Diagnostic Value of Pancreatic Biopsy

Path. Res. Pract. 164,357-384 (1979)

Review

Institute of Pathology, University of Hamburg (Director: Prof. Dr. G. Seifert) Hamburg, West Germany

Diagnostic Value of Pancreatic Biopsy') G. SEIFERT and G. KLOPPEL

Summary This review emphasizes that the value of pancreatic biopsy is unquestionable for the preoperative and peroperative diagnosis of pancreatic carcinoma. Improvement of biopsy methods will further increase the importance of the preoperative pancreatic biopsy. However, the considerable technical difficulties and the time expenditure associated with these methods do not allow the use of pancreatic biopsy or one of the other diagnostic procedures as a screening procedure for detecting pancreatic carcinoma before it has led to subjective symptoms such as biliary obstruction. We should concentrate on the development of an immunological test for identifying the asymptomatic patients. Some progress on this area has been initiated by an attempt to characterize a pancreas-specific oncofetal antigen (Hobbs, 1976). The early demonstration of such an antigen in serum and pancreatic fluid would substantially improve the otherwise unfavourable diagnosis of pancreatic carcinoma. Therefore, we hope that the pessimism regarding the diagnosis and prognosis of pancreatic cancer will be replaced by realistic optimism in the future.

Introduction Since pancreatic biopsy, in contrast to liver or gastric biopsy, is rarely used, owing to technical difficulties and the low number of pancreas diseases where a biopsy would be relevant, uncertainty and controversial views are often found concerning the diagnostic value of this method. It is the aim of the study to give a general, critical review of the current state and value of the pancreatic biopsy, and to portray its morphologic spectrum.

1 Read as a guest lecture before the XL Annual Symposium of the European Pancreatic Club, Zurich, Switzerland, August 24.-26., 1978.

24 Path. Res. Pract. Vol. 164

35 8 . G. Seifert and G. Kloppel

Pancreatic carcinoma has always been the focus of the diagnostic spectrum of pancreatic diseases. Because of its rapid invasion rate at the outset, which makes its prognosis so unfavorable, it is necessary to concentrate all our efforts upon an early diagnosis of pancreatic carcinoma. Apart from the technical difficulties of the available diagnostic procedures, there is the permanent problem of differential diagnosis between pancreatic carcinoma and chronic pancreatitis. This applies particularly in the case of pancreatic biopsy. Based on these questions, our review will deal with the following topics: (I) morphologic methods employed for the evaluation of pancreatic biopsies, (2) pre- and peroperative methods as regards their accuracy, value, and risk, (3) diseases of diagnostic relevance (typing and staging), (4) the differential diagnosis of pancreatitis and carcinoma, (5) factor analysis for the etiologic background of both diseases, and (6) comparison of the value of preoperative diagnostic procedures currently used.

Morphologic Methods The frozen section technique for histological evaluation of tissue specimens obtained by wedge biopsy and large needle biopsy (Vim-Silverman-, Menghini-, Trucut-needle; diameter 2.6-1.4 mm) and the procedure for cytologic evaluation of fine needle (diameter 0.6 mm) aspiration material and endoscopically aspirated fluid permit an examination within 10 to 20 minutes after taking the biopsy. It should be pointed out that it is often difficult to make a definitive diagnosis from frozen sections on material obtained by large needle biopsy. The permanent paraffin sections can be specially stained for the demonstration of mucus (PAS, alcian blue), connective tissue (Masson-Goldner), or islet tissue (aldehyde-fuchsin). Immunohistology, electron microscopy, or tissue culture are used for answering special questions, as for instance in the case of endocrine tumors.

Preoperative Methods The first graph (Fig. I) gives a schematic survey of the four methods currently used for preoperative pancreatic biopsy: Duodenal and pancreatic duct apsiration cytology, and peritoneoscopically and sonographically guided fine needle biopsies. Instead of using sonography for localizing the lesion prior to biopsy, fine needle biopsy has been performed during angiography (Searson et al., 1972; Tylen et al., 1976) and endoscopic retrograde cholangiopancreatography (ERCP) (Me Loughlin et al., 1978). The histori-

Diagnostic Value of Pancreatic Biopsy . 359 Table 1. Preoperative Methode of Pancreatic Biopsy Methods

Authors

Cytology of duodenal aspirates

Lemon and Byrnes, 1949

Cytology of duodenal aspirates after secretin stimulus

Wenger and Raskin, 1958

Cytology of pancreatic duct fluid obtained during endoscopic cannulation

Endo et all., 1974 Hatfield et aI., 1974

Cytology/Histology of fine needle or forceps biopsy during peritoneoscopy

Meyer-Burg, 1973

Cytology of percutaneous fine needle ultrasonic guidance

Hancke et aI., 1975 Smith et aI., 1975

biopsy under

- during angiography

Tylen et aI., 1970

- during ERCP

McLoughlin et aI., 1978

Table 2.

Accuracy of Preoperative Histo- and Cytodiagnosis of Pancreatic cancer

Methods

Duodenal aspiration cytology

Correct Diagnosis Authors Positive n/Total n (0/0) 4/7

(60)

Lemon and Byrnes, 1949

Duodenal aspiration cytology after se- 18/32 cretin stimulus

(56)

Wenger and Raskin, 1958

Duodenal aspiration cytology after se- 18/24 cretin stimulus

(76)

Goldstein and Ventzke, 1968

Pancreatic duct fluid cytology

11/14

(80)

Endo et aI., 1974

Pancreatic duct fluid cytology

2/4

(50)

Hatfield et aI., 1974

Pancreatic duct fluid cytology

5/7

(70)

Kawanishi et aI., 1975

Pancreatic duct fluid cytology

10116

(62)

Czeczatka et aI., 1976

Fine neelde biopsy during peritoneo- 13/17 scopy

(77)

Meyer-Burg et aI., 1973

Large needle biopsy during peritoneoscopy

6/13

(46)

Meyer-Burg et aI., 1973

Percutaneous aspiration cytology

5/6

(83)

Smith et aI., 1975

Percutaneous aspiration cytology

17/21

(81)

Hancke et aI., 1975

Percutaneous aspiration cytology

22/29

(76)

Tylen et aI., 1976

Percutaneous aspiration cytology

16/18

(89)

McLoughlin et aI., 1978

360 . G. Seifert and G. Kloppel PREOPERATIVE METHODS OF PANCREATIC BIOPSY ENDOSCOPIC ASPIRATION CYTOLOGY

NEEDLE OR FORCEPS BIOPSY OUR ING PER ITONEOSCOPY

SONOGRAPHICALLY GUIDED NEEDLE BIOPSY

Fig. I. Schematic survey of preoperative methods of pancreatic biopsy currently employed.

Table 3. Value of Preoperative Biopsy Methods Methods

Advantage

Disadvantage

Peritoneoscopy: Puncture biopsy/Aspiration cytology Sonography: Percutaneous aspiration cytology

Combination of macroscopic and microscopic findings. Assessment of tumor spread by directed biopsy Uncomplicated method for accomplishing a definitive diagnosis in advanced cases

Difficult technique, limited by hidden location of pancreas

Endoscopic cannulation of pancreatic duct: Aspiration cytology

Combined endoscopic approach for evaluation of ERCP, CEA/ Oncofoetal pancreatic antigen, and well preserved cytology

Limited to cases with a tumour diameter greater than 3 cm

Considerable rate of unsuccesful atternps because of technical and anatomical reasons

cal development of preoperative methods is briefly described in Table I. What is the accuracy of the different methods, and which of these techniques is most helpful in the early diagnosis of pancreatic cancer? In Table 2, the various methods are compared as regards their frequency of correct

Diagnostic Value of Pancreatic Biopsy . 3 61

diagnosis. From those data it follows that: first, the average accuracy is 70%; second, the values vary between 500/0 and 80% although the same method may be used, implying that apart from the method, experience in cytologic examination plays an important role; and third, the method of percutaneous aspiration cytology under ultrasonic guidance shows the highest accuracy, with 890/0. Diagnostic accuracy, however, is not the only parameter in determining the value of biopsy methods. Table 3, therefore, tries to summarize the major advantages and disadvantages influencing the reliability of the preoperative methods. The possibility of obtaining histologic and cytologic material during peritoneoscopy (Look et aI., 1972; Meyer-Burg et aI., 1973; Strauch et aI., 1973; Henning and Look, 1976) leads to a morphologic diagnosis based both upon macroscopic and microscopic findings. Furthermore, the spread of a tumor can be grossly determined preoperatively. On the other hand, this method is handicapped by technical difficulties and the hidden anatomic location of the pancreas, which strongly limits the peritoneoscopic inspection of the pancreas. Percutaneous fine needle aspiration cytology under ultrasonic guidance appears to be a relatively simple method. Loughlin and collaborators call it a "reasonably safe and reliable method of obtaining a preoperative diagnosis and advocate the procedure as desirable in all patients in whom malignant disease is suspected and can be localized." However, this method can only be applied to advanced tumor cases, since the size of the tumor usually has to exceed 2.5 to 3 em to be detected by sonography or radiography. Thus, this method is not reliable for the early diagnosis of pancreatic cancer, although it may prevent the patients from useless operations. With an increasing number of physicians experienced in endoscopic cannulation of the papilla of Vater, aspiration cytology of pure pancreatic juice is becoming more and more available. In this method, large quantities of pancreatic fluid with well preserved duct cells (Fig. 2) can be obtained for cytologic examination. The most important cytologic criteria for malignancy in the duct cells are irregular enlargement and hyperchromatism of the nuclei, dominant nucleoli, and irregular arrangement of the cells (Fig. 3). The same material can be used for detecting the carcinoembryonic antigen (CEA), or for the newly postulated oncofoetal pancreatic antigen (Hobbs et aI., 1976). The major limiting factor of this method is that cannulation of the papilla of Vater requires a great deal of time and experience. Furthermore, false negative results may be obtained when the lesions are small and peripherally localized, or when the exocrine activity of the pancreas is greatly depressed (Endo et aI., 1974; Czeczatka et aI., 1976). No false positive results have been reported so far.

362 . G. Seifert and G. Kloppel

Fig. .2. Normal pancreatic duct cells in pancreatic JUIce aspirated from the pancreatic duct. Regularly sized cells with mucus production. Papanicolaou; X 1,300.

Fig. 3. Malignant cells in fluid aspirated from the pancreatic duct. Clumping of irregularly sized cells, with large hyperchromatic nuclei and prominent nucleoli. Papanicolaou; X 1,300.

Diagnostic Value of Pancreatic Biopsy . 363 Table 4. Peroperative Methods of Pancreatic Biopsy Authors

Methods Pancreatectomy

Whipple, 1935

Peroperative wedge biopsy Peroperative Vim-Silverman needle biopsy

Probstein et al., 1950

Pcroperative aspiration cytology from pancreatic duct

Rosen et al., 1968

Kirtland, 1951

Peroperative aspiration cytology

Christoffersen and Poll, 1970

Peroperative aspiration cytology

Arnesjo et al., 1972

Peroperative aspiration cytology

Lederer and Bodner, 1974

Table 5. Accuracy of Peroperative Histodiagnosis of Pancreatic Cancer ---

Methods

-

--------

--------

Complications 0/0 Cases Non lethal lethal

Correct diagnosis Positive n/Toral n in (%)

--------

- - ---

--

~

--------

Probstein et al., 1950

Wedge biopsy

10/23

(48)

Wedge biopsy

43/49

(88)

Wedge biopsy Vim-Silverman

42/48

(87)

Wedge biopsy Vim-Silverman

26/50 53/83

(46) (68) (65)

209

2.0

159

5.7

Wedge biopsy Vim-Silverman

Authors

68

3

1.4

Spjut and Ramos, 1957 Ackerman and Ramirez, 1959 Cote et al., 1959

3.8 Schultz and Sanders, 1963

Wedge biopsy Vim-Silverman

68/80

(85)

80

6.3

Wedge biopsy Vim-Silverman

37/38

(96)

50

2.0

Wedge biopsy Vim -Silverman

16/19 28/36

(84)

25

(78)

Wedge biopsy Vim-Silverman

67/81

(82)

81

3.7

Dencker, 1972

Wedge biopsy 310/326 Vim -Silverman

(95)

112

6.2

Isaacson et al., 1974

Wedge biopsy

31/35

(89)

47

Wedge biopsy Vim-Silverman

67/77 5/10

(87) (50)

177

--------,

Winegarner et al., 1966 2.0

20

Forsgren et al., 1968 Lund,1969

George et al., 1975 4.7

1.7 -

Lightwood et al., 1976

---------

---_._----

~

---------

364 . G. Seifert and G. Kloppel

Peroperative Methods Whipple (Whipple et aI., 1935) introduced the method of pancreatectomy for the surgical treatment of cancer in the head of the pancreas. The decision to perform a pancreatectomy requires and exact intraoperative diagnosis, which only can be achieved by pancreatic biopsy. The methods currently used to establish an peroperative diagnosis are illustrated in Figure 4, while the historical development of these techniques is presented in Table 4. Since pancreatic biopsy, obtained by wedge excision or by puncture with a large needle, was often found to be of limited accuracy and, moreover, is accompanied by a considerable risk of complications, its use is a matter of continuing controversy. It seems that by introduction of peroperative fine needle aspiration cytology, a great deal of the controversial problems have been solved. As to the accuracy of the peroperative histodiagnosis of pancreatic cancer, the relevant data reported in literature are listed in Table 5. The lowest rate of correct diagnosis, namely 46010, was given by Cote and associates; the highest rate, namely 96010, by Forsgren and collaborators (1968). The overall average rate is 76%. Reasons for false negative diagnosis are either the resection or the puncture of superficial, unrepresentative tissue or misinterpretation of the morphologic findings. Difficulties in recognizing a pancreatic carcinoma arise mostly in cases with a well differentiated duct carcinoma which is embedded in sclerotic tissue (Fig. 5). Unrepresentative tissue is usually given to the pathologist when the lesion is small and deeply seated. A false positive diagnosis may be given when aberrant ducts in the wall of the small intestine and pronounced chronic pancreatitis with atrophy and dilation of acini and ducts (Fig. 6) are mistaken for carcinoma. However, much more aggravating than the unsettled certainty of the diagnosis is the rate of complications accompanying open wedge biopsy or large needle biopsy. The complications result from bleeding, fistulas, pancreatitis or peritonitis, and are fatal in 2010-3010 of the cases (Table 5). This fact prompted us to examine the question of how many ducts, islets, and vessels are encountered in a biopsy specimen (Seifert et aI., 1976). Using the Menghini needle with a diameter of 1.4 mm, pancreas biopsies from the head, body, and tail of the pancreas were obtained in 60 autopsy cases. About 40% of the biopsies showed interlobular and large intralobular ducts, 30% showed islets, and 40% showed arterial or venous vessels (Table 6). Ducts were most frequent in the head, and islets in the tail, whereas vessels were about equally distributed. From these data, which demonstrate a relatively high number of ducts and vessels in the biopsies, the considerable complication rate could be explained.

Diagnostic Value of Pancreatic Biopsy . 3 65 PER OPERATIVE METHODS OF PANCREATIC BIOPSY

VIM-SILVERMAN

TRANSDUOOENAL BIOPSY

LYMPH NODE BIOPSY

FINE NEEDLE BIOPSY

Fig. 4. Schematic survey of peroperative methods of pancreatic biopsy currently employed.

Fig. 5. Peroperative large needle biopsy of the pancreas, with well differentiated adenocarcinoma growing in a fibrous stroma . The atypical ducts (arrows) are lined by an irregularly shaped epithelium . HE ; X 12 0.

36 6 . G. Seifert and G. Kloppel

Fig. 6. Peroperative large needle biopsy of the pan creas in a case with chronic pancreatitis. Small proliferated ducts, atrophic acini, and islet cell complexes are irregularly arranged in the sclerotic tissue. This lesion should not be misdiagnosed as invasive carcinoma. PAS; X 120.

Table 6. Frequenc y of Du cts, Vessels and Islets in Pancreatic Biopsies 180 Menghini Biopsies (Diamet er 1.4 mm) from 60 Autopsy Cases H istological structures

Frequency per biopsy

Ducts (interlobular and large intralobular ducts)

21% 1 duct 18% 2 Ducts and more

Islets

Vessels

39%

Total

15% 15% 3C%

1 Islet 2 Islets and more Total

26%

1 Vessel 2 or mor e vessels Total

38%

64%

Diagnostic Value of Pancreatic Biopsy . 3 67

For peroperative cytodiagnosis, material is usually aspirated from the pancreas by means of a Franzen needle or a normal syringe needle 0.6 to 0.7 mm in diameter. This safe and quick method yields a high rate of correct diagnosis, ranging between 82% and 100% (Table 7)' The average accuracy is 92%. Since the risk of complications is extremely low, the procedure can be repeated so that even a doubtful diagnosis can eventually be clarified. If we consider the advantages and disadvantages of the peroperative methods, the following points may be made (Table 8). Although there is a high rate of correct histodiagnosis when representative tissue is offered, wedge or large needle biopsy face a serious complication rate which strongly limits its general use. By contrast, fine needle aspiration cytology with its consistently high accuracy, is not impaired by complications and can be performed repeatedly at various sites. We know that the question as to which of these methods one should give preference depends not only on the data shown above, but is also a personal question involving the individual surgeon. However, from our point of view, we recommend that wedge biopsies or Vim-Silverman biopsies only ought to be done when the tumor is localized and still operable by a radical procedure. In inoperable tumor cases, the biopsy histodiagnosis may be performed on lymph node metastases or other metastatic tissue (Lund, 1969). On the other hand the use of fine needle biopsy may be recommended without limitations.

Diseases of DiagnosticRelevance for Pancreatic Biopsy Four main diseases of the pancreas, namely chronic pancreatitis, pancreatic carcinoma, endocrine tumors of the pancreas, and metastases, are of particular interest for pre- or peroperative diagnosis because of their clinical importance and the possibility of cure by surgical resection (Fortner, 1973; Hermreck et al., 1974; Brooks and Culebras, 1976; Kiimmerle et al., 1976; Ruckert and Kiimmerle, 1978). In this review we deal only with the morphology of pancreatic cancer. The histologic typing of pancreatic carcinoma, as shown on Table 9, is aimed at setting up a correlation between histologic type and clinical prognosis. For example, cystadenocarcinoma has a much better prognosis than the common adenocarcinoma. About 90% of pancreatic carcinomas originate from the pancreatic ducts. These tumors show predominantly a well differentiated pattern of ductular adenocarcinoma, with a mixture of tubular, papillary, and cystic structures (Fig. 7-9). Sometimes the histologic pattern appears so well differentiated that it is difficult to decide whether

3 68 . G. Seifert and G. Kloppel Table 7.

Accura cy of Peroperative C ytodiagnosis of Pa ncrea tic Cancer Correct diagnosis Authors Positive n /Total n o/ e

Met hods

-

-

-

- ~

9/1 I 5/5 I6II8

(100)

Fine needle aspiration cytology

(89)

Arnesjo et aI., 1972

F ine needle aspiration cytology

20121

(95)

Ko ivuniemi ct al ., 1972

Pancreatic du ct aspiration cyto logy Fine needle aspiration cy to logy

--

Rosen et al., 1968

(8z)

Christoffersen and Poll, 1970

Forsgren and Orell, 1973

Fine needle aspiration cytology

28/z9

(97)

Fine needle aspiration cytology

8/8

(100)

Fine needle aspiration cytol ogy

18!I9

(95)

Lederer and Bodner, 1974 Kline and Neal, 1975

F ine needle aspi ra tion cytology

16II8

(89)

Fine needle asp irat ion cytology

18II 8

(100)

Fine needle asp iration cytology

21129

(72)

Fine needle aspiration cytology

22 /22

(100)

Halveg er aI., 1973

Shorey, 1975 Fr edericksen and T hommesen (197 6) Eggert et aI., 1978 -

T able 8.

---

-

-~ -

Value of Peroperarive Biop sy Methods

Methods

Advantage

Di sadvantage

Wedge /Puncture biop sy of pancreatic tissue

Histologic (immunohistolo gic) eva luat ion

Variab le diagnostic accuracy because of diff icult ies in obtaining representative tissue. Complications (bleeding. fistula)

Fine needle aspiration cytology of pancreatic tissue

Multiple punctures at va rious sit es. No complications

this represent s carcinomatous elements or merely benign ductul ar proliferations due to chronic pancreatitis or both. Pancreatic carcinomas usually occlude the main pancreatic duct or one of its branches, thus leading to atrophy and sclerosis in upstream port ions of the organ, called chronic obstructive pancreatitis. However, the carcinoma itself may also induce a sclerotic stroma . Early invasion of peripancreatic tissues is one of the facts which limit the prognosis of pancreatic carcinoma . Even in small tumors the histology

Diagnostic Value of Pancreatic Biopsy . 369

Fig. 7. Well differentiated duct adenocarcinoma of the pancreas ansmg from a large pancreatic duct and invading the surrounding parenchyma. PAS; X 40.

Table 9. Histologic Classification of Pancreatic Carcinoma Pancreatic duct adenocarcinoma Well differentiated

Poorly differentiated Undifferentiated Mucoepidermoid carcinoma Cystadenocarcinoma Squamous carcinoma Acinic cell carcinoma Endocrine pancreatic tumor Metastases

- Tubular - Papillary - Mucinous - Tubular - Solid - Pleomorphic

370

G. Seifert and G. Kloppel

Fig. 8. Well differentiated pancreatic duct carcinoma: malignant cells with papillary epithelial proliferation, embedded in sclerotic and chronically inflamed tissue. HE; X 60.

Fig. 9. Well differentiated pancreatic duct adenocarcinoma (CA) adjacent to a benign duct (BD). Note the pleomorphism of malignant cells in contrast to the benign duct cells. HE; X 680.

Diagnostic Value of Pan creat ic Biopsy . 37I

Fig. 10.

Per ipancreatic exten sion of pancreati c carcinoma (arrows). PAS ; X

Fig. II.

Perineural infiltration by pancreatic carcinoma (arro w). HE ; »;

120.

120.

37 2

•

G. Seifert and G. Kloppel

often reveals peripancreatic extension of the tumor (Fig. 10). Pathways for tumor extension include the nerve shears (Fig. I I) and the lymphatic channels. Regional lymph node metastases are found predominantly in the superior head and the posterior pancreatico-duodenal lymph node groups (Cubilla et al., 1978). Recent efforts have been made to introduce a staging classification for pancreatic carcinoma in order to correlate tumor extension at the time of resection with survival rate. Table 10 compares the staging classifications according to Hermreck, Thomas and Friesen (1974) with our own staging system, which proposes a TNM classification similar to the currently used TNM scheme for other tumors. How do pancreatic carcinomas in surgical resections fit into this staging? To answer this question we reevaluated 40 pancreatectomy specimens with carcinomas of the pancreas or of the ampulla of Vater according to localization, size, and spread of the tumors (Table II). Only 15010 of the tumors, i.e., 6 out of 40 cases, were I em in diameter. In about two thirds of the cases, the tumor size was I to 3 em, and in the remaining cases it exceeded 3 em. Moreover, the increase in tumor size was directly related to the frequency of peripancreatic infiltration and lymph node metastases. When these findings were transferred to the proposed TNM-staging, 25% of the cases were confined to the 'I'[No stage (Table I2). Twenty-five percent appears to be a hopeful number, but half these cases were ampullary carcinomas, which are known to have a more favorable prognosis than pancreatic carcinomas. The average size of 'I'[-tumors ranged between I and 2 em. The two larger tumors with a diameter between 4 and 8 em represented cystadenocarcinomas, which are rare but also well-known for their good prognosis. Thirty-five percent of all cases fall into the T 2No category, with an average tumor size between 2 and 3 em. The advanced tumors in stage T 2N i comprised 40% of the cases. They showed almost the same average diameter as the T 2No-tumors. When we compare our data with those of other authors, we find a remarkable similarity. Fitzgerald and collaborators (1978), reporting on an examination of 27 surgical resections of the pancreas for pancreatic carcinoma, gave the following numbers. Stage I, which is identical with our stage Tj N«, was present in only 11 % of the cases. All other carcinomas belonged to stage II and III, in which the tumors had already extended beyond the pancreas and involved the lymph nodes. These numbers underscore the fact that the majority of pancreatic carcinomas become apparent during the process of invading the peripancreatic tissue, and during this stage the prognosis becomes poor tor the patient.

Diagnostic Value of Pancreatic Biopsy . 373 Table 10. Pathologic Staging of Pancreatic Carcinoma Proposed TNM - Staging

Stage (Hermreck ct al ., 1974) I - Local tumour II - Peripancreatic tumor invasio

Tl

- Tumor limited to the pancreas

T2

- Tumor extends beyond the pancreas

T3

- Tumor invades ad jacent organs (Stomach, Spl een) and peritoneum

Nil - No lymph nod e involvement - Regional lymph node metastases Mil - No hematogenous metastases

III - Regional lymph node metastases

Nj

IV - Liver metastases and oth ers; peritoneal implants

M] Mjh Mil M1Y

-

Haematogenic metastases Liver metastases Lung metastases Other metastases ------

-- - - -

Table II. Size and Spread of Pancreatic and Ampullary Carcinomas tectom y Specimens Localization 0/0 Ampulla Head Body

Size of tumor Frequenzy 0/0 (em) n -- -

1-2

6 12

66 6

3° 33 7 15

3 6 --

40 Pancrea-

Lymph node metastases 0/0

- - -

15

13

Peripancreatic infiltration 0/0

In

-

33

17

75 95 100

5° 38 66

66

33

33 94 85 66

33

5°

5°

IS

_ .-

-

- -

-- --

Table 12. Staging of Pancreas and Ampulla Carcinomas in 40 Pancreatectomy Specimens Staging (Proposed TNM Scheme)

Localization (n) Ampulla Head Bod y

3

1-2

2

14

25 Path. Res. Pracl. Vol. 164

Fre quency

4- 8

0/0

2

25

6

13

.:. 4 ampulla carcinoma ; ".".

Size (ern) 2- 3 3-4

2

I

ampulla carcinoma

6

2

2

374 . G. Seifert and G. Klopp el

Fig. 12. Papillary ductal hyperplasia in the unin volved part of a pancreas with carcinoma in the head. PAS ; X 60.

Tabl e 13. Morphologic Alterat ions Frequently Associated with Pancreati c Carcinoma in 40 Pan creat ectom y Specimens Lesions

Frequency °/0

Chronic obstru cti ve pancreatiti s modera te severe

22

Papillary ductal hyp erplasia with at ypi a

45 18

In tr adu ctal ca rcinoma (all adjacent

55

to

tumor )

Other morphologic alterations associated with pancreatic carcinoma, which may be important for pancreatic carcinogenesis, are papillary duct hyperplasia and intraductal carcinoma (Table 13). Papillary ductal hyperplasia occurred in 45% of our cases (Fig. 12), and the same lesion showed signs of cellular atypia in 18%. In 5% of cases, an intraductal carcinoma

Diagnostic Value of Pancreatic Biopsy. 375

Fig. 13. Papillary ductal hyperplasia and epithelial atypia in the uninvolved portion of pancreas with carcinoma of the head. Note atypical duct cells (arrows) opposite from normal duct cells. HE; X 500.

Fig. 14. Papillary ductal hyperplasia in a hamster treated for 14 weeks with Nenirrosohis (a-hydroxypropyljamine. PAS; X 120.

37 6 . G. Seifert and G. Kloppel

Fig. 15. Hamster pancreas with papillary ductal hyperplasia and intraductal carcinoma. Hamster treated as in figure 14. PAS; X 120.

was observed. Intraductal carcinomas, also called carcinoma in situ (Fig. 13), were all located adjacent to the main tumor in the head of the pancreas. These epithelial proliferations, which have also been frequently observed by other authors (Sommers et al., 1954; Cubilla and Fitzgerald, 1976), may represent precancerous lesions from which pancreas carcinomas develop. This view is supported by experimental findings in hamsters with carcinogen-induced pancreatic carcinomas (Pour et al., 1975). The papillary precancerous lesions of the ducts seen in hamsters strongly resemble papillary duct hyperplasia in man (Kloppel et al., I978b) (Fig. 14, IS). In advanced cases of secondary chronic pancreatitis, there are severe islet changes which are of interest with regard to the pathogenesis of pancreatic diabetes (Kloppel et al., 1978 a). The main findings are accumulation of islets, ductular-insular proliferation called nesidioblastosis, B-cell reduction, A-cell hyperplasia, and intrainsular fibrosis (Fig. 16). Based on these findings, our hypothetical scheme (Fig. 17) concerning the pathogenesis of pancreatic diabetes favors a reduced local circulation due to scarring of the tissue as the most important factor causing B cell reduction and functional insufficiency. Additional factors, such as a loss of yet unknown trophic influences or a diabetic predisposition, may also play an etiological role in pancreatic diabetes.

Diagnostic Value of Pa ncrea tic Biopsy . 377

Fig. [6.

Chronic pa ncrea titis wit h accumulation of islets in sclerotic tissue. PAS ; X

1 20.

PATHOGHUI C FACTORS IN PANCREATI C DIABETES ATROPHY AND SCLEROSIS OF EXOCRINE PANCREAS

..

INTRAINSULA:SCL£R OSIS .. REDUCED LOCAL CIRCULATION

~

LOSS OF TROPHIC FACTORS ?

JJ'

B - CELL INSUFFI CIENCY

•

( ADDITiONAL DIABETIC PRED ISPOS ITION)

Fig. 17. Hypothetical scheme of th e pathogenesis of pancreat ic dia betes.

Differential Diagnosis Between Chronic Pancreatitis and Carcinoma The separation between chronic pancreatitis and pancreas carcinoma is the most important point in th e differential diagnosis of a pan creatic biopsy, since chronic pancr eat itis can be second ar y to underlying carcinoma, and conversel y pancreatitis can mimic pancreas carcinoma (Gambill, 1971 ; Seifert et aI., 1978). Helpful clues for the differentiation bet ween pro-

378 . G. Seifert and G. Kloppe l Table 14. Differential Diagnosis Chronic sclerosing pancreatitis

Chronic obstructive pancreatitis

Irre gular duct dilatations

Regular cystic duct dilatation

Calcified detritus (calculi )

No calculi

Focal epithelial destruction

No epithelial destruction

Pseudocyst s

No pseudocysts

Irregular sclerosis with focal inflammatory infiltrates

Periductal sclerosis with mild inflammatory infiltrates

Irre gular parench ymal atr ophy

Per iductal paren chymal atrophy

Table 15. Factor Anal ysis for the Coincidence of Chronic Pancreatitis and Pancreatic Carcinoma I.

2.

Primary carcinoma with seconda ry obstructive pancreatitis Pr imar y chronic pancre atitis with seconda ry carcinoma. Precan ccrosis in chronic pan creatitis?

3. Common risk lactors? Pancreat itis: Alcohol ism N utrition (fat) Biliar y diseases H yperl ipemia Familial pancreatitis

Ca rcinoma : Cigarette smoking Nutrition (fat ) Diabet es (women)

liferated benign ducts and their malignant counterparts are abnormal shape, frequently an increase in mucus production, and irregular size of the lining cells of the carcinomatous ducts. The findings by which primary chronic pancreatitis can be differentiated from secondary chronic pancreatitis, are listed on Table 14. The term chronic sclerosing pancreatitis denotes a far adv anced lesion of the pancreas, predominantly caused by alcoholism. Chronic obstructive pancreatitis due to pancreatic carcinoma frequently appears as a moderate focal pancreatitis. In our study, moderate chronic pancreatitis occurred in 55% of cases (Table 13)' The more severe and more diffuse form was seen in 22%. Some histologic features of primary and secondary chronic pancreatitis are illustrated in Figures 18 and 19.

Diagnostic Value of Pan creatic Biopsy· 379

Fig. 18. Primary chroni c pan creatit is duct s. PAS ; X 120.

In

a chron ic alcoholi c: protein plugs

In

dilated

Fig. 19. Secondary chronic pan creat itis: concent ric periductal sclerosis with minimal inflammation. HE; X 12 0 .

3 80 . G. Seifert and G. Kloppel

Factor Analysis for the Coincidence of Chronic Pancreatitis and Pancreas Carcinoma The question of whether patients who have chronic pancreatitis are exposed to an increased risk of developing subsequent carcinoma has never been settled. There are follow-up studies in large single series of patients with chronic pancreatitis, which either favor (Creutzfeldt et al., 1970; Sarles and Gerolami-Santandrea, 1972) or deny (Mohr et al., 1975) an etiologic relationship of pancreatitis and cancer. Taken together, the coincidence of pancreatitis and cancer can be seen as follows (Table 15): First, chronic obstructive pancreatitis secondary to carcinoma has to be distinguished strictly from primary chronic pancreatitis, if stati stical argumentation is not to be falsified. Second, if chronic pancreatitis results in secondary carcinoma, one would expect an increased incidence of precancerous lesions such as papillary ductal hyperplasia with atypia, or carcinoma in situ or multifocal tumor formation. In our material of chronic sclerosing pancreatitis, we were not able to record a significant increase of such changes (Kloppel et al., 1978 b). Third, it must be determined whether there are common risk factors for both diseases. According to the study of Wynder (1975), nutrition, i.e., high fat intake, is one epidemiological factor

Table 16. Comparison of Diagnostic Procedures in Det ecting Pancreatic Cancer (Fitzgerald et al., 1978) - -- - -

Procedures

- --

-

- ---- - -

Pancreat ic cancer Positive False - negat ive 0/0 0/0

- -- -

Computerized trans axial tomography Celia c angiography 75Se-Selenomethionine scan Ultrasonography ERCP Duodenal aspiration Alkaline phosphatase

- - - - --

_.

94 83 75 67

--

---- ----

2,5 ng 5,0 ng

Non cancer Fal se - positive °/0

- -- -

6

4°

17

J2

25

31 28 21

73 17 82

33 27 83 18

83

17

57

43

33

Carcino-embryonic antigen

- -- -- - - -

49 II --

---

---

-- --

------- - -

Diagnostic Value of Pancreatic Biopsy . 381

associated with pancreatic carcinoma, and this factor also plays a well known role in the pathogenesis of pancreatitis. All other factors such as alcoholism, biliary diseases, hyperlipemia, cigarette smoking, and diabetes are either associated with pancreatitis or with carcinoma but not both. Only in the the rare cases of familial pancreatitis does there also seem to be a significant risk of developing pancreatic carcinoma. However, epidemiologic studies of pancreatic carcinoma are only in their early stages, so that further elucidation of these questions may be expected in the future.

Comparison of Preoperative Diagnostic Procedures Finally, we should like to comment on the value of preoperative pancreatic biopsy within a synopsis of the diagnostic procedures currently available for diagnosing pancreatic cancer. We refer to a study recently published by Fitzgerald and associates (1978), who examined the accuracy of different diagnostic procedures in 184 patients suspected of having pancreatic carcinoma. Table 16 shows that computerized transaxial tomography (CTT) was found to be the method with the highest frequency of correct diagnoses. CTT was followed in descending order by celiac angiography, 75-selenomethionine scanning, ultrasonography, and ERCP. According to this study, duodenal aspiration cytology ranks last, with a minimal accuracy of 170/0. However, when this result is compared with the data shown above for the accuracy of pancreatic fluid aspiration cytology, it may be regarded as an extreme underestimate of the cytologic method. The accuracy of all diagnostic methods strongly depends on the experience of the examiner and the technical improvements the method has undergone. In our opinion, endoscopically guided pancreas cytology can compete with all other diagnostic procedures as regards its average rate of positive (700/0), false negative (340/0), and false positive (00/0) diagnosis, especially since it is the only method which definitely makes the diagnosis. Pancreatic fluid cytology ideally supplements ERCP, and moreover the same pancreatic fluid which is taken for cytologic examination can also be used for a CEA test.

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Key words: Morphologic methods - Preoperative methods - Peroperative methods - Diseases of diagnostic relevance - Differential diagnosis of chronic pancreatitis and pancreas carcinoma Prof. Dr. Gerhard Seifert, Priv.-Doz. Dr. Giinter Kloppel, Institute of Pathology, University of Hamburg, UKE, Martinistr. 52, D-2000 Hamburg 20, West-Germany