Conference 02 - 2013 Case: 04 20130918

Signalment:

13-year-old neutered female Labrador retriever dog (Canis familiars).This dog had a two-day history of rear limb edema and an activity level that had declined over several months. Abdominal ultrasound revealed 2 large masses in the region of the liver, one of which was compressing the vena cava. It was suspected that postcaval compression by this mass had caused the limb edema.

Gross Description:

Bilaterally, the subcutaneous tissues of the rear limbs are thickened up to 1.5 cm by gelatinous pale yellow fluid, and this fluid became red, with discoloration of the adjacent tissue below the hock. A 13x12x8cm firm red mass is present on the left lateral liver lobe, and a smaller similar mass is present on the left medial lobe. The liver weighed 6.3% of the body weight. An externally firm 8x7x5 cm mass is present on the right lobe of the pancreas. When sectioned, the mass is soft and dark red continuing several pale nodules that measure 0.5 cm or less in diameter. The pancreatic lymph nodes were firm, tan and measure 3 cm in length.

Histopathologic Description:

Pancreas: Compressing the adjacent pancreatic parenchyma and expanding the fibrous capsule is a multi-lobular, moderately cellular mass arranged in acini and tubules. These are separated by fibrovascular stroma that is expanded by amorphous eosinophilic hyaline material. Individual neoplastic cells are cuboidal or polygonal, with distinct cytoplasmic borders and abundant amphophilic to granular eosinophilic cytoplasm. The basal nuclei are round, possessing finely stippled chromatin and a variably distinct nucleolus. No mitotic figures are found in ten 400X fields. Focal necrosis is apparent. Neoplastic cells do not infiltrate the capsule of the organ, but lymphatic emboli occurred in some sections.

Morphologic Diagnosis:

Pancreas: Exocrine pancreas: adenocarcinoma, hyalinizing

Condition:

Hyalinizing exocrine pancreatic adenocarcinoma

Contributor Comment:

The pancreatic mass is consistent with pancreatic exocrine adenocarcinoma of hyalinizing type. Overall, exocrine pancreatic tumors are most frequent in dogs amongst the domestic species, with a higher prevalence in older females according to some studies. Extensive implantation and metastases to lymph nodes and liver are often evident by the onset of clinical signs.

Carcinomas may be manifest as single or multiple masses in the organ. They are histologically variable and are classified as acinar, which look like normal exocrine tissue, tubular, which appear more similar to ducts, or undifferentiated, when cells occur in sheets. Hyalinizing carcinomas contain interstitial glassy eosinophilic matrix in tubular lumina or expanding the matrix.(1) This substance is not congophilic and fails to stain immunohistochemically with reagents to serum amyloid A, amylin, α1-antitrypsin or immunoglobulin light chain. The nature of this matrix is not known. In a small case series, these carcinomas tended to favor the acinar pattern and patients that were not euthanized immediately after surgery had a somewhat longer survival than expected.(1) A case with clear cell morphology and similarly increased interstitial matrix has been recently reported in a dog, in which the matrix was PAS+.4 Our case has a mixed pattern with sheets of undifferentiated cells as well as acini.

Cytokeratin labeling has been disappointing(2) for use in identifying pancreatic carcinomas in dogs, and has the draw-back of staining cytokeratin on other organs when utilized to identify metastases. In cats pancreatic exocrine neoplasms are often positive for one or both reagents, as is normal pancreas. In dogs, pancreatic ducts are reported to express cytokeratin 7, but acini were negative, while acinar tissue reacted with neither reagent. Four pancreatic exocrine neoplasms tested in this series were also uniformly negative. Recently claudin-4 has been suggested as a reagent useful in negative poorly differentiated exocrine tumors and ductular tumors from between differentiated acinar neoplasms, which are positive.(3)

The patient had very severe rear leg swelling with marked subcutaneous edema, which histologically was found to contain numerous neutrophils. Two of the cases in reference 1 also had one or more areas of suppurative panniculitis, although the lesions were in other locations. This patient had severe postcaval compression from one of its hepatocellular carcinomas, and this may have been the cause of edema.

JPC Diagnosis:

Exocrine pancreas: Hyalinizing pancreatic adenocarcinoma

Conference Comment:

The most notable characteristic of this neoplasm, and the feature that distinguishes it from the more common variants of canine exocrine pancreatic carcinoma (EPC), is the extensive extracellular deposition of homogenous to globular eosinophilic material.(1) This substance is consistent with the microscopic appearance of amyloid, however, as noted by the contributor, it is generally not congophilic or birefringent and is immunohistochemically negative for serum amyloid A, amylin, α1-antitrypsin and immunoglobulin light chain; the origin of this material remains unknown.(1) Interestingly, in this case, the application of Massons trichrome stained the hyaline eosinophilic material blue.

Canine hyalinizing pancreatic adenocarcinoma is a well-differentiated, solitary mass most commonly seen in the right limb of the pancreas. The most frequent clinicopathological abnormalities are elevated serum amylase and lipase.(1) Hyalinizing pancreatic adenocarcinoma is a form of EPC, and the main differential diagnoses are other variants of EPC, such as anaplastic (undifferentiated) EPC or pancreatic acinar or ductal carcinomas.(4) Pancreatic acinar cell carcinomas are further classified histologically as well-differentiated, which are less invasive, or poorly-differentiated, which tend to metastasize or invade adjacent tissue. One recent report found that loss of expression of claudin-4, a tight junction integral protein normally expressed in canine pancreatic acinar cell membranes, may lead to cellular detachment, disorientation and invasion in poorly-differentiated EPCs. The same study suggested immunohistochemical staining for claudin-4 as a marker to distinguish well-differentiated from poorly-differentiated acinar cell carcinomas.(3) Canine hyalinizing pancreatic adenocarcinomas behave less aggressively than the other, more common variants of canine EPC. Dennis, et al. speculate that this more benign behavior may be secondary either to the hyaline matrix material mechanically or biochemically impeding malignancy, or to the degree of tumor differentiation (or both).(1)

In the sections submitted for the conference, there is a diffuse loss of cellular detail and differential staining within the tumor, and because the contributor observed that some sections contained neoplastic emboli within lymphatics this led several conference participants to speculate that the entire neoplasm could be infarcted.

References:

1. Dennis MM, OBrien TD, Wayne T, Kuipel M, Powers BE. Hyalinizing pancreatic adenocarcinoma in 6 dogs. Vet Pathol. 2008;45:475-483.

2. Espinosa de los Monteros A, Fern+â-ídez A, Mill+â-ín MY, Rodriguez F, Herr+â-íez P, Martin de las Mulas J. Coordinate expression of cytokeratins 7 and 20 in feline and canine carcinomas. Vet Pathol. 1999;36:179-190.

3. Jakab CS, Rusvai M, Demeter Z, G+â-ílfi P, Szab³ Z, Kulka J. Expression of claudin-4 molecule in canine exocrine pancreatic acinar cell carcinomas. Histol Histopathol. 2011;26:1121-1126.

4. Pavone S, Manuali E. Eleni C, Ferrari A, Bonano E, Carioli A. Canine pancreatic clear acinar cell carcinoma showing unusual mucinous differentiation. J Comp Path. 2011;145:355-358.