AJCP / Case Report
Well-Differentiated Papillary Mesothelioma of the Peritoneum A Diagnostic Dilemma on Fine-Needle Aspiration Cytology Jitendra G. Nasit, MD, and Gauravi Dhruva, MD From the Department of Pathology, Pandit Deendayal Upadhyay Government Medical College and Hospital, Gujarat, India. Key Words: Fine-needle aspiration cytology; Peritoneum; Well-differentiated papillary mesothelioma Am J Clin Pathol August 2014;142:233-242 DOI: 10.1309/AJCPOTO9LBB4UKWC
ABSTRACT Objectives: Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is an uncommon subtype of epithelioid mesothelioma. Usually, WDPMP has a benign course, while a few patients have multiple recurrence and malignant transformation on long-term follow-up. The histology of WDPMP has been well studied compared with the cytology. Although accurate diagnosis is based only on histology and immunohistochemical stains, knowledge of the cytologic features of WDPMP in context with clinical and radiologic features is essential to predict a preoperative diagnosis and guide proper management, after excluding reactive mesothelial hyperplasia, malignant mesothelioma, and serous neoplasms of the ovaries and peritoneum. Surgical excision gives a favorable outcome. Methods: We describe a case of 28-year-old woman who sought treatment for chronic lower abdominal pain, dysuria, and dyspareunia. Results: Radiologic findings suggested multiple metastatic peritoneal deposits. Ultrasound-guided fine-needle aspiration cytology showed many papillae, tubulopapillary and spheroid groups, monolayered pavement-like sheets, and many dispersed cells. Papillae showed many layers of round to ovoid cells, with minimal atypia. Atypical mitoses and necrosis were not found. A cytologic diagnosis of WDPMP was suggested. After complete resection of all the tumor nodules, histopathology and immunohistochemical findings were compatible with WDPMP. On follow-up, she developed tumor recurrence at 9 months and was managed successfully with adjuvant chemotherapy. Conclusions: This article highlights the cytologic features of WDPMP with relevant review of the literature and differential diagnosis.
© American Society for Clinical Pathology
Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare but distinct subtype of epithelioid mesothelioma.1-4 WDPMP is common in young women, without definite cause.1,3,5-8 WDPMP is usually asymptomatic and often an incidental finding.1-3,5,9 Because of its rarity, cytopathologists are not familiar with WDPMP. The preoperative diagnosis of WDPMP requires careful evaluation of the cytologic features in context with clinical and radiologic findings.1-3,6-8,10-12 Sometimes, differentiation of WDPMP from other mesothelial lesions and serous neoplasms of the ovaries and peritoneum can be difficult only on the basis of cytology and even routine H&E-stained histology. In such instances, application of immunohistochemistry is required for accurate diagnosis.1-4,7,8,10,12-14 Although complete surgical resection of WDPMP gives a favorable outcome, a few patients show recurrence and malignant transformation on long-term follow-up.1,3,9,10 Here, we present a case of WDPMP in a 28-year-old woman, with special attention to the cytologic findings, including imprint cytology and corresponding histopathologic findings with its differential diagnosis.
Case Report A 28-year-old woman had a history of chronic lower abdominal pain for 5 years. For the past 8 months, the pain was aggravated during micturition and sexual intercourse. She had no history of medical illness, laparotomies, or asbestos exposure. On examination, a vague abdominal lump was palpable in the suprapubic region. Systemic examination was unremarkable. Biochemical and hematologic parameters were within normal limits. Serum CA-125, a-fetoprotein, and bhuman chorionic gonadotropin levels were within the normal limits. An abdominal computed tomography scan revealed many solid-cystic masses in the peritoneum and on the surface of the urinary bladder, with a small amount of fluid in the
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cul-de-sac. Radiologic findings suggested multiple metastatic deposits from an unknown primary malignancy. Fine-needle aspiration cytology (FNAC) was performed by a cytologist (J.G.N.) under ultrasound guidance using a 22-gauge needle attached to a disposable 10-mL syringe. The two attempts of FNAC yielded blood-mixed aspirate and 5 mL of clear yellowish fluid. Prepared smears were fixed in 95% alcohol for the H&E stain. Cytology smears were markedly cellular, composed of many papillae and tubulopapillary and spheroid clusters of uniform epithelioid cells. Few flat monolayered pavement-like sheets showed slit-like
intercellular spaces. Cohesive clusters and many single cells were also present. Papillae were lined with many layers of uniform polygonal epithelioid cells. The cells showed round to ovoid, centrally located, bland vesicular nuclei; fine granular nuclear chromatin with occasional small conspicuous nucleoli; and a moderate amount of well-defined cytoplasm. Few cells showed intranuclear grooving and minimal atypia. Occasional papillary clusters showed reactive mesothelial cells with vacuolated cytoplasm. Few foamy histiocytes, lymphocytes, and neutrophils were present in the background. Atypical mitoses, psammoma bodies, and necrosis were not evident ❚Image 1❚.
A
B
C
D
❚Image 1❚ A, B, Cellular smears show papillae and tubulopapillary and spheroid structures of cells with many cohesive clusters and single cells (H&E, ×100). C, Flat monolayered sheet of uniform polygonal epithelioid cells with round to ovoid, centrally located bland vesicular nuclei; fine granular nuclear chromatin; small conspicuous nucleoli; and moderate amount of well-defined cytoplasm. Many cells show intranuclear grooves. Slit-like intercellular spaces give pavement-like appearance (H&E, ×400). D, Papillary, tubulopapillary, and spheroid structures are lined with many layers of cells. Occasional mesothelial cells show mild degree of nuclear atypia and cytoplasmic vacuolation. Few macrophages, lymphocytes, and neutrophils are present in the background (H&E, ×400). 234 234
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AJCP / Case Report
In correlation with a long clinical history and many solid-cystic peritoneal nodules on radiology, cytologic findings suggested WDPMP. At exploratory laparotomy, many nodules were found diffusely in the peritoneum, omentum, and on the surface of the urinary bladder. Mild fibrous adhesions were observed. Uterus, ovaries, colon, and pouch of Douglas were free of any lesion. Complete surgical excision of all tumor nodules was achieved. Grossly, many grayish-white tumor nodules were evident. The largest and smallest nodules measured 7.8 × 7.1 × 5.9 cm and 1.0 × 1.0 × 0.8 cm, respectively. The cut surface was a solid yellowish-gray with few cystic areas ❚Image 2❚. In the fresh-cut specimen, imprint cytology revealed a similar cytomorphology to that of FNAC ❚Image 3❚. The surgical specimen was fixed in 10% neutral buffered formalin and embedded in paraffin, and cut sections were stained with H&E. Histologically, the tumor showed many papillae and tubulopapillary and spheroid/glomeruloid structures in a predominantly solid pattern. Cystic areas were lined by distinct papillary and tubulopapillary structures. Papillae were composed of fibrous cores surrounded by a single or many layers of tumor cells. The fibrous cores were composed of thin vascular cores or acellular myxoid substance without vessels. Tumor cells were uniform cuboidal to polygonal in shape with bland vesicular nuclei, fine granular chromatin, occasional small conspicuous nucleoli, and a scanty to moderate amount of cytoplasm. Few tumor cells showed mild atypia and intranuclear grooves. Foamy histiocytes and inflammatory cells were also seen. Atypical mitoses, necrosis, invasion, and desmoplasia were not observed ❚Image 4❚. On immunohistochemistry, the tumor cells showed strong nuclear and cytoplasmic positivity for calretinin. Tumor cells were also A
positive for mesothelin, epithelial membrane antigen (EMA), and pancytokeratin, but negative for cytokeratin 5/6, cytokeratin 7, cytokeratin 20, Ber-EP4, carcinoembryonic antigen (CEA), estrogen receptor (ER), and progesterone receptor (PR) ❚Image 5❚. These findings confirmed the cytologic diagnosis of WDPMP. The postoperative course was uneventful. The patient developed tumor recurrence (two nodular lesions) in the peritoneum at the 9-month follow-up. Tumor recurrence was successfully managed with intravenous cisplatin and doxorubicin administration.
Discussion WDPMP is an extremely rare but distinct subtype of mesothelioma.1-4 The etiopathology of WDPMP remains poorly understood. Occasional cases have been associated with asbestos exposure.1,2,4,5,9,15 A history of asbestos exposure should not be considered when diagnosing a mesothelial lesion.14 Few cases have been reported in association with endometrial, ovarian, renal, rectal, colon, pancreatic, and breast cancers.1,2,5,13 Some benign conditions such as adenomyosis, ovarian serous cystadenoma, mucinous cystadenoma, and teratoma have also been reported in association with WDPMP.3,5,8,9 However, no definite causation has ever been confirmed.1-5,9,13 In some cases, the combined occurrence of well-differentiated papillary mesothelioma (WDPM) in association with adenomatoid tumor and multicystic mesothelioma suggested a histogenetic relationship among these three less aggressive mesotheliomas.16,17 Recently, Ribeiro et al18 showed a germline BAP1 mutation in two women with WDPMP in the same family. BRCA-1 associated protein 1 B
❚Image 2❚ A, Many grayish-yellow solid-cystic nodules are found diffusely over the omentum. The largest and smallest nodules measure 7.8 × 7.1 × 5.9 cm and 1.0 × 1.0 × 0.8 cm, respectively. B, Cut surface is a solid yellowish-gray with few cystic areas. © American Society for Clinical Pathology
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A
B
C
D
❚Image 3❚ A, Papillary, tubulopapillary, and spheroid structures are admixed with many dispersed cells (H&E, ×100). B, Papillae show many layers of relatively uniform cuboidal to flattened epithelium, with mild degree of nuclear atypia (H&E, ×200). C, Loose aggregates of uniform cuboidal to flattened cells show round to ovoid bland nuclei, fine granular chromatin, occasional small conspicuous nucleoli, and moderate amount of cytoplasm. Many inflammatory cells are seen in the background (H&E, ×400). D, Flat monolayer sheets of polygonal epithelioid cells with areas of overcrowding and mild atypia (H&E, ×400).
(BAP1) is a tumor suppressor gene located on chromosome 3. Germline mutations in BAP1 have been reported in families predisposed to developing a wide clinical spectrum of cancer, including uveal melanoma, cutaneous melanoma, and other tumor types, including lung, neuroendocrine, stomach, and breast cancer; renal cell carcinoma; meningioma, paraganglioma; and mesothelioma. However, a full spectrum of disease association with a germline BAP1 mutation has yet to be ascertained. Patients or families with the BAP1 mutation and melanoma should undergo a search for other tumors, including mesotheliomas.18 WDPMP arises primarily in the peritoneum, although it has also been reported at other sites: pleura, pericardium, omentum, cul-de-sac, tunica vaginalis, 236 236
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colonic serosa, mesentery, stomach serosa, liver, ovary, uterine serosa, fallopian tubes, abdominal wall, and inguinal hernia.1-3,7,9,10,12,13,15,19 In the present case, it involved the peritoneum, omentum, and the surface of the urinary bladder. Although WDPMP is common in young women, it can occur in age ranges from 2 to 74 years.2,4,6,9,13 WDPMP is frequently an asymptomatic, slow-growing tumor and often an incidental finding during surgery or a radiologic examination for other reasons.1-3,5,7,9 A history of endometriosis and previous surgery is common.19 WDPMP can present with acute and chronic abdominal pain, bloating, weight loss, dyspareunia, menorrhagia, chronic pelvic inflammatory disease, and ascites.1-4,9,13 Multiple lesions are more common than solitary © American Society for Clinical Pathology
AJCP / Case Report
A
B
C
D
❚Image 4❚ A, Tumor shows numerous papillary, tubulopapillary, and spheroid/glomeruloid structures arranged in a solid pattern with few inflammatory cells (H&E, ×100). B, Cystic area is lined with distinct papillary and tubulopapillary structures and filled with foamy macrophages and lymphocytes (H&E, ×100). C, Papillae have fibrous cores surrounded by a single or many layers of tumor cells. Fibrous cores consist of thin vessels or acellular myxoid substance. Focal area of coarse papillary structures shows mild atypia (H&E, ×400). D, Tumor cells are uniform cuboidal to polygonal with bland vesicular nuclei, fine granular chromatin, occasional small conspicuous nucleoli, and moderate amount of cytoplasm. Few cells show intranuclear grooves (H&E, ×400).
lesions.1,4,5,9,13 The size of tumor nodules varies from 0.5 cm to several centimeters in diameter.7 Peritoneal mesotheliomas have generally nonspecific radiologic features.13 Clinical features, associated disease, cytologic and histologic diagnosis, treatment, and follow-up of previously reported cases of WDPMP are given in ❚Table 1❚ with the present case.1-3,6-12 The histology of WDPMP has been well documented compared with the cytology.5,9,16,17,19 To date, only nine reports have described the cytology of WDPMP.1-3,6-8,10-12 Detailed cytologic features of all previously reported cases of WDPMP in comparison with the present case are given in the ❚Table 2❚.1-3,6-12 Classically, cytology smears contain moderate © American Society for Clinical Pathology
to high cellularity. The present case showed many papillae, tubulopapillary fragments, spheroid cell groups, monolayered pavement-like sheets, and many dispersed tumor cells with bland cytologic features. Few reactive mesothelial cells with vacuolated cytoplasm, occasional intranuclear grooves, slitlike intercellular spaces, foamy histiocytes, and inflammatory cells were seen, similar to previously reported cases. Papillae were lined with many layers of tumor cells. Tumor cells were uniformly polygonal in shape, with round to ovoid, centrally located, bland nuclei with smooth contours; fine granular nuclear chromatin; occasional small conspicuous nucleoli; and a scant to moderate amount of well-defined cytoplasm.
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❚Table 1❚ Clinical Features, Associated Disease, Cytologic and Histologic Diagnosis, Treatment, and Follow-up of Previously Reported Cases of WDPMP in Comparison With the Present Case Author
Age, y/Sex
Clinical Presentation
Associated Disease
Gong et al1
64/F
Asymptomatic; a 4.2-cm pedunculated peritoneal mass on the posterior surface of the right lobe of the liver
At present, 3-cm left adrenal mass; 11 years ago, hemicolectomy and chemotherapy for colonic adenocarcinoma
Rathi et al2
62/F
Vaginal bleeding; small amount of ascites; at laparotomy, an extensive peritoneal nodular deposits, raising the possibility of metastatic disease
At present, high-grade endometrioid adenocarcinoma of the endometrium; 12 years ago, complex endometrial hyperplasia with atypia
Haba et al3
48/F
Hypermenorrhea for 3 years; at operation, 7-cm hemorrhagic cyst in the right ovary and six papillary nodules, 2 cm or less, found in the serosa of the pelvic cavity (left ovary, appendix, uterus, and broad ligament of uterus)
Uterine adenomyosis and ovarian endometriotic cyst
Ikeda et al6
73/F
Asymptomatic; signs of peritoneal effusion during a routine examination
—
Wheeler et al7
63/M
Slowly growing 3.5-cm nontender and manually reducible left inguinal hernia mass over 7 years and a concurrent 8-cm mass in the anterior peritoneal wall; moderate amount of ascites
Seven years ago, left groin hydrocele and surgical repair
Hejmadi et al10
38/F
(1) Short history of ascites, which subside spontaneously; (2) recurrence of ascites after 1 year; (3) persistence of ascites after 3 years; and (4) ascites, weight loss, bowel obstruction, suprapubic mass, and widespread tumor deposits after 9 years
—
Jayaram and Ashok11
Young/M
Abdominal pain and mass
—
Fukunaga12
70/M
Scrotal (paratesticular) swelling with hydrocele for 1 month
—
Lacoste-Collin et al8
46/F
Asymptomatic; peritoneal masses were discovered during exploratory laparotomy for a left ovarian polycystic mass
Benign mucinous cystadenoma
Present case
28/F
Chronic lower abdominal pain for 5 years; pain was aggravated by micturition and sexual intercourse for 8 months
No associated disease
CEA, carcinoembryonic antigen; CK, cytokeratin; EMA, epithelial membrane antigen; ER, estrogen receptor; PR, progesterone receptor; WDPMP, well-differentiated papillary mesothelioma of the peritoneum; +, focal positive; ++, positive; +++, strong positive; –, negative; —, no comment/not defined.
❚Table 2❚ Cytologic Features of Previously Reported Cases of WDPMP in Comparison With the Present Case
Author
Cellularity
Papillary and/or Tubulopapillary Pattern
Fibrovascular Core With Single or Multiple Layer of Cuboidal Cells
Gong et al1
+++
Abundant
Abundant
Rathi et al2
+++
Predominant
Present
al3
++
Many
Present
Ikeda et al6
++
Present
Present
Wheeler et al7
++
Predominant
Predominant
Hejmadi et al10
++
Present
—
Jayaram and Ashok11
++
Present
—
Fukunaga12
++
Many
Present
Lacoste-Collin et al8
++
Present
Present
Present case
+++
Many
Occasional
Haba et
WDPMP, well-differentiated papillary mesothelioma of the peritoneum; +, scanty; ++, moderate; +++, abundant; —, no comment/not defined.
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❚Table 1❚ (cont) Number of WDPMP Lesions
Immunohistochemistry and Cytologic Diagnosis Histologic Diagnosis
Treatment
Follow-up
Solitary
WDPMP
Calretinin: +++, pancytokeratin: +++, WT-1: + (nuclear), CK 5/6: –, Ber-EP4: –, MOC-31: –, CD31: –, Ki-67: 2% of tumor cells; WDPMP
Surgical resection
Disease free 1.5 years after resection of WDPMP
Multiple
Mesothelial reaction
Calretinin: +++, WT-1: +++, CK 5/6: +, B72.3: –; ER: –, PR: –; WDPMP
Total abdominal hysterectomy with bilateral salpingooophorectomy; adjuvant pelvic radiotherapy for 6 weeks
At 10 months, she remains well without disease recurrence
Multiple
A specific diagnosis is not given
Pancytokeratin: +++, calretinin: +++, thrombomodulin: +++, vimentin: –, CEA: –; WDPMP
—
—
WDPMP
Calretinin: ++, D2-40: ++, HBME-1: ++; WDPMP
—
—
Multiple
A specific diagnosis is not given; differential diagnosis is rendered
Calretinin: +++, EMA: ++, Ber-EP4: –, CEA: –, CD15: –, desmin: –, mucicarmine: –, Ki-67: less than 5% positivity of tumor cells; WDPMP
Surgical resection
Disease free without any treatment for 13 months
Multiple
(1) –, (2) –, (3) –, and (4) increased cytologic atypia over 8 years
(1) –, (2) WDPMP, (3) –, and (4) diffuse malignant mesothelioma; calretinin: ++, EMA: ++, thrombomodulin: ++, Ber-EP4: –, CEA: –
Surgical resection
Death due to widespread diffuse malignant mesothelioma after 1 week of surgery
Multiple
WDPMP
Benign multifocal mesothelioma
—
Patient is well 50 months after the onset of symptoms
Solitary
Benign mesothelial lesion
EMA: +++, D2-40: +++, vimentin: +++, CAM 5.2: +++, calretinin: + (nuclear), MIB-1: less than 1% of tumor cells; WDPMP
Right radical orchiectomy
Patient is alive with no evidence of disease at 18 months
Multiple
Mesothelioma
Calretinin: ++, CK 7: ++, CK 5/6: ++, EMA: ++, HBME-1: ++, Ber-EP4: ++, desmin: +, B72.3: –, CEA: –; WDPMP
Surgical resection without any adjuvant treatment
No recurrent disease at 9 months
Multiple
WDPMP
Calretinin: +++, mesothelin: ++, EMA: ++, pancytokeratin: ++, CK 5/6: –, CK 7: –, CK 20: –, Ber-EP4: –, CEA: –, ER: –, PR: –, WDPMP
Complete surgical resection of all the tumor nodules
The patient developed tumor recurrence (two nodular lesions) in the peritoneum at the 9-month follow-up; tumor recurrence was successfully managed with chemotherapy
❚Table 2❚ (cont)
Mitoses
Foamy Histiocytes and Inflammatory Cells
Reactive Mesothelial Cells
Monolayer Sheets
Scattered Single Cells
Slit-Like Collagenous Balls in Spherical Clusters/ Intercellular Rosette-Like Clusters or Morules Spaces
Abundant
Numerous
—
Present
Mild
No
Scattered
—
Present
—
—
—
Mild
No
Large number
Present
Many
Many
—
—
Mild
No
—
—
—
—
Numerous
—
Mild
No
—
—
Present
Numerous
—
Present
Mild
No
Present
Present
—
—
Many
—
Mild
—
—
—
—
Present
—
—
Mild
No
—
—
—
—
—
—
Mild
No
Few
—
—
—
Few/rare
—
Mild
No
—
—
Few
Numerous
Occasional
Present
Mild
No
Few
Present
© American Society for Clinical Pathology
Cellular Atypia
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A
B
C
D
E
❚Image 5❚ A, The tumor cells are strongly positive for calretinin (×100). B, The tumor cells are positive for mesothelin (×100). C, The tumor cells are positive for epithelial membrane antigen (×400). D, The tumor cells are negative for estrogen receptor (×100). E, The tumor cells are negative for progesterone receptor (×100).
However, in contrast to previously reported cases, abundant tight papillary groups with a fibrovascular core, rosette-like clusters, collagenous balls with spherical clusters, hyalinized stroma, binucleate and multinucleate cells, signet ring–like cells, intranuclear inclusions, and psammoma bodies were not seen in this case. Papillae and tubulopapillary fragments with a mild degree of atypia were common and constant features in all cases, including the present case.1-3,6-12 Similar to previously described cases, the histology of the present case showed many papillae and tubulopapillary spheroid/glomeruloid structures with fibrovascular cores in a solid pattern. Cystic areas were lined by distinct papillary and tubulopapillary structures. Papillae showed fibrous cores surrounded by single or many layers of cuboidal to flattened 240 240
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mesothelial cells with bland nuclear features. The fibrous cores consisted of thin vascular cores or acellular myxoid substance without vessels. Atypical mitoses, necrosis, and invasion typically were not seen. Foamy histiocytes and inflammatory cells were seen. However, branching cords of tumor cells, extensive fibrosis with irregularity of the glandular elements, multinucleate giant cells, psammoma bodies, calcification, and osseous metaplasia were not seen in the present case, unlike previously reported cases. A mild degree of atypia is a common and constant feature in all cases.1-3,5-9,10-12 Sometimes the association of WDPMP with endometrial carcinoma may cause diagnostic confusion.2 There is no gold standard immunohistochemical panel to cover all the diagnostic “mesothelial” problems. The © American Society for Clinical Pathology
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International Mesothelioma Panel recommends at least two mesothelial markers and two markers for the other tumor (dependent on the differential diagnosis based on morphology) besides a pancytokeratin. The panel also recommends that markers have either sensitivity or specificity greater than 80%.14 Calretinin, WT-1, D2-40, h-caldesmon, and thrombomodulin are the best positive markers for mesothelioma, while MOC-31, B72.3, Ber-EP4, S-100 protein, Leu-M1 (CD45), CEA, TTF-1, ER, and PR are negative markers for mesothelioma. Tumor cells can be positive for mesothelin, EMA, and pancytokeratin. The tumor cells may show negative, weak positive, or frank positive results for cytokeratin 5/6. The Ki-67 index was low in all previously described cases.1-3,5-9,10-12,16 Weak or focal staining of less than 10% of the cells should be considered a negative when interpreting a panel of stains. False-positive immunostaining may be seen in tiny needle biopsy specimens with crush artifact and at the edges of biopsy samples.14 Because of nonspecific clinical and radiologic features, overall indolent disease course, and different management modalities, it is necessary to recognize WDPMP on cytology preoperatively and distinguish it from metastatic well-differentiated adenocarcinoma, especially serous neoplasms of the ovaries and peritoneum, reactive mesothelial hyperplasia (RMP), and malignant mesothelioma (MM), to prevent underand overdiagnosis.1-4,7,8,13,15 Multiple peritoneal nodules of WDPMP can be confused with peritoneal carcinomatosis.9,13 Peritoneal carcinomatosis can be of ovarian, gastric, pancreatic, colonic, and rarely breast origin.14 In the present case, such possibilities were excluded by the absence of cytologic features of malignancy in correlation with clinical and radiologic information. Although the presence of mucin has been classically used to support a diagnosis of adenocarcinoma, a faint rim of mucicarmine positivity is common in the vacuoles of mesotheliomas and should not be considered a diagnostic feature of adenocarcinoma.14 Clinical and radiologic examination may not help in excluding low-grade serous papillary adenocarcinoma of the peritoneum. Subtle cytologic features in favor of low-grade serous papillary adenocarcinoma of the peritoneum over WDPMP are hierarchical branching papillae, stratified epithelium, more cytologic atypia, and frequent mitoses.3,7,8,12 When the lesions of WDPMP are small, RMP should be ruled out. On cytology, many similarities are present between these two. Papillary changes may occur in RMP but are rarely conspicuous.1-3,6,7,9,12,14,15 In addition, RMP may show high cellularity and slight to moderate cytologic atypia, including nuclear enlargement, pleomorphism and hyperchromasia, numerous mitotic figures, the presence of necrosis, and entrapment of mesothelial cells within the fibrous tissue mimicking invasion.14 RMP tends to show a uniformity of growth (regular sheets and sweeping fascicles of cells that respect © American Society for Clinical Pathology
mesothelial boundaries) in contrast to the multiple solid-cystic nodules (many papillae, tubulopapillary structures with fibrovascular or hyalinized stromal core, spheroid clusters, monolayered pavement-like sheets, and many dispersed cells) seen in WDPMP.14 The hyalinized stromal core, a characteristic finding of WDPMP, is also found in RMP.1-3,6,7,9,12,14,15 However, Ikeda et al6 described that the numbers of hyalinized stromal cores are more abundant in WDPMP than in RMP. In this case, many solid-cystic masses, predominant papillary structures without reactive changes in the cells, and the absence of antecedent disease favor WDPMP. Although some mesothelial markers are more typically positive in benign proliferations and others in malignant proliferations, they should not be solely relied on to differentiate reactive, benign, and malignant mesothelial cells.14 MCM2 and AgNOR staining may be useful, but they present technical difficulties and are not widely used. Telomerase transcriptase expression discriminates between hyperplastic and neoplastic mesothelium, but subsequent studies showed limited usefulness. GLUT-1 positivity suggests MM, but GLUT-1 negativity is not helpful.14 The expression of calretinin cannot distinguish reactive from malignant mesothelial cells. In such instances, desmin is preferentially expressed in the reactive mesothelial cells, while strong membranous staining of EMA suggests neoplastic mesothelial cells, including MM and WDPMP.2,7,8,10,12,15 Similarly, in the present case, EMA expression supports the neoplastic nature of the lesion and favors WDPMP as the distinct subtype of mesothelioma. In MM, the tumor masses are bulkier than that of WDPMP. Some cases of MM can show a prominent papillary pattern. However, adequate sampling of MM usually shows an admixture of solid sheets and papillae of atypical mesothelial cells (enlarged nucleus, hyperchromasia, multinucleation, and prominent large nucleoli). Atypical cells in three-dimensional groups with scalloped edges, cell-cell engulfment, stromal invasion, and necrosis are common in MM, while these findings are extremely rare in WDPMP.1-3,7,9,12,14,15 No specific mesothelial markers can differentiate WDPMP from MM.14 A low Ki-67 index may suggest a low-grade mesothelial lesion/ WDPMP than MM. Ultimately, careful evaluation of the cytomorphology is necessary to avoid misinterpretation.14 Usually, patients with WDPMP have prolonged survival, suggesting a benign behavior.1-3,9,11,12,15 According to Malpica et al,19 death due to WDPMP is highly unusual. However, some WDPMP should be considered a lesion of low malignant potential since they can show tumor recurrence and occasional malignant transformation on long-term followup.1,3,4,7-10,12,13,15,20 These findings support the designation of well differentiated to such a low-grade tumor. In a case reported by Hejmadi et al,10 cellular morules, clusters, and scattered isolated pleomorphic cells with vesicular nuclei, a high nucleocytoplasmic ratio, prominent nucleoli on cytology
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smears and invasive features with solid sheets, and a papillary and acinar pattern of malignant cells on histology favor malignant transformation of WDPMP. Management of WDPMP remains controversial.4,5,13 Patient outcome is usually favorable after tumor debulking surgery, without adjuvant therapy.4,5,9,13 However, after complete tumor debulking surgery, the patient in the present case showed tumor recurrence on short-term follow-up. Adjuvant therapy is not recommended until there is a clear indication of the tumor progression.3,4,9 In this case, tumor recurrence was successfully managed with adjuvant chemotherapy. Some cases can be treated with laparoscopy.13 Close observation or serial biopsy for surveillance of WDPMP is necessary for early recognition of possible recurrences and malignant transformation, as well as to prevent misdiagnosis due to an undersampled MM.10,13,19
Conclusion WDPMP is a rare neoplasm of benign or at most low malignant potential. Cytopathologists should be aware of the characteristic cytologic features of WDPMP, and in proper context with clinicoradiologic features a diagnosis of WDPMP can be suggested. However, great care should be taken to differentiate WDPMP from serous neoplasms of the ovaries and peritoneum, RMP, and MM purely on the basis of cytology. Sometimes a specific diagnosis of WDPMP can be difficult only on the basis of cytology. In such instances, histology and immunohistochemistry are required for accurate diagnosis and to guide proper management. Panels of antibodies are used according to the differential diagnosis. Extensive surgical therapy and chemotherapy are recommended for WDPMP with an aggressive course. Address reprint requests to Dr Nasit: C/4, Suryadeep Society, Near Nutan School, Behind Chankyapuri Society, New Sama Rd, Vadodara–390024, Gujarat, India; [email protected].
References 1. Gong Y, Ren R, Ordóñez NG, et al. Fine needle aspiration cytology of well-differentiated papillary mesothelioma: a case report. Acta Cytol. 2005;49:537-542. 2. Rathi V, Hyde S, Newman M. Well-differentiated papillary mesothelioma in association with endometrial carcinoma: a case report. Acta Cytol. 2010;54:793-797. 3. Haba T, Wakasa K, Sasaki M. Well-differentiated papillary mesothelioma in the pelvic cavity: a case report. Acta Cytol. 2003;47:88-92. 4. Clarke JM, Helft P. Long-term survival of a woman with well differentiated papillary mesothelioma of the peritoneum: a case report and review of the literature. J Med Case Rep. 2010;4:346.
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5. Hoekstra AV, Riben MW, Frumovitz M, et al. Welldifferentiated papillary mesothelioma of the peritoneum: a pathological analysis and review of the literature. Gynecol Oncol. 2005;98:161-167. 6. Ikeda K, Suzuki T, Tate G, et al. Cytomorphologic features of well-differentiated papillary mesothelioma in peritoneal effusion: a case report. Diagn Cytopathol. 2008;36:512-515. 7. Wheeler YY, Burroughs F, Li QK. Fine-needle aspiration of a well-differentiated papillary mesothelioma in the inguinal hernia sac: a case report and review of literature. Diagn Cytopathol. 2009;37:748-754. 8. Lacoste-Collin L, Basset-Léobon C, d’Aure D, et al. Cytological diagnosis of a peritoneal well-differentiated papillary mesothelioma. Cytopathology. 2009;20:269-271. 9. Daya D, McCaughey WT. Well-differentiated papillary mesothelioma of the peritoneum: a clinicopathologic study of 22 cases. Cancer. 1990;65:292-296. 10. Hejmadi R, Ganesan R, Kamal NG. Malignant transformation of a well-differentiated peritoneal papillary mesothelioma. Acta Cytol. 2003;47:517-518. 11. Jayaram G, Ashok S. Fine needle aspiration cytology of welldifferentiated papillary peritoneal mesothelioma: report of a case. Acta Cytol. 1988;32:563-566. 12. Fukunaga M. Well-differentiated papillary mesothelioma of the tunica vaginalis: a case report with aspirate cytologic, immunohistochemical, and ultrastructural studies. Pathol Res Pract. 2010;206:105-109. 13. Jang HS, Kim SR, Ryu KY, et al. A laparoscopic diagnosis of well-differentiated papillary mesothelioma of the peritoneum in a woman with ascites: a case report. J Womens Med. 2009;2:81-84. 14. Husain AN, Colby TV, Ordóñez NG, et al. Guidelines for pathologic diagnosis of malignant mesothelioma: a consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med. 2009;133:1317-1331. 15. Ryu HS, Jin M-S, Choi H-S, et al. Fine needle aspiration cytologic features of well-differentiated papillary mesothelioma in the pleura: a case report. Korean J Pathol. 2009;43:583-588. 16. Chen X, Sheng W, Wang J. Well-differentiated papillary mesothelioma: a clinicopathological and immunohistochemical study of 18 cases with additional observation. Histopathology. 2013;62:805-813. 17. Hatano Y, Hirose Y, Matsunaga K, et al. Combined adenomatoid tumor and well differentiated papillary mesothelioma of the omentum. Pathol Int. 2011;61:681-685. 18. Ribeiro C, Campelos S, Moura CS, et al. Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation. Ann Oncol. 2013;24:21472150. 19. Malpica A, Sant’Ambrogio S, Deavers MT, et al. Welldifferentiated papillary mesothelioma of the female peritoneum: a clinicopathologic study of 26 cases. Am J Surg Pathol. 2012;36:117-127. 20. Washimi K, Yokose T, Amitani Y, et al. Well-differentiated papillary mesothelioma, possibly giving rise to diffuse malignant mesothelioma: a case report. Pathol Int. 2013;63:220-225.
© American Society for Clinical Pathology
Well-Differentiated Papillary Mesothelioma of the Peritoneum A Diagnostic Dilemma on Fine-Needle Aspiration Cytology Jitendra G. Nasit, MD, and Gauravi Dhruva, MD From the Department of Pathology, Pandit Deendayal Upadhyay Government Medical College and Hospital, Gujarat, India. Key Words: Fine-needle aspiration cytology; Peritoneum; Well-differentiated papillary mesothelioma Am J Clin Pathol August 2014;142:233-242 DOI: 10.1309/AJCPOTO9LBB4UKWC
ABSTRACT Objectives: Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is an uncommon subtype of epithelioid mesothelioma. Usually, WDPMP has a benign course, while a few patients have multiple recurrence and malignant transformation on long-term follow-up. The histology of WDPMP has been well studied compared with the cytology. Although accurate diagnosis is based only on histology and immunohistochemical stains, knowledge of the cytologic features of WDPMP in context with clinical and radiologic features is essential to predict a preoperative diagnosis and guide proper management, after excluding reactive mesothelial hyperplasia, malignant mesothelioma, and serous neoplasms of the ovaries and peritoneum. Surgical excision gives a favorable outcome. Methods: We describe a case of 28-year-old woman who sought treatment for chronic lower abdominal pain, dysuria, and dyspareunia. Results: Radiologic findings suggested multiple metastatic peritoneal deposits. Ultrasound-guided fine-needle aspiration cytology showed many papillae, tubulopapillary and spheroid groups, monolayered pavement-like sheets, and many dispersed cells. Papillae showed many layers of round to ovoid cells, with minimal atypia. Atypical mitoses and necrosis were not found. A cytologic diagnosis of WDPMP was suggested. After complete resection of all the tumor nodules, histopathology and immunohistochemical findings were compatible with WDPMP. On follow-up, she developed tumor recurrence at 9 months and was managed successfully with adjuvant chemotherapy. Conclusions: This article highlights the cytologic features of WDPMP with relevant review of the literature and differential diagnosis.
© American Society for Clinical Pathology
Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare but distinct subtype of epithelioid mesothelioma.1-4 WDPMP is common in young women, without definite cause.1,3,5-8 WDPMP is usually asymptomatic and often an incidental finding.1-3,5,9 Because of its rarity, cytopathologists are not familiar with WDPMP. The preoperative diagnosis of WDPMP requires careful evaluation of the cytologic features in context with clinical and radiologic findings.1-3,6-8,10-12 Sometimes, differentiation of WDPMP from other mesothelial lesions and serous neoplasms of the ovaries and peritoneum can be difficult only on the basis of cytology and even routine H&E-stained histology. In such instances, application of immunohistochemistry is required for accurate diagnosis.1-4,7,8,10,12-14 Although complete surgical resection of WDPMP gives a favorable outcome, a few patients show recurrence and malignant transformation on long-term follow-up.1,3,9,10 Here, we present a case of WDPMP in a 28-year-old woman, with special attention to the cytologic findings, including imprint cytology and corresponding histopathologic findings with its differential diagnosis.
Case Report A 28-year-old woman had a history of chronic lower abdominal pain for 5 years. For the past 8 months, the pain was aggravated during micturition and sexual intercourse. She had no history of medical illness, laparotomies, or asbestos exposure. On examination, a vague abdominal lump was palpable in the suprapubic region. Systemic examination was unremarkable. Biochemical and hematologic parameters were within normal limits. Serum CA-125, a-fetoprotein, and bhuman chorionic gonadotropin levels were within the normal limits. An abdominal computed tomography scan revealed many solid-cystic masses in the peritoneum and on the surface of the urinary bladder, with a small amount of fluid in the
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cul-de-sac. Radiologic findings suggested multiple metastatic deposits from an unknown primary malignancy. Fine-needle aspiration cytology (FNAC) was performed by a cytologist (J.G.N.) under ultrasound guidance using a 22-gauge needle attached to a disposable 10-mL syringe. The two attempts of FNAC yielded blood-mixed aspirate and 5 mL of clear yellowish fluid. Prepared smears were fixed in 95% alcohol for the H&E stain. Cytology smears were markedly cellular, composed of many papillae and tubulopapillary and spheroid clusters of uniform epithelioid cells. Few flat monolayered pavement-like sheets showed slit-like
intercellular spaces. Cohesive clusters and many single cells were also present. Papillae were lined with many layers of uniform polygonal epithelioid cells. The cells showed round to ovoid, centrally located, bland vesicular nuclei; fine granular nuclear chromatin with occasional small conspicuous nucleoli; and a moderate amount of well-defined cytoplasm. Few cells showed intranuclear grooving and minimal atypia. Occasional papillary clusters showed reactive mesothelial cells with vacuolated cytoplasm. Few foamy histiocytes, lymphocytes, and neutrophils were present in the background. Atypical mitoses, psammoma bodies, and necrosis were not evident ❚Image 1❚.
A
B
C
D
❚Image 1❚ A, B, Cellular smears show papillae and tubulopapillary and spheroid structures of cells with many cohesive clusters and single cells (H&E, ×100). C, Flat monolayered sheet of uniform polygonal epithelioid cells with round to ovoid, centrally located bland vesicular nuclei; fine granular nuclear chromatin; small conspicuous nucleoli; and moderate amount of well-defined cytoplasm. Many cells show intranuclear grooves. Slit-like intercellular spaces give pavement-like appearance (H&E, ×400). D, Papillary, tubulopapillary, and spheroid structures are lined with many layers of cells. Occasional mesothelial cells show mild degree of nuclear atypia and cytoplasmic vacuolation. Few macrophages, lymphocytes, and neutrophils are present in the background (H&E, ×400). 234 234
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In correlation with a long clinical history and many solid-cystic peritoneal nodules on radiology, cytologic findings suggested WDPMP. At exploratory laparotomy, many nodules were found diffusely in the peritoneum, omentum, and on the surface of the urinary bladder. Mild fibrous adhesions were observed. Uterus, ovaries, colon, and pouch of Douglas were free of any lesion. Complete surgical excision of all tumor nodules was achieved. Grossly, many grayish-white tumor nodules were evident. The largest and smallest nodules measured 7.8 × 7.1 × 5.9 cm and 1.0 × 1.0 × 0.8 cm, respectively. The cut surface was a solid yellowish-gray with few cystic areas ❚Image 2❚. In the fresh-cut specimen, imprint cytology revealed a similar cytomorphology to that of FNAC ❚Image 3❚. The surgical specimen was fixed in 10% neutral buffered formalin and embedded in paraffin, and cut sections were stained with H&E. Histologically, the tumor showed many papillae and tubulopapillary and spheroid/glomeruloid structures in a predominantly solid pattern. Cystic areas were lined by distinct papillary and tubulopapillary structures. Papillae were composed of fibrous cores surrounded by a single or many layers of tumor cells. The fibrous cores were composed of thin vascular cores or acellular myxoid substance without vessels. Tumor cells were uniform cuboidal to polygonal in shape with bland vesicular nuclei, fine granular chromatin, occasional small conspicuous nucleoli, and a scanty to moderate amount of cytoplasm. Few tumor cells showed mild atypia and intranuclear grooves. Foamy histiocytes and inflammatory cells were also seen. Atypical mitoses, necrosis, invasion, and desmoplasia were not observed ❚Image 4❚. On immunohistochemistry, the tumor cells showed strong nuclear and cytoplasmic positivity for calretinin. Tumor cells were also A
positive for mesothelin, epithelial membrane antigen (EMA), and pancytokeratin, but negative for cytokeratin 5/6, cytokeratin 7, cytokeratin 20, Ber-EP4, carcinoembryonic antigen (CEA), estrogen receptor (ER), and progesterone receptor (PR) ❚Image 5❚. These findings confirmed the cytologic diagnosis of WDPMP. The postoperative course was uneventful. The patient developed tumor recurrence (two nodular lesions) in the peritoneum at the 9-month follow-up. Tumor recurrence was successfully managed with intravenous cisplatin and doxorubicin administration.
Discussion WDPMP is an extremely rare but distinct subtype of mesothelioma.1-4 The etiopathology of WDPMP remains poorly understood. Occasional cases have been associated with asbestos exposure.1,2,4,5,9,15 A history of asbestos exposure should not be considered when diagnosing a mesothelial lesion.14 Few cases have been reported in association with endometrial, ovarian, renal, rectal, colon, pancreatic, and breast cancers.1,2,5,13 Some benign conditions such as adenomyosis, ovarian serous cystadenoma, mucinous cystadenoma, and teratoma have also been reported in association with WDPMP.3,5,8,9 However, no definite causation has ever been confirmed.1-5,9,13 In some cases, the combined occurrence of well-differentiated papillary mesothelioma (WDPM) in association with adenomatoid tumor and multicystic mesothelioma suggested a histogenetic relationship among these three less aggressive mesotheliomas.16,17 Recently, Ribeiro et al18 showed a germline BAP1 mutation in two women with WDPMP in the same family. BRCA-1 associated protein 1 B
❚Image 2❚ A, Many grayish-yellow solid-cystic nodules are found diffusely over the omentum. The largest and smallest nodules measure 7.8 × 7.1 × 5.9 cm and 1.0 × 1.0 × 0.8 cm, respectively. B, Cut surface is a solid yellowish-gray with few cystic areas. © American Society for Clinical Pathology
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A
B
C
D
❚Image 3❚ A, Papillary, tubulopapillary, and spheroid structures are admixed with many dispersed cells (H&E, ×100). B, Papillae show many layers of relatively uniform cuboidal to flattened epithelium, with mild degree of nuclear atypia (H&E, ×200). C, Loose aggregates of uniform cuboidal to flattened cells show round to ovoid bland nuclei, fine granular chromatin, occasional small conspicuous nucleoli, and moderate amount of cytoplasm. Many inflammatory cells are seen in the background (H&E, ×400). D, Flat monolayer sheets of polygonal epithelioid cells with areas of overcrowding and mild atypia (H&E, ×400).
(BAP1) is a tumor suppressor gene located on chromosome 3. Germline mutations in BAP1 have been reported in families predisposed to developing a wide clinical spectrum of cancer, including uveal melanoma, cutaneous melanoma, and other tumor types, including lung, neuroendocrine, stomach, and breast cancer; renal cell carcinoma; meningioma, paraganglioma; and mesothelioma. However, a full spectrum of disease association with a germline BAP1 mutation has yet to be ascertained. Patients or families with the BAP1 mutation and melanoma should undergo a search for other tumors, including mesotheliomas.18 WDPMP arises primarily in the peritoneum, although it has also been reported at other sites: pleura, pericardium, omentum, cul-de-sac, tunica vaginalis, 236 236
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colonic serosa, mesentery, stomach serosa, liver, ovary, uterine serosa, fallopian tubes, abdominal wall, and inguinal hernia.1-3,7,9,10,12,13,15,19 In the present case, it involved the peritoneum, omentum, and the surface of the urinary bladder. Although WDPMP is common in young women, it can occur in age ranges from 2 to 74 years.2,4,6,9,13 WDPMP is frequently an asymptomatic, slow-growing tumor and often an incidental finding during surgery or a radiologic examination for other reasons.1-3,5,7,9 A history of endometriosis and previous surgery is common.19 WDPMP can present with acute and chronic abdominal pain, bloating, weight loss, dyspareunia, menorrhagia, chronic pelvic inflammatory disease, and ascites.1-4,9,13 Multiple lesions are more common than solitary © American Society for Clinical Pathology
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A
B
C
D
❚Image 4❚ A, Tumor shows numerous papillary, tubulopapillary, and spheroid/glomeruloid structures arranged in a solid pattern with few inflammatory cells (H&E, ×100). B, Cystic area is lined with distinct papillary and tubulopapillary structures and filled with foamy macrophages and lymphocytes (H&E, ×100). C, Papillae have fibrous cores surrounded by a single or many layers of tumor cells. Fibrous cores consist of thin vessels or acellular myxoid substance. Focal area of coarse papillary structures shows mild atypia (H&E, ×400). D, Tumor cells are uniform cuboidal to polygonal with bland vesicular nuclei, fine granular chromatin, occasional small conspicuous nucleoli, and moderate amount of cytoplasm. Few cells show intranuclear grooves (H&E, ×400).
lesions.1,4,5,9,13 The size of tumor nodules varies from 0.5 cm to several centimeters in diameter.7 Peritoneal mesotheliomas have generally nonspecific radiologic features.13 Clinical features, associated disease, cytologic and histologic diagnosis, treatment, and follow-up of previously reported cases of WDPMP are given in ❚Table 1❚ with the present case.1-3,6-12 The histology of WDPMP has been well documented compared with the cytology.5,9,16,17,19 To date, only nine reports have described the cytology of WDPMP.1-3,6-8,10-12 Detailed cytologic features of all previously reported cases of WDPMP in comparison with the present case are given in the ❚Table 2❚.1-3,6-12 Classically, cytology smears contain moderate © American Society for Clinical Pathology
to high cellularity. The present case showed many papillae, tubulopapillary fragments, spheroid cell groups, monolayered pavement-like sheets, and many dispersed tumor cells with bland cytologic features. Few reactive mesothelial cells with vacuolated cytoplasm, occasional intranuclear grooves, slitlike intercellular spaces, foamy histiocytes, and inflammatory cells were seen, similar to previously reported cases. Papillae were lined with many layers of tumor cells. Tumor cells were uniformly polygonal in shape, with round to ovoid, centrally located, bland nuclei with smooth contours; fine granular nuclear chromatin; occasional small conspicuous nucleoli; and a scant to moderate amount of well-defined cytoplasm.
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❚Table 1❚ Clinical Features, Associated Disease, Cytologic and Histologic Diagnosis, Treatment, and Follow-up of Previously Reported Cases of WDPMP in Comparison With the Present Case Author
Age, y/Sex
Clinical Presentation
Associated Disease
Gong et al1
64/F
Asymptomatic; a 4.2-cm pedunculated peritoneal mass on the posterior surface of the right lobe of the liver
At present, 3-cm left adrenal mass; 11 years ago, hemicolectomy and chemotherapy for colonic adenocarcinoma
Rathi et al2
62/F
Vaginal bleeding; small amount of ascites; at laparotomy, an extensive peritoneal nodular deposits, raising the possibility of metastatic disease
At present, high-grade endometrioid adenocarcinoma of the endometrium; 12 years ago, complex endometrial hyperplasia with atypia
Haba et al3
48/F
Hypermenorrhea for 3 years; at operation, 7-cm hemorrhagic cyst in the right ovary and six papillary nodules, 2 cm or less, found in the serosa of the pelvic cavity (left ovary, appendix, uterus, and broad ligament of uterus)
Uterine adenomyosis and ovarian endometriotic cyst
Ikeda et al6
73/F
Asymptomatic; signs of peritoneal effusion during a routine examination
—
Wheeler et al7
63/M
Slowly growing 3.5-cm nontender and manually reducible left inguinal hernia mass over 7 years and a concurrent 8-cm mass in the anterior peritoneal wall; moderate amount of ascites
Seven years ago, left groin hydrocele and surgical repair
Hejmadi et al10
38/F
(1) Short history of ascites, which subside spontaneously; (2) recurrence of ascites after 1 year; (3) persistence of ascites after 3 years; and (4) ascites, weight loss, bowel obstruction, suprapubic mass, and widespread tumor deposits after 9 years
—
Jayaram and Ashok11
Young/M
Abdominal pain and mass
—
Fukunaga12
70/M
Scrotal (paratesticular) swelling with hydrocele for 1 month
—
Lacoste-Collin et al8
46/F
Asymptomatic; peritoneal masses were discovered during exploratory laparotomy for a left ovarian polycystic mass
Benign mucinous cystadenoma
Present case
28/F
Chronic lower abdominal pain for 5 years; pain was aggravated by micturition and sexual intercourse for 8 months
No associated disease
CEA, carcinoembryonic antigen; CK, cytokeratin; EMA, epithelial membrane antigen; ER, estrogen receptor; PR, progesterone receptor; WDPMP, well-differentiated papillary mesothelioma of the peritoneum; +, focal positive; ++, positive; +++, strong positive; –, negative; —, no comment/not defined.
❚Table 2❚ Cytologic Features of Previously Reported Cases of WDPMP in Comparison With the Present Case
Author
Cellularity
Papillary and/or Tubulopapillary Pattern
Fibrovascular Core With Single or Multiple Layer of Cuboidal Cells
Gong et al1
+++
Abundant
Abundant
Rathi et al2
+++
Predominant
Present
al3
++
Many
Present
Ikeda et al6
++
Present
Present
Wheeler et al7
++
Predominant
Predominant
Hejmadi et al10
++
Present
—
Jayaram and Ashok11
++
Present
—
Fukunaga12
++
Many
Present
Lacoste-Collin et al8
++
Present
Present
Present case
+++
Many
Occasional
Haba et
WDPMP, well-differentiated papillary mesothelioma of the peritoneum; +, scanty; ++, moderate; +++, abundant; —, no comment/not defined.
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❚Table 1❚ (cont) Number of WDPMP Lesions
Immunohistochemistry and Cytologic Diagnosis Histologic Diagnosis
Treatment
Follow-up
Solitary
WDPMP
Calretinin: +++, pancytokeratin: +++, WT-1: + (nuclear), CK 5/6: –, Ber-EP4: –, MOC-31: –, CD31: –, Ki-67: 2% of tumor cells; WDPMP
Surgical resection
Disease free 1.5 years after resection of WDPMP
Multiple
Mesothelial reaction
Calretinin: +++, WT-1: +++, CK 5/6: +, B72.3: –; ER: –, PR: –; WDPMP
Total abdominal hysterectomy with bilateral salpingooophorectomy; adjuvant pelvic radiotherapy for 6 weeks
At 10 months, she remains well without disease recurrence
Multiple
A specific diagnosis is not given
Pancytokeratin: +++, calretinin: +++, thrombomodulin: +++, vimentin: –, CEA: –; WDPMP
—
—
WDPMP
Calretinin: ++, D2-40: ++, HBME-1: ++; WDPMP
—
—
Multiple
A specific diagnosis is not given; differential diagnosis is rendered
Calretinin: +++, EMA: ++, Ber-EP4: –, CEA: –, CD15: –, desmin: –, mucicarmine: –, Ki-67: less than 5% positivity of tumor cells; WDPMP
Surgical resection
Disease free without any treatment for 13 months
Multiple
(1) –, (2) –, (3) –, and (4) increased cytologic atypia over 8 years
(1) –, (2) WDPMP, (3) –, and (4) diffuse malignant mesothelioma; calretinin: ++, EMA: ++, thrombomodulin: ++, Ber-EP4: –, CEA: –
Surgical resection
Death due to widespread diffuse malignant mesothelioma after 1 week of surgery
Multiple
WDPMP
Benign multifocal mesothelioma
—
Patient is well 50 months after the onset of symptoms
Solitary
Benign mesothelial lesion
EMA: +++, D2-40: +++, vimentin: +++, CAM 5.2: +++, calretinin: + (nuclear), MIB-1: less than 1% of tumor cells; WDPMP
Right radical orchiectomy
Patient is alive with no evidence of disease at 18 months
Multiple
Mesothelioma
Calretinin: ++, CK 7: ++, CK 5/6: ++, EMA: ++, HBME-1: ++, Ber-EP4: ++, desmin: +, B72.3: –, CEA: –; WDPMP
Surgical resection without any adjuvant treatment
No recurrent disease at 9 months
Multiple
WDPMP
Calretinin: +++, mesothelin: ++, EMA: ++, pancytokeratin: ++, CK 5/6: –, CK 7: –, CK 20: –, Ber-EP4: –, CEA: –, ER: –, PR: –, WDPMP
Complete surgical resection of all the tumor nodules
The patient developed tumor recurrence (two nodular lesions) in the peritoneum at the 9-month follow-up; tumor recurrence was successfully managed with chemotherapy
❚Table 2❚ (cont)
Mitoses
Foamy Histiocytes and Inflammatory Cells
Reactive Mesothelial Cells
Monolayer Sheets
Scattered Single Cells
Slit-Like Collagenous Balls in Spherical Clusters/ Intercellular Rosette-Like Clusters or Morules Spaces
Abundant
Numerous
—
Present
Mild
No
Scattered
—
Present
—
—
—
Mild
No
Large number
Present
Many
Many
—
—
Mild
No
—
—
—
—
Numerous
—
Mild
No
—
—
Present
Numerous
—
Present
Mild
No
Present
Present
—
—
Many
—
Mild
—
—
—
—
Present
—
—
Mild
No
—
—
—
—
—
—
Mild
No
Few
—
—
—
Few/rare
—
Mild
No
—
—
Few
Numerous
Occasional
Present
Mild
No
Few
Present
© American Society for Clinical Pathology
Cellular Atypia
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A
B
C
D
E
❚Image 5❚ A, The tumor cells are strongly positive for calretinin (×100). B, The tumor cells are positive for mesothelin (×100). C, The tumor cells are positive for epithelial membrane antigen (×400). D, The tumor cells are negative for estrogen receptor (×100). E, The tumor cells are negative for progesterone receptor (×100).
However, in contrast to previously reported cases, abundant tight papillary groups with a fibrovascular core, rosette-like clusters, collagenous balls with spherical clusters, hyalinized stroma, binucleate and multinucleate cells, signet ring–like cells, intranuclear inclusions, and psammoma bodies were not seen in this case. Papillae and tubulopapillary fragments with a mild degree of atypia were common and constant features in all cases, including the present case.1-3,6-12 Similar to previously described cases, the histology of the present case showed many papillae and tubulopapillary spheroid/glomeruloid structures with fibrovascular cores in a solid pattern. Cystic areas were lined by distinct papillary and tubulopapillary structures. Papillae showed fibrous cores surrounded by single or many layers of cuboidal to flattened 240 240
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mesothelial cells with bland nuclear features. The fibrous cores consisted of thin vascular cores or acellular myxoid substance without vessels. Atypical mitoses, necrosis, and invasion typically were not seen. Foamy histiocytes and inflammatory cells were seen. However, branching cords of tumor cells, extensive fibrosis with irregularity of the glandular elements, multinucleate giant cells, psammoma bodies, calcification, and osseous metaplasia were not seen in the present case, unlike previously reported cases. A mild degree of atypia is a common and constant feature in all cases.1-3,5-9,10-12 Sometimes the association of WDPMP with endometrial carcinoma may cause diagnostic confusion.2 There is no gold standard immunohistochemical panel to cover all the diagnostic “mesothelial” problems. The © American Society for Clinical Pathology
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International Mesothelioma Panel recommends at least two mesothelial markers and two markers for the other tumor (dependent on the differential diagnosis based on morphology) besides a pancytokeratin. The panel also recommends that markers have either sensitivity or specificity greater than 80%.14 Calretinin, WT-1, D2-40, h-caldesmon, and thrombomodulin are the best positive markers for mesothelioma, while MOC-31, B72.3, Ber-EP4, S-100 protein, Leu-M1 (CD45), CEA, TTF-1, ER, and PR are negative markers for mesothelioma. Tumor cells can be positive for mesothelin, EMA, and pancytokeratin. The tumor cells may show negative, weak positive, or frank positive results for cytokeratin 5/6. The Ki-67 index was low in all previously described cases.1-3,5-9,10-12,16 Weak or focal staining of less than 10% of the cells should be considered a negative when interpreting a panel of stains. False-positive immunostaining may be seen in tiny needle biopsy specimens with crush artifact and at the edges of biopsy samples.14 Because of nonspecific clinical and radiologic features, overall indolent disease course, and different management modalities, it is necessary to recognize WDPMP on cytology preoperatively and distinguish it from metastatic well-differentiated adenocarcinoma, especially serous neoplasms of the ovaries and peritoneum, reactive mesothelial hyperplasia (RMP), and malignant mesothelioma (MM), to prevent underand overdiagnosis.1-4,7,8,13,15 Multiple peritoneal nodules of WDPMP can be confused with peritoneal carcinomatosis.9,13 Peritoneal carcinomatosis can be of ovarian, gastric, pancreatic, colonic, and rarely breast origin.14 In the present case, such possibilities were excluded by the absence of cytologic features of malignancy in correlation with clinical and radiologic information. Although the presence of mucin has been classically used to support a diagnosis of adenocarcinoma, a faint rim of mucicarmine positivity is common in the vacuoles of mesotheliomas and should not be considered a diagnostic feature of adenocarcinoma.14 Clinical and radiologic examination may not help in excluding low-grade serous papillary adenocarcinoma of the peritoneum. Subtle cytologic features in favor of low-grade serous papillary adenocarcinoma of the peritoneum over WDPMP are hierarchical branching papillae, stratified epithelium, more cytologic atypia, and frequent mitoses.3,7,8,12 When the lesions of WDPMP are small, RMP should be ruled out. On cytology, many similarities are present between these two. Papillary changes may occur in RMP but are rarely conspicuous.1-3,6,7,9,12,14,15 In addition, RMP may show high cellularity and slight to moderate cytologic atypia, including nuclear enlargement, pleomorphism and hyperchromasia, numerous mitotic figures, the presence of necrosis, and entrapment of mesothelial cells within the fibrous tissue mimicking invasion.14 RMP tends to show a uniformity of growth (regular sheets and sweeping fascicles of cells that respect © American Society for Clinical Pathology
mesothelial boundaries) in contrast to the multiple solid-cystic nodules (many papillae, tubulopapillary structures with fibrovascular or hyalinized stromal core, spheroid clusters, monolayered pavement-like sheets, and many dispersed cells) seen in WDPMP.14 The hyalinized stromal core, a characteristic finding of WDPMP, is also found in RMP.1-3,6,7,9,12,14,15 However, Ikeda et al6 described that the numbers of hyalinized stromal cores are more abundant in WDPMP than in RMP. In this case, many solid-cystic masses, predominant papillary structures without reactive changes in the cells, and the absence of antecedent disease favor WDPMP. Although some mesothelial markers are more typically positive in benign proliferations and others in malignant proliferations, they should not be solely relied on to differentiate reactive, benign, and malignant mesothelial cells.14 MCM2 and AgNOR staining may be useful, but they present technical difficulties and are not widely used. Telomerase transcriptase expression discriminates between hyperplastic and neoplastic mesothelium, but subsequent studies showed limited usefulness. GLUT-1 positivity suggests MM, but GLUT-1 negativity is not helpful.14 The expression of calretinin cannot distinguish reactive from malignant mesothelial cells. In such instances, desmin is preferentially expressed in the reactive mesothelial cells, while strong membranous staining of EMA suggests neoplastic mesothelial cells, including MM and WDPMP.2,7,8,10,12,15 Similarly, in the present case, EMA expression supports the neoplastic nature of the lesion and favors WDPMP as the distinct subtype of mesothelioma. In MM, the tumor masses are bulkier than that of WDPMP. Some cases of MM can show a prominent papillary pattern. However, adequate sampling of MM usually shows an admixture of solid sheets and papillae of atypical mesothelial cells (enlarged nucleus, hyperchromasia, multinucleation, and prominent large nucleoli). Atypical cells in three-dimensional groups with scalloped edges, cell-cell engulfment, stromal invasion, and necrosis are common in MM, while these findings are extremely rare in WDPMP.1-3,7,9,12,14,15 No specific mesothelial markers can differentiate WDPMP from MM.14 A low Ki-67 index may suggest a low-grade mesothelial lesion/ WDPMP than MM. Ultimately, careful evaluation of the cytomorphology is necessary to avoid misinterpretation.14 Usually, patients with WDPMP have prolonged survival, suggesting a benign behavior.1-3,9,11,12,15 According to Malpica et al,19 death due to WDPMP is highly unusual. However, some WDPMP should be considered a lesion of low malignant potential since they can show tumor recurrence and occasional malignant transformation on long-term followup.1,3,4,7-10,12,13,15,20 These findings support the designation of well differentiated to such a low-grade tumor. In a case reported by Hejmadi et al,10 cellular morules, clusters, and scattered isolated pleomorphic cells with vesicular nuclei, a high nucleocytoplasmic ratio, prominent nucleoli on cytology
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smears and invasive features with solid sheets, and a papillary and acinar pattern of malignant cells on histology favor malignant transformation of WDPMP. Management of WDPMP remains controversial.4,5,13 Patient outcome is usually favorable after tumor debulking surgery, without adjuvant therapy.4,5,9,13 However, after complete tumor debulking surgery, the patient in the present case showed tumor recurrence on short-term follow-up. Adjuvant therapy is not recommended until there is a clear indication of the tumor progression.3,4,9 In this case, tumor recurrence was successfully managed with adjuvant chemotherapy. Some cases can be treated with laparoscopy.13 Close observation or serial biopsy for surveillance of WDPMP is necessary for early recognition of possible recurrences and malignant transformation, as well as to prevent misdiagnosis due to an undersampled MM.10,13,19
Conclusion WDPMP is a rare neoplasm of benign or at most low malignant potential. Cytopathologists should be aware of the characteristic cytologic features of WDPMP, and in proper context with clinicoradiologic features a diagnosis of WDPMP can be suggested. However, great care should be taken to differentiate WDPMP from serous neoplasms of the ovaries and peritoneum, RMP, and MM purely on the basis of cytology. Sometimes a specific diagnosis of WDPMP can be difficult only on the basis of cytology. In such instances, histology and immunohistochemistry are required for accurate diagnosis and to guide proper management. Panels of antibodies are used according to the differential diagnosis. Extensive surgical therapy and chemotherapy are recommended for WDPMP with an aggressive course. Address reprint requests to Dr Nasit: C/4, Suryadeep Society, Near Nutan School, Behind Chankyapuri Society, New Sama Rd, Vadodara–390024, Gujarat, India; [email protected].
References 1. Gong Y, Ren R, Ordóñez NG, et al. Fine needle aspiration cytology of well-differentiated papillary mesothelioma: a case report. Acta Cytol. 2005;49:537-542. 2. Rathi V, Hyde S, Newman M. Well-differentiated papillary mesothelioma in association with endometrial carcinoma: a case report. Acta Cytol. 2010;54:793-797. 3. Haba T, Wakasa K, Sasaki M. Well-differentiated papillary mesothelioma in the pelvic cavity: a case report. Acta Cytol. 2003;47:88-92. 4. Clarke JM, Helft P. Long-term survival of a woman with well differentiated papillary mesothelioma of the peritoneum: a case report and review of the literature. J Med Case Rep. 2010;4:346.
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5. Hoekstra AV, Riben MW, Frumovitz M, et al. Welldifferentiated papillary mesothelioma of the peritoneum: a pathological analysis and review of the literature. Gynecol Oncol. 2005;98:161-167. 6. Ikeda K, Suzuki T, Tate G, et al. Cytomorphologic features of well-differentiated papillary mesothelioma in peritoneal effusion: a case report. Diagn Cytopathol. 2008;36:512-515. 7. Wheeler YY, Burroughs F, Li QK. Fine-needle aspiration of a well-differentiated papillary mesothelioma in the inguinal hernia sac: a case report and review of literature. Diagn Cytopathol. 2009;37:748-754. 8. Lacoste-Collin L, Basset-Léobon C, d’Aure D, et al. Cytological diagnosis of a peritoneal well-differentiated papillary mesothelioma. Cytopathology. 2009;20:269-271. 9. Daya D, McCaughey WT. Well-differentiated papillary mesothelioma of the peritoneum: a clinicopathologic study of 22 cases. Cancer. 1990;65:292-296. 10. Hejmadi R, Ganesan R, Kamal NG. Malignant transformation of a well-differentiated peritoneal papillary mesothelioma. Acta Cytol. 2003;47:517-518. 11. Jayaram G, Ashok S. Fine needle aspiration cytology of welldifferentiated papillary peritoneal mesothelioma: report of a case. Acta Cytol. 1988;32:563-566. 12. Fukunaga M. Well-differentiated papillary mesothelioma of the tunica vaginalis: a case report with aspirate cytologic, immunohistochemical, and ultrastructural studies. Pathol Res Pract. 2010;206:105-109. 13. Jang HS, Kim SR, Ryu KY, et al. A laparoscopic diagnosis of well-differentiated papillary mesothelioma of the peritoneum in a woman with ascites: a case report. J Womens Med. 2009;2:81-84. 14. Husain AN, Colby TV, Ordóñez NG, et al. Guidelines for pathologic diagnosis of malignant mesothelioma: a consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med. 2009;133:1317-1331. 15. Ryu HS, Jin M-S, Choi H-S, et al. Fine needle aspiration cytologic features of well-differentiated papillary mesothelioma in the pleura: a case report. Korean J Pathol. 2009;43:583-588. 16. Chen X, Sheng W, Wang J. Well-differentiated papillary mesothelioma: a clinicopathological and immunohistochemical study of 18 cases with additional observation. Histopathology. 2013;62:805-813. 17. Hatano Y, Hirose Y, Matsunaga K, et al. Combined adenomatoid tumor and well differentiated papillary mesothelioma of the omentum. Pathol Int. 2011;61:681-685. 18. Ribeiro C, Campelos S, Moura CS, et al. Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation. Ann Oncol. 2013;24:21472150. 19. Malpica A, Sant’Ambrogio S, Deavers MT, et al. Welldifferentiated papillary mesothelioma of the female peritoneum: a clinicopathologic study of 26 cases. Am J Surg Pathol. 2012;36:117-127. 20. Washimi K, Yokose T, Amitani Y, et al. Well-differentiated papillary mesothelioma, possibly giving rise to diffuse malignant mesothelioma: a case report. Pathol Int. 2013;63:220-225.
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