Title: Metastatic Pancreatic Adenosquamous Carcinoma to the Scalp: A Case Report

and Review of the Literature

Short title: Pancreatic Adenosquamous Carcinoma to Scalp

Behzad Salari, M.D.1, David M. Sheinbein, M.D.2, Ilana S. Rosman, M.D.1,2, Louis P.

Dehner, M.D.1

1Lauren V. Ackerman Laboratory of Surgical Pathology, School of Medicine,

Washington University Medical Center, St. Louis, MO

2Division of Dermatology, School of Medicine, Washington University Medical Center,

St. Louis, MO

Corresponding author: Louis P. Dehner, Department of Pathology and Immunology,

Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8118, 3rd

Floor, Rm 3421, Institute of Health Bldg. (IOH), St. Louis, MO, USA 63110. Tel:

+1(314)-362-0150, Fax +1(314)-747-4392, E-mail: dehner@wustl.edu.

Presentations: poster presentation at 55th ASDP Annual meeting, Chicago, IL, USA,

2018.

Disclosures:

Competing interests: None.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article
as doi: 10.1111/cup.13582

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Sponsorships: None.

Acknowledgments: The authors would like to thank Mrs. Linda Hankins for her

contribution.

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Abstract

Metastatic carcinoma to the skin occurs in only a minority of patients with a visceral

or internal malignancy, with breast, lung and colorectum accounting for the majority

of cases. We present the case of a 66-year-old man with a recent violaceous nodule of

the left scalp (1.2 x 1.0 x 0.2 cm) that was a metastatic pancreatic adenosquamous

carcinoma, representing a seemingly rare event. Two months prior, after complaining

of right hip pain, an image revealed a right femoral lesion. A biopsy of that lesion

showed moderately differentiated adenocarcinoma. Subsequent imaging showed a

mass in the pancreatic tail and also markedly elevated serum tumor markers, CA 19-

9 and CEA (5325 U/mL and 111.5 U/mL, respectively). Before the appearance of the

scalp nodule, the patient received radiotherapy and was started on chemotherapy,

which was continued after diagnosis and resection of the nodule. Subsequent

metastases developed in the liver, lung and additional cutaneous lesions. He died

eleven months after initial presentation with right hip pain. As this case

demonstrates, cutaneous metastases confer a poor prognosis, often with less than a

year survival following their appearance.

Case history

A 66-year-old man presented with a recent violaceous scalp nodule (1.2 x 1.0 x 0.2

cm) on the left parietal region. Two months prior, after complaining of right hip pain,

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an x-ray revealed a lucent lesion in the right femur which on biopsy revealed a

moderately differentiated mucin-producing adenocarcinoma (Figure 1). A

subsequent computed tomography (CT) imaging disclosed a mass (4.2 x 2.6 cm) in

the tail of the pancreas extending into the splenic hilum, consistent with a primary

pancreatic carcinoma. In addition, there were numerous hepatic lesions (maximum

3.6 cm) and L5 vertebral body lytic lesions (maximum 1.7 cm) suspicious for

metastatic disease along with a few indeterminate pulmonary nodules (<1.0 cm). No

further biopsies were performed at the moment. Serum tumor markers including CA

19-9 and CEA were markedly elevated at 5325 U/mL and 111.5 U/mL, respectively.

The scalp nodule (Figure 2) was initially noticed by the patient as a small papular

lesion that grew rapidly over the course of the next three weeks. Meanwhile, the

patient completed palliative radiation and received two cycles of chemotherapy

(FOLFIRINOX). Following resection of the scalp nodule, he continued receiving a total

of twelve cycles of FOLFIRINOX.

Four months after resection of the scalp nodule, an indeterminate nodule (0.9 cm)

was noted in the subcutaneous tissue of the posteromedial left distal thigh and

monitored with surveillance imaging. CT scan showed stable pancreatic tail mass,

liver nodules and sclerotic lesions in the spine, but interval increase in size of a right

hilar mass and worsening of mediastinal lymphadenopathy. Later, he was started on

Gemcitabine/Abraxane, as well. Eventually, eleven months after initial presentation

with right hip pain, he died due to complications of his cancer.

Pathology

The scalp nodule consisted of a poorly differentiated adenocarcinoma replacing the

dermis and with an intact uninvolved epidermis. Solid nests of tumor cells with

abundant eosinophilic cytoplasms and poorly formed ductal structures were

identified (Figure 3). A focused panel of immunohistochemistry, to differentiate

metastasis from pancreatic origin versus primary skin carcinoma, demonstrated the

following phenotype of the tumor cells: CK5/6, p63, EMA, CK19, CA 19-9, CK7 and

CEA. Mucicarmine was focally positive (Figure 4). The tumor was interpreted as an

adenosquamous carcinoma.

Molecular genetic studies performed on the bone metastasis identified KRAS

mutation, exon 2 (p.G120) and TP53 mutation, exon 5 (p. R175H).

Discussion

The present case demonstrates one of the clinical presentations of a visceral

carcinoma with metastatic disease to the bone, which was followed by a cutaneous

metastasis in the scalp. In a male in the mid-60s, lung, kidney and prostate were

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candidate primary sites until the CT scan identified a mass in the tail of the pancreas.

Both elevated serum CA 19-9 and CEA further supported the pancreas as the primary

site in the absence of other potential sites. The bone metastasis was a poorly

differentiated adenocarcinoma, and the cutaneous metastasis was equally poorly

differentiated but the immunophenotype was indicative of squamous differentiation

in addition to the poorly formed glandular component. The biopsy of the scalp nodule

was interpreted as an adenosquamous carcinoma (ASCA), an uncommon variant of

ductal adenocarcinoma of the pancreas, accounting for only 1% of cases.1,2 Even for a

pancreatic adenocarcinoma, the presentation with distant metastatic disease in

contrast to the more common locoregional disease, is unusual. It is generally

acknowledged that pancreatic ASCA is one of the “most aggressive forms of

pancreatic cancer.”3 A median survival of 14.3 months is reported in comparison to

20.2 months overall for all ductal adenocarcinoma.2 In another smaller series, the

median survival was 10.9 months after adjuvant chemoradiation therapy.4 Our

patient survived only 11 months following diagnosis.

Exclusive of hematolymphoid malignancies and malignant melanoma, visceral

carcinoma of various sites and types infrequently metastasize to the skin which is

reported in 1%-2% of cases and as high as 9%-10% in the minority of series.5-10

Approximately 2%-3% of invasive breast carcinoma metastasizes to the skin whereas

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carcinomas arising in other sites such as the lung and colorectum are seen in less than

2% of cases.7 There is a difference between men and women in terms of the primary

sites where the breast, lung and colorectum are the sites in descending order in

women whereas the lung, colorectum and kidney are the most common sites in

males.8 In 5%-10% of patients with cutaneous metastasis, the primary site is occult

at the time of clinical presentation, however, when our patient presented with the

nodule in the scalp, the bone metastasis and a mass in the tail of the pancreas were

already known. In the case of an as yet undiscovered primary neoplasm, a biopsy of

the cutaneous lesion, whether an adenocarcinoma, squamous cell carcinoma or small

cell carcinoma offers the differential diagnosis of a primary versus secondary

neoplasm. Immunohistochemical evaluation is useful in the case of an

adenocarcinoma with limitations and small cell carcinoma must be differentiated

from primary neuroendocrine (Merkel cell) carcinoma. In general, adenocarcinomas

are more likely than squamous cell carcinomas to spread to the skin.7

Cutaneous metastasis from pancreatic carcinoma is sufficiently uncommon that it is

not listed separately among the various primary sites or is represented by 2 or 3 cases

in series, which are dominated by breast, lung and colorectum.7,9 The umbilical

centered metastasis or the eponymic Sister Mary Joseph nodule is the most common

cutaneous site of metastatic pancreatic carcinoma where it may be the initial sign of

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disease.11-15 However, our patient is unusual in several respects with a non-umbilical

metastasis to the scalp as an example of distant metastasis of a pancreatic carcinoma;

this atypical presentation of bone and skin metastases is reasonably explained by the

well-documented aggressive ASCA with its abbreviated median survival compared to

the other pathologic types of pancreatic ductal carcinoma. It is difficult to know

whether this case is the first example of pancreatic ASCA with a cutaneous metastasis

since most other cases in the literature are only characterized as “adenocarcinomas.”

Of the previously reported 11 scalp metastases, pancreatic adenocarcinoma was

described in eight of the patients; the subtype of carcinoma was not specified in the

other three cases.16-18 The present case is the first specific report of pancreatic

adenosquamous carcinoma metastasizing to the scalp. To the best of our knowledge,

pancreatic adenosquamous carcinoma metastasizing to the non-scalp skin has been

reported only in one patient.19 These relatively rare tumors are larger and more

commonly found in the body or tail of the pancreas. An analysis of the National Cancer

Database revealed that adenosquamous carcinoma of the pancreas is associated with

worse outcome in stage I/II resected patients when compared to pancreatic

adenocarcinoma.20

A study by Lookingbill et al.9 concluded that skin involvement could occur by three

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different mechanisms: direct invasion, local spread or distant metastasis. The latter

is the least common mechanism and when it occurs, the lesions arise as multiple

nodules grouped in a localized body area. Although incompletely understood, several

theories have been proposed for the biologic basis of skin metastasis in pancreatic

cancers. It has been suggested that such a spread could be partly explained by Paget's

theory (soil and seed).21 Circulating cancer cells can reach all cutaneous tissues via

blood or the lymphatic system seeking for a familiar microenvironment in distant

tissues to settle themselves.22 However, the molecular basis for the selection of skin

as a proper destination is still incompletely understood. The role of CCL19/CCL21

and VEGF‐D/C‐/VEGFR‐3 signaling pathways in lymph node metastasis in pancreatic

cancers is currently being studied.23

Because of the nonspecific clinical presentation of cutaneous metastases, they can be

confused for more common benign skin lesions.24 On histopathological analysis,

differentiating a primary skin adnexal carcinoma from a metastases from visceral

carcinoma can be challenging in the majority of the cases without the benefit of

clinical history.24 Additionally, using an appropriate panel of immunohistochemical

stains is essential to find primary tumor diagnosis. The majority of pancreatic

adenocarcinomas are reactive for CK19 and CK7 markers. While CA-19-9 and CEA are

also frequently positive in these tumors, CK20 is nonreactive in the majority of the

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cases (40-80%).25-27 Table 1 summarizes useful immunohistochemical markers in

differentiating the tumors of the breast, lung, gastrointestinal, kidney and prostate as

the most common carcinomas metastasizing to the skin.8

Skin metastasis represents a grave prognostic sign in pancreatic cancers with median

survival time of 5 months after diagnosis of skin metastases and a cumulative 2-year

survival rate of 3.5%.28 Horino et al. 28 showed that receiving chemotherapy or

chemoradiotherapy (CRT) is the only prognostic factor of skin metastases from

pancreatic cancer. In their study, the median survival time of patients who were

treated with chemotherapy or CRT was 6.5 months, while still a poor prognosis, this

was statistically longer in comparison to patients without treatment.

Conclusion

Pancreatic cancers progress rapidly and have dismal prognosis with a short median

survival time of less than a year after diagnosis. Non-umbilical skin metastases,

including scalp are rare in pancreatic cancers and have been reported as the

presenting complaint of underlying malignancy in some cases. Diagnosis of skin

metastases is challenging without the benefit of clinical history and

immunohistochemical stains.

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In the present report, the scalp metastasis developed later in the course of the disease,

while the patient was undergoing treatment with chemotherapy and palliative

radiation.

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Figure legend

Figure 1- Biopsy of the bony lesion, which is a moderately differentiated mucin-

producing adenocarcinoma.

Figure 2- Patient with a new violaceous scalp nodule.

Figure 3- Biopsy of the scalp nodule.

Figure 4- Immunohistochemical findings compatible with metastatic adenosquamous

carcinoma from a pancreatobiliary primary tumor.

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Table 1. Immunohistochemical markers for the most common organs metastasizing
to the skin
Primary site Histopathology Positive markers Negative markers
Lung Small cell TTF-1, CK20, CD99
carcinoma synaptophysin,
chromogranin A,
CAM5.2, Ber-EP4
Squamous cell P63, CK5/6, EMA CK20, CK7, TTF-1,
carcinoma CEA
Adenocarcinoma TTF-1, CK7, Ber- CK20, CK5/6
EP4, CEA,
Surfactant,
NapsinA
Breast Invasive ductal CK7, ER, PR, Her2, CK20, CK5/6
carcinoma mammaglobin,
GCDFP-15,
CEA, c-erbB-2, E-
cadherin
Invasive lobular CK7, PR, PR, Her2, S100, P63, E-
carcinoma mammaglobin, cadherin,
GCDFP-15, podoplanin
CEA, EMA
GI (luminal)
Esophagus Adenocarcinoma CK5/6, Ber-EP4, CK20, CK7+/-
CK19+/-
Stomach Adenocarcinoma CK20, CDX2, CEA, CK7+/-
EMA
Colorectal Adenocarcinoma CK20, CDX2, CEA, CK7
mucin
GI (Solid organ)
Liver Hepatocellular Hep All CKs, EMA,
carcinoma Par 1, AFP, monoclonal CEA
arginase-1,
polyclonal CEA,
glypican 3

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 Pancreas Adenocarcinoma CK7, CK19, CK20
CA19.9, CK8,
CK18, CEA, CA125
Kidney Renal cell AE1/AE3, CD10, CK20, CK7, Inhibin,
carcinoma CAIX, RCC, PAX8, melan-A, TTF-1
PAX2, vimentin,
EMA, S100,
CAM 5.2
Prostate Adenocarcinoma PSA, prostatic acid CK20, CK7,
phosphatase, thrombomodulin,
AMACR, NKX3.1 CEA, WT1, TTF1
GI, Gastrointestinal; TTF-1, Thyroid transcription factor 1; CEA, carcinoembryonic
antigen; ER, Estrogen receptor; PR, Progesterone receptor; GCDFP, gross cystic
disease fluid protein; EMA, epithelial membrane antigen; Hep Par 1, hepatocyte
paraffin 1; AFP, Alpha-fetoprotein; RCC-ma, renal cell carcinoma marker; PSA,
prostate-specific antigen; AMACR, alpha-methylacyl-CoA racemase.

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References

1. Boyd CA, Benarroch-Gampel J, Sheffield KM, Cooksley CD, Riall TS. 415

patients with adenosquamous carcinoma of the pancreas: a population-based

analysis of prognosis and survival. J Surg Res. 2012;174(1):12-19.

2. Pokrzywa CJ, Abbott DE, Matkowskyj KA, et al. Natural history and treatment

trends in pancreatic cancer subtypes. J Gastrointest Surg. 2019;23(4):768-778.

3. Brody JR, Costantino CL, Potoczek M, et al. Adenosquamous carcinoma of the

pancreas harbors KRAS2, DPC4 and TP53 molecular alterations similar to

pancreatic ductal adenocarcinoma. Mod Pathol. 2009;22(5):651-659.

4. Voong KR, Davison J, Pawlik TM, et al. Resected pancreatic adenosquamous

carcinoma: clinicopathologic review and evaluation of adjuvant chemotherapy

and radiation in 38 patients. Hum Pathol. 2010;41(1):113-122.

5. Sariya D, Ruth K, Adams-McDonnell R, et al. Clinicopathologic correlation of

cutaneous metastases: experience from a cancer center. Arch Dermatol.

2007;143(5):613-620.

6. Hu SC, Chen GS, Lu YW, Wu CS, Lan CC. Cutaneous metastases from different

internal malignancies: a clinical and prognostic appraisal. J Eur Acad Dermatol

Venereol. 2008;22(6):735-740.

This article is protected by copyright. All rights reserved.

7. Hu SC, Chen GS, Wu CS, Chai CY, Chen WT, Lan CC. Rates of cutaneous

metastases from different internal malignancies: experience from a Taiwanese

medical center. J Am Acad Dermatol. 2009;60(3):379-387.

8. Alcaraz I, Cerroni L, Rutten A, Kutzner H, Requena L. Cutaneous metastases

from internal malignancies: a clinicopathologic and immunohistochemical

review. Am J Dermatopathol. 2012;34(4):347-393.

9. 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(2 Pt 1):228-236.

10. Mueller TJ, Wu H, Greenberg RE, et al. Cutaneous metastases from

genitourinary malignancies. Urology. 2004;63(6):1021-1026.

11. Kaoutzanis C, Chang MC, Abdul Khalek FJ, Kreske E. Non-umbilical cutaneous

metastasis of a pancreatic adenocarcinoma. BMJ Case Rep. 2013;2013.

12. Miyahara M, Hamanaka Y, Kawabata A, et al. Cutaneous metastases from

pancreatic cancer. Int J Pancreatol. 1996;20(2):127-130.

13. Yendluri V, Centeno B, Springett GM. Pancreatic cancer presenting as a Sister

Mary Joseph's nodule: case report and update of the literature. Pancreas.

2007;34(1):161-164.

This article is protected by copyright. All rights reserved.

14. Bhardwaj R, Gautam A, Bhardwaj G, Dharan M. Sister Mary Joseph's Nodule

(SMJN): an uncommon initial presentation of metastatic pancreatic

adenocarcinoma. Am J Gastroenterol. 2017;112:S691-S692.

15. Prabhu R, Krishna S, Shenoy R, Natarajan A. Pancreatic cancer presenting as a

Sister Mary Joseph's nodule. BMJ Case Rep. 2013;2013.

16. Nakano S, Narita R, Yamamoto M, Ogami Y, Osuki M. Two cases of pancreatic

cancer associated with skin metastases. Am J Gastroenterol. 1996;91(2):410-

411.

17. Puri AS, Saraswat VA, Krishnani N, Salunke PN. Cutaneous metastases in

pancreatic adenocarcinoma. Indian J Pathol Microbiol. 1995;38(1):99-101.

18. van Akkooi AC, Dokter J, Boxma H. Unusual first presentation of metastatic

pancreatic cancer as skin metastases in a burn patient. Burns.

2010;36(6):e111-114.

19. Zhou HY, Wang XB, Gao F, Bu B, Zhang S, Wang Z. Cutaneous metastasis from

pancreatic cancer: a case report and systematic review of the literature. Oncol

Lett. 2014;8(6):2654-2660.

20. Hester CA, Augustine MM, Choti MA, et al. Comparative outcomes of

adenosquamous carcinoma of the pancreas: an analysis of the National Cancer

Database. J Surg Oncol. 2018;118(1):21-30.

This article is protected by copyright. All rights reserved.

21. de Groot AE, Roy S, Brown JS, Pienta KJ, Amend SR. Revisiting seed and soil:

examining the primary tumor and cancer cell foraging in metastasis. Mol

Cancer Res. 2017;15(4):361-370.

22. Pontinen T, Melin A, Varadi G, et al. Cutaneous metastasis of pancreatic

adenocarcinoma after kidney transplant: a case report and review of the

literature. Exp Clin Transplant. 2010;8(4):273-276.

23. Xiao Z, Luo G, Liu C, et al. Molecular mechanism underlying lymphatic

metastasis in pancreatic cancer. Biomed Res Int. 2014;2014.

24. Requena L, Kiryu H, Ackerman AB. Ductal carcinoma. Neoplasms with apocrine

differentiation. Philadelphia: Lippincott-Raven; 1998.

25. Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20 expression in

epithelial neoplasms: a survey of 435 cases. Mod Pathol. 2000;13(9):962.

26. Jain R, Fischer S, Serra S, Chetty R. The use of cytokeratin 19 (CK19)

immunohistochemistry in lesions of the pancreas, gastrointestinal tract, and

liver. Appl Immunohistochem Mol Morphol. 2010;18(1):9-15.

27. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human

cytokeratins: patterns of expression in normal epithelia, tumors and cultured

cells. Cell. 1982;31(1):11-24.

28. Horino K, Takamori H, Ikuta Y, et al. Cutaneous metastases secondary to

pancreatic cancer. World J Gastrointest Oncol. 2012;4(7):176-180.

This article is protected by copyright. All rights reserved.

Accepted Article
Accepted Article
Accepted Article