperplasia. With current thinking, this probably represented a villous or serrated lowgrade mucinous neoplasm of the appendix. We also interpret their photomicrograph as such. Impressively, both lungs manifested numerous bilateral intravascular tumor emboli in vessels ranging from medium-sized arteries to capillaries; there was no evidence of parenchymal involvement by tumor.27 Roulet28 described a 45-year-old man with PP related to what appeared to be a low-grade mucinous neoplasm of the appendix. After 4 years and several abdominal surgical procedures, soft tissue lesions of the third and seventh right intercostal spaces developed. Although the tumor grew to the pleura, the pleural space was uninvolved. Histologically, the thoracic tumors were said to be mucinous microcysts with bland columnar cells. Roulet28 proposed that these metastases were lymphatic-borne. Finally, we believe that the demonstration of thoracic involvement, whether positive pleural effusions or parenchymal metastases, despite often bland morphologic features, adds even further emphasis to the main concept promoted in the previous study.15 All cases of sustained independent proliferation of appendiceal neoplasia beyond the right lower abdominal quadrant are best considered carcinomas, regardless of the initial tumor’s histologic features.13-15 From the Departments of 1Pathology 2and Surgery, Wake Forest University School of Medicine and the North Carolina Baptist Hospital, Winston-Salem, NC. Address reprint requests to Dr Geisinger: Dept of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1072. Acknowledgments: We thank David H. Buss, MD, for the translation of reference 28. We also appreciate the valuable assistance of Janet Hanson in manuscript preparation.

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2. Young RH, Gilks CB, Scully RE. Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei: a clinicopathologic analysis of 22 cases supporting an origin in the appendix. Am J Surg Pathol. 1991;15:415-429. 3. Prayson RA, Hart WR, Petras RE. Pseudomyxoma peritonei: a clinicopathologic study of 19 cases with emphasis on site of origin and nature of associated ovarian tumors. Am J Surg Pathol. 1994;18:591-603. 4. Ronnett BM, Kurman RJ, Zahn CM, et al. Pseudomyxoma peritonei in women: a clinicopathologic analysis of 30 cases with emphasis on site or origin, prognosis, and relationship to ovarian mucinous tumors of low malignant potential. Hum Pathol. 1995;26:509-524. 5. Ronnett BM, Zahn CM, Kurman RJ, et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis: a clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei.” Am J Surg Pathol. 1995;19:1390-1408. 6. Cuatrecasas M, Matias-Guiu X, Prat J. Synchronous mucinous tumors of the appendix and the ovary associated with pseudomyxoma peritonei: a clinicopathologic study of six cases with comparative analysis of c-Ki-ras mutations. Am J Surg Pathol. 1996;20:739-746. 7. Chuaqui RF, Zhuang Z, Emmert-Buck MR, et al. Genetic analysis of synchronous mucinous tumors of the ovary and appendix. Hum Pathol. 1996;27:165-171. 8. Ronnett BM, Shmookler BM, Diener-West M, et al. Immunohistochemical evidence supporting the appendiceal origin of pseudomyxoma peritonei in women. Int J Gynecol Pathol. 1997;16:1-9. 9. Szych C, Staebler A, Connolly DC, et al. Molecular genetic evidence supporting the clonality and appendiceal origin of pseudomyxoma peritonei in women. Am J Pathol. 1999;154:1849-1855. 10. Lamps LW, Gray GF Jr, Dilday BR, et al. The coexistence of low-grade mucinous neoplasms of the appendix and appendiceal diverticula: a possible role in the pathogenesis of pseudomyxoma peritonei. Mod Pathol. 2000;13:495-501. 11. Ronnett BM, Yan H, Kurman RJ, et al. Patients with pseudomyxoma peritonei associated with disseminated peritoneal adenomucinosis have a significantly more favorable prognosis than patients with peritoneal mucinous carcinomatosis. Cancer. 2001;92:85-91. 12. Jackson SL, Fleming RA, Loggie BW, et al. Gelatinous ascites: a cytohistologic study of pseudomyxoma peritonei in 67 patients. Mod Pathol. 2001;14:664-671. 13. Carr NJ, McCarthy WF, Sobin LH. Epithelial noncarcinoid tumors and tumor-like lesions of the appendix: a clinicopathologic study of 184 patients with a multivariate analysis of prognostic factors. Cancer. 1995;75:757-768.

14. Misdraji J, Yantiss RK, Graeme-Cook FM, et al. Appendiceal mucinous neoplasms. Am J Surg Pathol. 2003;27:1089-1103. 15. Bradley RF, Stewart JH IV, Russell GB, et al. Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 patients uniformly treated at a single institution, with literature review. Am J Surg Pathol. 2006;30:551-559. 16. Mets T, Van Hove W, Louis H. Pseudomyxoma peritonei: report of a case with extraperitoneal metastasis and invasion of the spleen. Chest. 1977;72:792-794. 17. Radosavljevic G, Nedeljkovic B, Kacar V. Pseudomyxoma of the pleural and peritoneal cavities. Thorax. 1993;48:94-95. 18. Peek DFPM, Beets GL. Pseudomyxoma peritonei in the pleural cavity: report of a case. Dis Colon Rectum. 1999;42:113116. 19. Pestieau SR, Esquivel J, Sugarbaker PH. Pleural extension of mucinous tumor in patients with pseudomyxoma peritonei syndrome. Ann Surg Oncol. 2000;7:199-203. 20. Lee BY, Kim HS, Lee SH, et al. Pseudomyxoma peritonei: extraperitoneal spread to the pleural cavity and lung. J Thorac Imaging. 2004;19:123-126. 21. Berge T. “Mucocele appendicis” with pseudomyxoma peritonei and pulmonary metastases. Acta Pathol Microbiol Scand. 1964;60:483-486. 22. Kreissig P, Dancourt J, Garner G. Maladie gélatineuse du péritoine avec métastases pulmonaires [correspondence]. La Press Med. 1991;31:1287. 23. Mortman KD, Sugarbaker PH, Shmookler BM, et al. Pulmonary metastases in pseudomyxoma peritonei syndrome. Ann Thorac Surg. 1997;64:1434-1436. 24. Pestieau SR, Wolk R, Sugarbaker PH. Congenital pleuroperitoneal communication in a patient with pseudomyxoma peritonei. J Surg Oncol. 2000;73:174-178. 25. Rossi G, Murer B, Gavazza Lori L, et al. Primary mucinous (socalled colloid) carcinoma of the lung: a clinicopathologic and immunohistochemical study with special reference to CDX-2 homeobox gene and MUC2 expression. Am J Surg Pathol. 2004;28:242-252. 26. Gao Z-h, Urbanski SJ. The spectrum of pulmonary mucinous cystic neoplasia: a clinicopathologic and immunohistochemical study of ten cases and review of the literature. Am J Clin Pathol. 2005;124:62-70. 27. Smith RRL, Sternberg SS, Paglia MA, et al. Fatal pulmonary tumor embolization following peritoneovenous shunting for malignant ascites. J Surg Oncol. 1981;16:27-35. 28. Roulet VR. Ueber das pseudomyxoma peritonei e processu vermiformi. Schweiz Med Wochenschr. 1938;29:849-852.

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