Title: First clinical presentation of pancreatic

adenocarcinoma- cutaneous metastasis

Introduction:
Pancreatic cancer has a high malignant potential and is
considered to have one of the worst prognoses. Since the
pancreas is located in the retroperitoneum and is a long,
slender organ with a thin film, local symptoms are not well
defined.(1)Pancreatic cancer is known to metastasize rapidly,
most commonly to the liver and peritoneum, followed by the
lungs, bones and brain (2,3). The occurrence of cutaneous
metastases is rare, predominantly presenting in close
proximity to the umbilicus and is termed Sister Mary Joseph’s
nodule (SMJN) (4). Non-umbilical cutaneous metastases are
rare, with only a small number of cases reported (4,5). Here, we
report an unusual case of pancreatic adenocarcinoma with
cutaneous metastasis and multiple lung and liver metastases.
Key words: Pancreatic cancer, cutaneous metastasis,
adenocarcinoma

Case report :
A 59-year-old woman presented to our hospital with multiple
swellings over scalp for past 6 months. She also complained
of jaundice and pruritis for past 10 days. No H/O pain
abdomen, fever, prodromal symptoms. She gives history of
weight loss of over 5kgs in 6months. Past history revealed
recent onset of type 2 diabetes mellitus for past 6 months. On
local examination, multiple swellings over the scalp- largest
measuring 4X4 cm and rest were around 1X2cm and 2X2 cm.
The nodules were ulcerated with minimal discharge. The
abdomen examination revelaed hepatomegaly , 2cm below the
costal margin. No other lymph node was palpable. Per rectal
examination was normal.
The routine blood chemistry revealed : white blood cells,
7,600 cells/μL; hemoglobin, 12.7 g/dL; platelets, 23.1
cells/μL; Liver fuction test revealed obstructive jaundice :
total bilirubin, 16.04 mg/dL, conjugated more than
unconjugated; SGOT, 200 U/L; SGPT, 87 U/L; alkaline
phosphatase, 1404 U/L; γ-glutamyltranspeptidase, 463 U/L;
amylase, 25 U/L; lipase, 27 U/L; BS, 117 mg/dL; HbA1c,
6.1%; renal function test and electrolytes were within normal
range. However, tumor markers were elevated:
carcinoembryonic antigen, 7.33 ng/mL; carbohydrate antigen
19-9, 32.86 U/mL.
USG and thoracoabdominal enhanced computed tomography
(CT) was performed due to suspected cancer. The imaging
results showed tumors in the pancreatic head with obstructive
biliary dilatation. Metastasis were seen to retroperitoneal
lymph nodes, bilateral adrenal metastasis and at multiple sites
in the lung and liver.
Meanwhile skin biopsy immunohistochemical staining
showed a positive reaction to CK 19, CK 7, CK 20, CDX-2
and CEA. These markers revealed metastatic adenocarcinoma
of pancreatobilliary origin.
Next, endoscopic ultrasound-guided fine needle aspiration
was performed for histological diagnosis. An irregular and
heterogeneous mass measuring 32 × 28 mm was observed in
the pancreatic head. It caused lower CBD compression and
IHBR dilation. Histochemical staining showed proliferation of
small atypical gland ducts, these findings indicate that the
primary cancer was pancreatic ductal adenocarcinoma with a
clear cytoplasm. Tissue obtained from the occipital ulcer
showed almost the same morphology as the primary tumor,
and therefore, we diagnosed a metastatic cutaneous tumor
derived from the pancreatic cancer.
Due to developing cholangitis and non-feasibility of ERCP,
patient underwent per-cutaneous trans biliary drainage was
performed to drain the left biliary system with micro-puncture
set. Liver function test improved significantly post drainage.
Combination chemotherapy (gemcitabine and nab-paclitaxel)
was started for advanced pancreatic cancer with distant
metastasis. About 4 months later, the patient developed right
lower back pain. Conditional abdominal CT imaging showed
partial sclerosis of the right iliac bone and multiple spinal
lesions, indicating multiple bone metastases (Fig. 3a, b).
Narcotic analgesics were started. Imaging also revealed
further growth of the pancreatic tumor and the multiple lung
tumors. Therefore, second-line combination chemotherapy
(FOLFIRINOX, i.e., leucovorin, fluorouracil, irinotecan, and
oxaliplatin) was started. Chemotherapy is ongoing, as there
have been no special adverse events or worsening of the
patient’s general condition since the diagnosis was made 10
months ago.
Discussion:
Metastasis of pancreatic cancer is the leading cause if disease
worldwide, and the pattern of metastasis commonly includes
the regional lymph nodes, liver, peritoneum, lungs and brain.
Uncommon sites of metastases from pancreatic cancer include
the muscle, skin, heart, pleura and stomach.6
Cutaneous metastasis from pancreatic carcinoma is considered
to be particularly rare. In a study of 420 patients with
cutaneous metastases, Lookingbill et al (7) identified just two
cases (0.48%) originating in the pancreas. Cubilla and
Fitzgerald (8) reported that 9/119 patients (7.6%) with
pancreatic cancer exhibited cutaneous metastases at autopsy.
Miyahara et al (9) reported that skin lesions were present in the
umbilicus in 16/22 cases (72.7%) of cutaneous metastasis of
pancreatic cancer. Our case is unique in that the unusual
cutaneous metastasis of pancreatic cancer as the first clinical
manifestation was on the scalp, in contrast to the umbilicus.
Trying to determine the primary source of the cutaneous
metastasis from occult tumor is very difficult. However,
immunohistochemistry may enable the physician to precisely
identify the primary neoplasm. CA 19-9, which was initially
found in colorectal adenocarcinoma, has the highest
sensitivity as a tumor marker for adenocarcinoma of the
pancreas. This antigen is also found in other tumors, as well as
in non-cancerous diseases. According to Ridwelski et al. (10),
monoclonal antibodies against cytokeratin may be more
specific and reliable than CA 19-9 at detecting disseminated
tumor cells in lymph nodes. This is especially true because the
false positivity or false negativity for CA 19-9 is related to the
level of CA 19-9. Many different types of CK that are specific
to various organs do exist. In the pancreas, CK 8 and CK 18
are produced by the exocrine acinar cells, the endocrine islets
and the duct cells. CK 17 and CK 19 are usually found only in
the ductal cells. Pancreaticobiliary ductal adenocarcinomas, in
general, have a cytokeratin immunophenotype identical to that
of normal pancreatic ducts, including being positive for CK 7,
8, 18 and 1916). Approximately 90% of pancreaticobiliary
adenocarcinomas stain diffusely with CK 7 antibody and 50%
stain diffusely with CK 19 antibody(11). Duval et al(12) have
recently reported that the majority of pancreatic carcinomas
and extrahepatic carcinomas were positive for CK 7 and
negative for CK 20. Therefore, the findings concerning the
immunohistochemical expression of CKs are considered as
being useful in the diagnosis of metastatic carcinomas.
Various theories of cutaneous metastasis have been proposed,
however, no specific mechanism has been elucidated. These
theories include the soil and seed hypothesis, direct invasion,
lymphatic or hematogenous dissemination and the chemotaxis
hypothesis.
Conclusion:
Cutaneous metastasis from pancreatic carcinoma is a rare
finding. Clinicians should be aware that metastatic cutaneous
lesions could be the initial presenting sign for pancreatic
cancer. Also, the immunohistochemical staining for CK 7 and
19 may be helpful for the diagnosis of metastatic pancreatic
adenocarcinoma.
References:
1. Cascinu S, Falconi M, Valentini V, Jelic S ESMO
Guidelines Working Group. Pancreatic cancer: ESMO
Clinical Practice Guidelines for diagnosis, treatment and
follow-up. Ann Oncol. 2010;21(Suppl 5):v55–v58.
2. Satoh K, Shimosegawa T. Pancreatic tumor: progress in
diagnosis and treatment. Topics: 1. Pancreatic carcinoma: 2.
Pathogenesis and pathobiology in pancreatic cancer. - The
molecular mechanisms of carcinogenesis, and invasion and
metastasis in pancreatic cancer. Nihon Naika Gakkai
Zasshi. 2012;101:7–16. (In Japanese)
3. Targarona Soler EM, Trias Folch M. Sister Mary Joseph’s
nodule. Med Clin (Barc) 1999;113:118–119. (In Spanish)
4. Kaoutzanis C, Chang MC, Abdul Khalek FJ, Kreske E.
Non-umbilical cutaneous metastasis of a pancreatic
adenocarcinoma. BMJ Case Rep. 20132013 bcr2012007931.
5.Sharma C, Eltawil KM, Renfrew PD, Walsh MJ, Molinari
M. Advances in diagnosis, treatment and palliation of
pancreatic carcinoma: 1990–2010. World J Gastroenterol.
2011;17(7):867–97.
6. Ahmed K, Sussman JJ, Wang J, Schmulewitz N. A case of
EUS-guided FNA-related pancreatic cancer metastasis to the
stomach. Gastrointest Endosc. 2011;74:231–233.
7. Lookingbill DP, Spangler N, Helm KF. Cutaneous
metastases in patients with metastatic carcinoma: a
retrospective study of 4020 patients. J Am Acad Dermatol.
1993;29:228–236.
8. Cubilla A, Fitzgerald PJ. Pancreas cancer. I Duct
adenocarcinoma A clinical-pathologic study of 380 patients.
Pathol Annu. 1978;13:241–289.
9. Miyahara M, Hamanaka Y, Kawabata A, Sato Y, Tanaka A,
Yamamoto A, et al. Cutaneous metastasis from pancreatic
cancer. Int J Pancreatol. 1996;20:127–130.
10. Ridwelski K, Meyer F, Fahlke J, Kasper U, Roesner A,
Lippert H. Value of cytokeratin and Ca 19-9 antigen in
immunohistological detection of disseminated tumor cells in
lymph nodes in pancreas carcinoma.
11. Chirurg 72:920-926, 2001 16) Ohshio G, Imamura T,
Okada N, Yamaki K, Suwa H, Imamura M, Sakahara H.
Cytokeratin 19 fragment in serum and tissues of patients with
pancreatic diseases. Int J Pancreatol 21:235-241, 1997 17)
12. Duval JY, Savas L, Banner BF. Expression of cytokeratins
7 and 20 in carcinomas of the extrahepatic biliary tract,
pancreas, and gallbladder. Arch Pathol Lab Med 124:1196-
1200, 2000

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