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Keywords:

  • adenosquamous carcinoma;
  • squamous cell carcinoma;
  • fine-needle aspiration biopsy;
  • pancreas;
  • pancreatic neoplasms

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

Adenosquamous carcinoma (ASCa) is a rare subtype of ductal adenocarcinoma of the pancreas with what to the authors' knowledge are limited cytologic descriptions. In the current study, the authors describe their experience with the fine-aspiration biopsy (FNAB) diagnosis of ASCa and characterize cytologic features in 14 cases.

METHODS

Fourteen cases of ASCa were identified from pathology case files. Cytologic material was examined for cellularity, grade, tumor cell necrosis, and specific features of glandular and squamous differentiation.

RESULTS

The 10 females and 4 males had an average age of 70 years. Nine patients (64%) were reported to have Stage IV disease at the time of presentation. All tumors were high grade, with moderate to high cellularity. Tumor cell necrosis was noted in 12. Nine of the 14 cases (64%) demonstrated predominantly squamous differentiation with keratinization. Seven of these nine contained at least focal intracellular mucin or honeycombed glandular sheets. Two of the nine had rare cytoplasmic vacuoles as the only evidence of glandular differentiation. Five cases (36%) were predominantly glandular. All but one of these five cases contained atypical to malignant keratinized cells. One of the five cases lacked keratinization but had tumor cells with dense cytoplasm; the diagnosis of ASCa was confirmed on histology. In 13 patients for whom followup was known, 12 had died of disease (mean, 5.6 months) and 1 was alive at 13 months of follow-up.

CONCLUSIONS

A specific diagnosis of ASCa is possible when aspirates show evidence of both squamous and glandular differentiation, although one component often predominates and features of dual differentiation may be focal. A purely squamous tumor should raise the suspicion of a metastasis, but also may represent undersampling of an ASCa. Cancer (Cancer Cytopathol) 2003;99:372–8. © 2003 American Cancer Society.

Pancreatic adenosquamous carcinoma (ASCa) is a rare variant of ductal adenocarcinoma that is reported to represent only 3–4% of exocrine pancreatic malignancies.1, 2 Also referred to as mucoepidermoid carcinoma and adenoacanthoma in older literature, pancreatic ASCa is characterized histologically by variable proportions of classic, often mucin-producing, glandular epithelium and malignant squamous epithelium, and carries a poor prognosis similar to that of classic ductal adenocarcinoma.3–6 Despite the growing role of fine-needle aspiration biopsy (FNAB) in the primary diagnosis of pancreatic masses, the cytologic characteristics of ASCa to our knowledge have been described only in case reports or in small case series.7–10 Recognition of the biphasic nature of the tumor on cytology may allow for the distinction between a rare primary pancreatic neoplasm and a metastasis to the pancreas. In the current study, we characterize the cytologic features of 14 cases of pancreatic ASCa in what to our knowledge is the largest cytology series reported to date, in an effort to better define the cytologic spectrum of this rare but lethal malignancy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

A computer-assisted search of the laboratory information system at the Department of Pathology at the Massachusetts General Hospital from 1992 to 2002 identified 14 cases of definite (11 cases) or probable (3 cases) pancreatic ASCa diagnosed either by FNAB or on histology for which prior FNAB material was available. One case of possible ASCa was excluded because of the patient's history of squamous cell carcinoma (SCC) of the lung requiring pneumonectomy 1 year prior to the presentation of the pancreatic mass. Specimens were obtained by either endoscopic ultrasound-guided FNAB (nine cases) or computed tomography (CT)-guided transabdominal FNAB (three cases), and direct smears were made. The slides of two cases were obtained from outside institutions, and the methods by which the FNAB specimens were obtained in these cases were unknown. A total of 51 smears and 5 cell blocks were reviewed (mean, 4 slides per case; range; 1–13 slides per case). Among the smears, the most common staining method was the Papanicolaou stain (78%), followed by hematoxylin and eosin (20%), the latter of which was used for rapid interpretations. All aspirates were characterized on the basis of cellularity, background, nuclear grade, and the presence of individual tumor cell necrosis. The determination of nuclear grade was based on the degree of nuclear enlargement, nuclear membrane irregularity, and pleomorphism. Each case was examined for specific cytologic features of both glandular and squamous differentiation and the relative proportions of malignant glandular and squamous components. Features considered definitive for glandular differentiation included honeycombed sheets, papillary groups, columnar cells, and intracellular mucin. Well defined cytoplasmic vacuoles that lacked obvious intracellular mucin were considered a feature suggestive of glandular differentiation. Keratinization (including tadpole cells) was considered definitive for squamous differentiation. The presence of dense, nonvacuolated cytoplasm with centrally placed, dark, “inky” nuclei was considered suggestive of squamous differentiation. The cytologic diagnosis was confirmed on histology in two cases in which surgical resections were performed. Clinical data and followup information for each case were obtained from review of pertinent medical records.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Clinical Features

Patient characteristics are shown in Table 1. The 10 females and 4 males had an average age of 70 years (range, 48–89 years). One patient (Case 12) had undergone a resection for pancreatic adenocarcinoma that was diagnosed 21 months earlier, and was treated with radiotherapy. In this case, the FNAB was performed to assess for recurrence in the pancreatic bed. Two other patients had prior cancer diagnoses that were not clinically relevant (Gleason 7/10 prostate adenocarcinoma in Case 13 and noninvasive papillary transitional cell carcinoma of the bladder in Case 9).

Table 1. Patient Demographics and Clinical Characteristics
CharacteristicFindings
Gender 
 Male4
 Female10
Age (yr) 
 Range48–89
 Mean69.7
 Median72.5
Presenting symptoms 
 Abdominal pain10
 Anorexia/weight loss8
 Jaundice3
Location of mass 
 Head6
 Body3
 Tail2
 Body and tail1
 Throughout pancreas1
 Unknown1
Size of mass (cm) 
 Range1.6–6.0
 Mean3.7
 Unknown size3 cases
Clinical stage of disease 
 Stage IV disease9
 Non–stage IV disease4
 Unknown1
Survival in 12 patients (mo) 
 Mean5.6
 Median4.0
 Mean for stage IV disease4.0
 Mean for non–stage IV disease9.7

Abdominal pain was the most common presenting symptom (10 patients), followed by anorexia and/or weight loss (8 patients), and jaundice (3 patients). Less frequent presenting symptoms included fatigue, malaise, nausea, and pruritus. Two patients had ascites, and one patient had a palpable abdominal mass. Two patients presented with complications of neoplasia-induced coagulopathy (one each with pulmonary embolus and bilateral deep venous thromboses). Ten patients demonstrated laboratory evidence of biliary obstruction, with elevated serum alkaline phosphatase or total bilirubin.

The mass most commonly involved the pancreatic head (six patients), followed by the body (three patients) and tail (two patients). The tumor involved both the body and tail in one case. For another patient (Case 12), endoscopic ultrasound demonstrated a 2- cm mass located in the pancreatic head that was associated with multiple cystic lesions throughout the pancreas, resembling an intraductal papillary mucinous neoplasm (IPMN). The location of the mass was unknown in one case. The size of the mass, known in 11 cases, ranged from 1.6–6 cm (mean, 3.7 cm). Nine patients (64%) had AJCC Stage IV disease at presentation, and 4 patients (29%) had Stage II or Stage III disease.11 The stage of disease was unknown in one case.

Cytologic Features

The cytologic features of the 14 cases are shown in Table 2. All of the smears exhibited moderate to high cellularity with a background of necrotic debris (seven cases), mucin (six cases), and/or blood (five cases). All the tumors were high grade, with individual cell necrosis noted in 12 cases. All the tumors exhibited dual differentiation with varying proportions of squamous and glandular epithelium.

Table 2. Cytologic Features of Adenosquamous Carcinoma in 14 Cases
Case no.Keratinizing squamous componentNonkeratinizing squamous componentGlandular componentTumor cell necrosisIntracellular mucinCytoplasmic vacuolesHoneycombed sheets/papillary groupsParakeratotic cellsDense cytoplasmInky nucleiTadpole cells
  1. R: rare; P, present; PT, prominent.

  2. Bold type indicates glandular predominance.

1R> 75%RPRPPPTP
250–75%25–50%RPRRPTPTPTP
3< 25%> 75%RPRPPPPP
450–75%25–50%< 25%PPTPTPTPPP
5R> 75%RPRRP
650–75%25–50%RPRPPP
7< 25%50–75%< 25%PPPPPTPT
8> 75%< 25%RPTPPPTPPP
9< 25%> 75%RPTRPPTPP
10< 25%> 75%PTPTPTPPTPPT
1125–50%50–75%PTPPTPPPR
12RR> 75%PPPP
13R> 75%PPPPPPP
14< 25%> 75%PRPP

Nine tumors (64%) exhibited predominantly squamous differentiation (> 50% of the smear), which was comprised of single cells and clusters of cells with centrally placed nuclei, distinct cytoplasmic borders, and dense, nonvacuolated cytoplasm. Keratinization was present in all of these cases and was prominent in 4 cases (> 50% of the smear) (Fig. 1). Tadpole cells were noted in six cases, but were not prominent. Seven of the nine cases showed definite features of glandular differentiation with at least focal intracellular mucin (six cases) and/or honeycombed glandular sheets (three cases) (Figs. 2–4). Two additional cases (Cases 6 and 9) contained rare, well defined cytoplasmic vacuoles as the only evidence of glandular differentiation (Fig. 5).

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Figure 1. A case of squamous predominance demonstrating a sheetlike arrangement of cells with dense, nonvacuolated cytoplasm and a suggestion of a squamous eddy (marked with an arrow) (Papanicolaou smear, ×200).

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Figure 2. Conspicuous glandular differentiation (marked with arrows), in the same case of squamous predominance as shown in FIGURE 1. Large mucin-filled intracellular vacuoles were present in association with nonkeratinized and focally keratinized cells (marked with an arrowhead) (Papanicolaou smear, ×600).

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Figure 3. Prominent glandular differentiation represented by a vacuolated cell containing intracellular mucin (marked with an arrow) in a case of squamous predominance with keratinization (Papanicolaou smear, ×600).

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Figure 4. A case of squamous predominance with subtle glandular features demonstrated by an occasional cell containing intracellular mucin (marked with an arrow) (Papanicolaou ThinPrep, ×600).

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Figure 5. Cytoplasmic vacuoles (marked with an arrow), suggestive of glandular differentiation, can be extremely rare as in this case with squamous predominance (Papanicolaou smear, ×600).

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Five tumors (36%) exhibited predominantly glandular differentiation (> 50% of the smear) comprised of honeycombed sheets or 3-dimensional groups of polarized columnar cells with focal to abundant intracellular mucin or cytoplasmic vacuoles. Four of these five cases also demonstrated atypical to obviously malignant keratinized cells (rare in two cases, prominent in one case) (Fig. 6). One tumor (Case 14) lacked keratinization but contained malignant cells with dense nonvacuolated cytoplasm and central nuclei.

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Figure 6. Malignant keratinized squamous cells in a case of adenosquamous carcinoma with glandular predominance (Papanicolaou smear, ×600).

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Cell blocks were available for review in four cases with squamous predominance. Two of these cases (Cases 2 and 9) contained solid groups of malignant cells with dense cytoplasm and no evidence of glandular differentiation. Glandular differentiation was focally present in two cases, with glandular formation in one (Case 1) and intracytoplasmic mucin on a periodic acid–Schiff stain after digestion with diastase stain in another (Case 3) noted.

Nine cases originally were diagnosed as “adenosquamous carcinoma” or “adenocarcinoma with squamous features.” Four cases were diagnosed as “squamous cell carcinoma.” One (Case 14) was diagnosed as “adenocarcinoma.”

Histologic Features

The diagnosis of ASCa was histologically confirmed in two cases in which pancreaticoduodenectomy had been performed. One (Case 14) was comprised predominantly of infiltrating small glands. Focal squamous areas were comprised of solid nests of cells with well defined cytoplasmic borders, centrally placed nuclei, and focal keratin formation. The other case (Case 8) revealed a poorly differentiated tumor with extensive necrosis, keratinization, focal keratin pearl formation, and focal areas of gland formation (Fig. 7).

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Figure 7. Histology of adenosquamous carcinoma demonstrating predominantly squamous differentiation with keratinization and focal glandular formation with lumenal mucin (marked with an arrow) (H & E, ×200).

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Outcome

Followup was available for 13 patients. Twelve patients died of disease within 3 weeks to 10 months of presentation, with an overall mean survival of 5.6 months (median, 4 months). One patient was alive 13 months after undergoing pancreaticoduodenectomy.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

ASCa is a rare neoplasm of the exocrine pancreas that carries a poor prognosis similar to that of ductal adenocarcinoma. Although the histologic features of pancreatic ASCa have been well described, to our knowledge the cytologic features of ASCa have been described only in case reports and small case series, despite the fact that these tumors are often unresectable and cytologic material is often the only tissue available on which to base the diagnosis.3–10, 12–15 The recognition of a pancreatic FNAB as ASCa may allow for the important distinction of a primary pancreatic tumor from metastatic carcinoma, particularly SCC. In the current study, we describe the cytologic features of pancreatic ASCa in 14 cases, which to our knowledge makes this report the largest cytology series published to date, and demonstrate that a specific diagnosis of ASCa is possible when aspirates demonstrate evidence of dual differentiation.

All the cases in the current study were high-grade tumors, the majority of which (11/14; 79%) demonstrated definite features of both glandular and squamous differentiation. The findings of the current study are similar to those of others. Lozano et al. described malignant squamous and glandular cells against a background of inflammation and necrosis in three cases of ASCa.10 Wilczynski et al. described a case of ASCa containing both malignant keratinized cells and groups of glandular cells with high nuclear grade in a background of inflammation and necrosis.9 Both of these studies comment on the presence of tadpole cells in their smears. The presence of tadpole cells defines a malignant squamous component but is believed to be insensitive because they were noted in only seven cases and were prominent in none. The presence of atypical to frankly malignant keratinized cells, with characteristic orangeophilia on Papanicolaou-stained smears, was the most reliable feature of squamous differentiation in the current series.

However, in the current study, we found that in many cases either the squamous or glandular component was predominant, and that features diagnostic of dual differentiation often were focal and easily overlooked. Five of nine cases with squamous predominance contained only a rare glandular component in the form of honeycombed glandular sheets or intracellular mucin, and two cases (Cases 6 and 9) had only rare cytoplasmic vacuoles as evidence of glandular differentiation. Three of five cases with predominantly glandular differentiation demonstrated only scant evidence of squamous differentiation. Among the cases reported in the current study, a specific diagnosis of ASCa was made on the original FNAB in 9 cases (64%), whereas 5 cases received a diagnosis of SCC or adenocarcinoma. This highlights the difficulty in diagnosing ASCa in all cases, and emphasizes the need to examine cases of pancreatic carcinoma carefully for the presence of dual differentiation.

One limitation of the current study was the lack of histologic confirmation in many of the cases. However, primary ASCa of the pancreas was the most likely diagnosis in all cases because all the smears demonstrated features at least suggestive of dual differentiation, and none of the patients had a history of other malignancies that might suggest metastasis. In contrast, we excluded one case on the basis of the patient's history of pulmonary SCC. The FNAB in this case demonstrated purely squamous features with prominent keratinization and no evidence of glandular differentiation. A diagnosis of metastatic SCC was favored over a new pancreatic primary, although the possibility of an undersampled ASCa could not be excluded. This particular case illustrates how the absence of dual differentiation on FNABs of pancreatic masses can help in the distinction between ASCa and either SCC or pancreatic ductal adenocarcinoma. To our knowledge, the distinction of ASCa from ductal adenocarcinoma carries few clinical implications because both tumors behave aggressively and are treated similarly. However, the distinction between ASCa and SCC is important because the latter likely represents metastasis rather than primary pancreatic SCC. Although rare cases of primary SCC of the pancreas have been reported, the existence of such a tumor remains highly disputed.4, 5 The diagnosis of primary pancreatic SCC is often based on cytologic material or core needle biopsy tissue alone, raising the possibility of an undersampled ASCa.16–20 Indeed, other cases believed to represent pancreatic SCC on FNAB or core needle biopsy later are found to contain foci of glandular differentiation on histologic examination.8, 13 In one report, SCC was diagnosed in 0.5% cases of pancreatic carcinoma, but data were retrieved from cancer registry databases rather than pathology slide material and details regarding individual cases were not known.21 It is worth noting that in two large morphologic case series of nonendocrine pancreatic neoplasms, no cases of pure SCC of the pancreas were described.1, 2 Unlike primary SCC of the pancreas, metastatic SCC to the pancreas is rare but well documented, including cases diagnosed by FNAB.16, 22–26 In these cases, the primary neoplasm is most often from the lung, and, occasionally, the esophagus or cervix. The tumor typically presents as a solitary pancreatic mass mimicking a pancreatic primary tumor. Therefore, the presence of only malignant squamous cells in an aspirate from a pancreatic mass more often represents metastatic SCC or an undersampled ASCa rather than a primary SCC of the pancreas. Such a finding may prompt careful reexamination of the smear for subtle features of glandular differentiation, thorough review of the patient's clinical history for prior malignancy, or consideration of investigations to uncover an occult primary tumor. It is worth noting that ASCa also may represent a metastasis to the pancreas arising from the lung or gynecologic tract. Obviously, knowledge of a prior diagnosis of ASCa in another site would demand consideration of metastatic ASCa rather than a new primary tumor.

Squamous metaplasia of preexisting adenocarcinoma has been suggested by some authors as a mechanism underlying the histogenesis of pancreatic ASCa.3, 5, 15 One patient in the current series (Case 12) had undergone a previous resection and radiotherapy for pancreatic ductal adenocarcinoma (reviewed and confirmed), and returned 21 months later with ASCa of the pancreatic bed. This case may represent an example of radiation-induced squamous metaplasia of ductal adenocarcinoma.

It is interesting to note that in 1 of the cases (Case 11), the endoscopic ultrasound demonstrated a 2-cm hypoechoic mass in the pancreatic head and multiple cysts throughout the pancreas associated with pancreatic duct dilatation suggestive of an IPMN. Although several cases of ASCa with cystification due to necrosis have been reported to date, tumor necrosis would not explain the findings in the case in the current study.7, 9, 13, 27 A case of ASCa arising in a mucinous cystadenocarcinoma has been reported, and it is interesting to speculate that our case may have arisen in an IPMN.28

The diagnosis of ASCa and its distinction from SCC and ductal adenocarcinoma can be made on FNAB. Smears often demonstrate both squamous and glandular differentiation, although one of these components may be inconspicuous. In cases with predominantly squamous features, subtle evidence of glandular differentiation may allow for a diagnosis of ASCa and potentially prevent an exhaustive search for a primary SCC elsewhere. However, even the absence of dual differentiation in cytologic material from a pancreatic malignancy may still represent sampling artifact of ASCa, particularly in those cases with only squamous differentiation.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors thank Dr. John M. Dugan of the Lahey Clinic, Burlington, Massachusetts, for contributing a case to this series.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES