Surg Today (2005) 35:692–695DOI 10.1007/s00595-004-2974-3

Humoral Hypercalcemia Complicating Adenocarcinoma ofthe Sigmoid Colon: Report of a Case

Jun Sakata1, Toshifumi Wakai1, Yoshio Shirai1, Eiko Sakata1, Go Hasegawa2, and Katsuyoshi Hatakeyama1

Divisions of 1 Digestive and General Surgery and 2 Pathomorphology, Niigata University Graduate School of Medical and Dental Sciences,1-757 Asahimachi-dori, Niigata 951-8510, Japan

roid hormone-related peptide (PTHrP) produced bytumor cells, and local osteolytic hypercalcemia, causedby extensive skeletal tumor involvement.1 Humoralhypercalcemia of malignancy complicates a variety ofmalignancies, most commonly squamous, renal, andurothelial tumors.1 Primary colorectal malignancies arerarely associated with HHM. In fact, we found only20 cases reported in the English-language literature(PubMed, National Library of Medicine, Bethesda,MD, USA) up to the end of 2003.2–18 We reviewed these20 cases and report a further case, in an attempt toclarify the clinicopathologic features of colorectal carci-noma associated with HHM.

Case Report

A 52-year-old Japanese woman underwent a radicalsigmoidectomy and lateral segmentectomy with partialhepatectomy for primary colonic cancer with synchro-nous liver metastases. The primary tumor was well-differentiated adenocarcinoma, and the resected liverspecimen contained ten metastatic deposits of poorlydifferentiated adenocarcinoma. For 12 months afterdischarge, she received 5-fluorouracil (500 mg/m2 perweek) and leucovorin (250mg/m2 per week) intrave-nously. However, a follow-up computed tomographyscan 2 years later showed metachronous metastasesin the remnant liver, and she was referred to ourdepartment for repeat hepatectomy. Her symptoms onadmission included upper abdominal pain, anorexia,constipation, muscle weakness, and lethargy. Labora-tory data showed an elevated serum calcium level of14.2 mg/dl (reference range, 8.7–10.0mg/dl) and a lowserum phosphorus level of 2.2mg/dl (reference range,2.5–4.6 mg/dl). The serum levels of carcinoembryonicantigen and carbohydrate antigen 19-9 were 14.1 ng/ml(reference range, 0–6 ng/ml) and 44U/ml (referencerange, 0–37 U/ml), respectively. A skeletal survey and

AbstractHumoral hypercalcemia can arise from a variety ofmalignancies, but its association with primary colorectalcarcinoma is rare, with only 20 such cases documentedin the English-language literature to date. We report anadditional case to clarify the clinicopathologic featuresof colorectal carcinoma with humoral hypercalcemia. A54-year-old woman was admitted with symptomatichypercalcemia of 14.2 mg/dl and multiple hepatic me-tastases, 2 years after resection of sigmoid colon cancer.The hypercalcemia was caused by the circulating par-athyroid hormone-related peptide (PTHrP) producedby poorly differentiated adenocarcinoma in the liver.The PTHrP level on admission was 13.5 pmol/l. Despitesystemic chemotherapy, the patient died of disease pro-gression 3 weeks after the humoral hypercalcemia wasdiagnosed. A review of the 21 reported cases, includingours, suggests that colorectal carcinoma associated withhumoral hypercalcemia is characterized by a poorlydifferentiated tumor with or without squamous or neu-roendocrine features, distant metastases, and a dismalprognosis.

Key words Humoral hypercalcemia of malignancy ·Parathyroid hormone-related peptide · Paraneoplasticsyndrome · Colorectal neoplasm · Prognosis

Introduction

Hypercalcemia is a common metabolic manifestation ofcancer. Malignancy-associated hypercalcemia is dividedinto two syndromes: humoral hypercalcemia of malig-nancy (HHM), which results from a circulating parathy-

Reprint requests to: T. WakaiReceived: January 5, 2004 / Accepted: November 16, 2004

693J. Sakata et al.: Humoral Hypercalcemia from Colonic Cancer

bone scan showed no evidence of bony metastases. Anelevated serum level of PTHrP (Allegro PTHrP kit,Nichols Institute Diagnostics, San Clemente, CA, USA)of 13.5pmol/l (reference range, <0.6pmol/l) and aserum level of intact parathyroid hormone (Allegro in-tact PTH kit, Nichols Institute Diagnostics) of less than5ng/l (reference range, 10–60ng/l) confirmed a diagno-sis of HHM. The patient was treated with intravenoussaline hydration followed by an infusion of 30mg ofpamidronate. Within 5 days, the calcium level de-creased to 11.5mg/dl and her clinical status improved.As computed tomography showed numerous metastaticdeposits throughout the entire liver, repeat hepatec-tomy was not considered. Systemic chemotherapywas started with oral TS-1 200mg/day (Taiho Pharma-ceutical, Tokyo, Japan), which consisted of tegafur 5-chloro-2,4-dihydroxypyridine, and potassium oxonate,in a molar ratio of 1 : 0.4 :1. Despite treatment, the livertumors continued to grow and multiple lung lesionsappeared. The patient died of progressive disease 3weeks after the HHM was diagnosed. Autopsy was notperformed.

Immunohistochemical examination of the primarysigmoid colon tumor, using a monoclonal antibodyagainst PTHrP (Oncogene Research Product, Cam-bridge, MA, USA) revealed negative staining. In con-trast, the resected liver metastases stained positively(Fig. 1).

Discussion

Humoral hypercalcemia of malignancy is a rare mani-festation of colorectal carcinoma. Kubota et al.5 re-ported only two cases of HHM among 1053 patients(0.02%) with colorectal carcinoma. The histopathologictype of both of these cancers was adenosquamous car-cinoma. A review of the 21 reported cases of HHMcomplicating colorectal carcinoma, including that of ourpatient, revealed that poorly differentiated/undifferen-tiated (n = 12) or adenosquamous carcinoma (n = 8)were the dominant histopathologic types (Table 1).Four reported cases also showed neuroendocrine fea-tures.6,13,16,18 In the case we described, immunohis-tochemical analysis revealed that PTHrP was positiveonly in the liver metastases of poorly differentiatedadenocarcinoma, indicating that the dedifferentiationof tumor cells may lead to excessive production ofPTHrP. Taken together, these findings suggest thatcolorectal carcinoma associated with HHM is character-ized by a poorly differentiated tumor with or withoutsquamous or neuroendocrine features.

The symptoms of HHM include nausea, vomiting,anorexia, constipation, muscle weakness, lethargy, andmental confusion,4,7 some of which were experienced byour patient. Thus, we recommend measuring the serumcalcium levels if patients with malignancies have thesesymptoms. Distant metastases are common in patientswith colorectal malignancies and HHM.11,12,16,17 All ofthe 17 patients with documented metastatic disease hadliver metastases. Thus, HHM should be considered

Fig. 1. Immunohistochemical analysis ofa metastatic lesion in the liver, done usinga monoclonal antibody against parathy-roid hormone-related peptide. The cyto-plasm of the poorly differentiated tumorcells was stained positively (¥200)

694 J. Sakata et al.: Humoral Hypercalcemia from Colonic Cancer

Tab

le 1

.R

epor

ted

case

s of

hum

oral

hyp

erca

lcem

ia a

ssoc

iate

d w

ith

colo

rect

al c

arci

nom

a

Out

com

e af

ter

Sex/

age

Pri

mar

yH

isto

logy

Seru

m c

once

ntra

tion

sde

tect

ion

ofF

irst

aut

horR

ef.

Yea

r(y

ears

)si

teSi

tes

of m

etas

tase

sT

ype

Gra

deC

alci

umP

TH

PT

HrP

hype

rcal

cem

ia

Cas

tlem

an2

1963

M/7

7C

olon

HE

P, L

YM

Ade

noG

3-4

14m

g/dl

ND

ND

3 w

eeks

; DO

DM

ozaf

fari

an3

1969

M/4

6C

olon

HE

PA

deno

ND

15m

g/dl

ND

ND

3 w

eeks

; DO

DO

men

n419

69M

/79

Col

onN

DN

DN

D17

.8m

g/dl

ND

ND

ND

; DO

DK

ubot

a519

80M

/43

Col

onH

EP

, PU

L, K

idne

yA

sN

D7.

6m

Eq/

lU

ndet

ecta

ble

ND

<1 m

onth

; DO

DK

ubot

a519

80M

/39

Rec

tum

HE

P, P

ER

As

G3

7.9

mE

q/l

Und

etec

tabl

eN

D1

wee

k; D

OD

Pal

vio6

1985

F/6

7R

ectu

mH

EP

, PU

L, A

DR

, OSS

,A

saG

44.

0m

mol

/lSl

ight

lyN

D2

mon

ths;

DO

DL

YM

, PE

R, P

LE

,el

evat

edT

hyro

idC

hevi

nsky

719

87F

/41

Col

onH

EP

, LY

MA

sG

318

.4m

g/dl

ND

ND

6 da

ys; D

OD

Ber

kelh

amm

er8

1989

M/7

4C

olon

HE

P, P

UL

As

G3

14.5

mg/

dlU

ndet

ecta

ble

ND

2 w

eeks

; DO

DM

arch

919

91M

/58

Rec

tum

HE

PA

deno

ND

17.6

mg/

dl15

ng/l

ND

ND

; DO

DG

urne

y1019

93N

DC

olon

ND

ND

ND

ND

ND

2–10

pmol

/lN

D; N

DG

urne

y1019

93N

DC

olon

ND

ND

ND

ND

ND

>20

pmol

/lN

D; N

DL

inks

1119

94M

/58

Col

onH

EP

As

G3

2.99

mm

ol/l

0.55

ng/m

l25

.5pm

ol/l

7 m

onth

s; D

OD

de S

ouza

1219

95F

/52

Rec

tum

HE

PA

deno

G3

4.52

mm

ol/l

0.3

pmol

/l16

2pm

ol/l

3 w

eeks

; DO

DSi

dler

1319

96M

/75

Col

onH

EP

, LY

MA

deno

aG

33.

3m

mol

/l6

ng/l

36.7

pg/m

l6

mon

ths;

DO

DP

etre

lli14

1996

F/3

7C

olon

HE

P, L

YM

As

ND

ND

ND

ND

ND

; DO

DSe

kine

1519

98M

/47

Col

onN

DN

DN

D16

.0m

g/dl

ND

ND

ND

; ND

Lor

thol

ary16

1999

F/5

4C

olon

HE

P, L

YM

Ade

noa

G3

3.75

mm

ol/l

1ng

/l18

pmol

/l5

wee

ks; D

OD

Lor

thol

ary16

1999

M/6

3R

ectu

mH

EP

, PU

L, L

YM

, SK

IA

deno

G1

4.27

mm

ol/l

12.7

ng/l

9.3

pmol

/l7

wee

ks; D

OD

Tho

mps

on17

2001

F/7

6C

olon

HE

P, L

YM

, SK

IA

sG

413

.6m

g/dl

6pg

/ml

25.7

pmol

/l10

mon

ths;

AW

DL

uh18

2002

M/4

2C

olon

HE

P, L

YM

, OSS

, SK

IA

deno

aG

316

.2m

l/dl

31.8

pg/m

l12

.1pm

ol/l

6 m

onth

s; D

OD

Pre

sent

cas

eF

/54

Col

onH

EP

, LY

M, P

UL

Ade

noG

314

.2m

g/dl

<5ng

/l13

.5pm

ol/l

3 w

eeks

; DO

D

PT

H, p

arat

hyro

id h

orm

one;

PT

HrP

, par

athy

roid

hor

mon

e-re

late

d pe

ptid

e; A

deno

, ade

noca

rcin

oma;

As,

ade

nosq

uam

ous

carc

inom

a; G

1, w

ell d

iffe

rent

iate

d; G

3, p

oorl

y di

ffer

enti

ated

; G4,

undi

ffer

enti

ated

; H

EP

, he

pati

c; L

YM

, ly

mph

nod

es;

PU

L,

pulm

onar

y; P

ER

, pe

rito

neum

; A

DR

, ad

rena

ls;

OSS

, os

seou

s; P

LE

, pl

eura

; SK

I, s

kin;

DO

D,

died

of

dise

ase;

AW

D,

aliv

e w

ith

dise

ase;

ND

, not

des

crib

edaT

hese

spe

cim

ens

also

had

neu

roen

docr

ine

feat

ures

695J. Sakata et al.: Humoral Hypercalcemia from Colonic Cancer

when marked hypercalcemia is found in patients withcolorectal carcinoma and distant metastases.

Pamidronate with intravenous saline hydration is thetreatment of choice for HHM.16,18 Our patient’s symp-toms resolved quickly after this treatment. Gurneyet al.10 reported that patients with serum PTHrP levels≥12 pmol/l had a poor response to pamidronate; how-ever, the combination of calcitonin and pamidronatemay be effective for patients with HHM caused by highlevels of PTHrP.15,19

Patients with colorectal malignancies associatedwith HHM have a very poor prognosis (Table 1).Since most tumors have spread beyond the scope ofsurgical resection at the time of diagnosis of HHM,systemic chemotherapy may be the only option forthese tumors; however, no effective chemotherapeuticregimen for colorectal carcinoma presenting with HHMhas been established.5,11,13,18 Further investigation is war-ranted to find an effective treatment regimen for thiscondition.

In conclusion, colorectal carcinoma associated withhumoral hypercalcemia is characterized by a poorlydifferentiated tumor with or without squamous or neu-roendocrine features, distant metastases, and a dismalprognosis. Although rare, this paraneoplastic syndromeshould be considered in patients with a history ofcolorectal carcinoma who present with distant meta-stases and marked hypercalcemia.

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