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case records of the massachusetts general hospital

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 356;17 www.nejm.org april 26, 20071760

Founded by Richard C. CabotNancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor

Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

From the Department of Medicine (M.V.S.),the Center for Cancer Risk Analysis (D.P.),the Department of Radiology (M.J.O.),and the Department of Pathology (E.O.),Massachusetts General Hospital; and theDepartments of Medicine (M.V.S.), Radi-ology (M.J.O.), and Pathology (E.O.), Har-vard Medical School.

N Engl J Med 2007;356:1760-9.Copyright © 2007 Massachusetts Medical Society.

Presentation of Case

A 46-year-old woman came to the Center for Cancer Risk Analysis at the CancerCenter of this hospital because of recent diagnoses of endometrial, ovarian, andcolonic cancers.

Fifteen weeks earlier, a routine Papanicolaou smear showed an atypical glandularcell, and she was referred to a gynecologist at this hospital. Fifteen years earlier,the patient had had abnormal findings on a Pap smear performed elsewhere; theuterine cervix was treated with cryotherapy. Over the next 14 years, repeated Papa-nicolaou smears were normal. She had had four early miscarriages at 6 to 8 weeks’gestation. Her menses were normal and regular. She had undergone two cycles of in vitro fertilization in the past that had not resulted in pregnancy. There was no di-ethylstilbestrol exposure, abnormal bleeding, postcoital bleeding, or change in bowelor bladder habits.

The general physical and gynecologic examinations were normal. The level of thyrotropin was 6.56 μU per milliliter (reference range, 0.40 to 5.00), the serumhuman chorionic gonadotropin level was less than 6 IU per liter, and the completeblood count was normal. A cold-knife cone biopsy, which included most of theendocervix, and a fractional dilatation and curettage were performed. Pathologicalexamination of the cone-biopsy specimen showed chronic cervicitis and squamousmetaplasia. Endocervical curettage showed dysplastic glandular mucosa, and endo-metrial curettage showed moderately differentiated adenocarcinoma. Immunohisto-chemical staining of the tumor cells was positive for both estrogen- and progesterone-

receptor proteins.Eight weeks before this consultation, computed tomography (CT) of the abdomenshowed a lesion in the fifth segment of the liver, 2.9 cm by 1.9 cm, which enhancedearly with iodinated contrast material, and a parapelvic cyst in the left kidney. CT of the pelvis showed heterogeneous enhancement of the cervix and a low-density regionextending from the endocervix into the lower uterine segment. A chest CT, an electro-cardiogram, a complete blood count, serum electrolyte measurements, and liver-and renal-function tests were normal.

Four weeks before this consultation, an exploratory laparotomy, radical hyster-ectomy, and bilateral salpingo-oophorectomy were performed. A mass in the mid-

Case 13-2007: A 46-Year-Old Woman with Gynecologic and Intestinal Cancers

Michael V. Seiden, M.D., Ph.D., Devanshi Patel, M.S., C.G.C., Mary Jane O’Neill, M.D.,and Esther Oliva, M.D.

The New England Journal of Medicine

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Copyright © 2007 Massachusetts Medical Society. All rights reserved.

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n engl j med 356;17 www.nejm.org april 26, 2007 1761

descending colon was identified during the oper-ation, and omentectomy, pelvic lymph-node dis-section, appendectomy, and hemicolectomy withcolostomy were performed. Pathological exami-nation showed three primary tumors: stage IBinvasive endometrial adenocarcinoma (endome-trioid histologic subtype), with squamous meta-

plasia (grade 1 of 3); stage 1B clear-cell adenofibro-mas of borderline malignancy with endometriosisin both ovaries; and low-grade adenocarcinomaof the descending colon, 2.5 cm in diameter, ex-tending into the muscularis propria. Cytologicalexaminations of regional lymph nodes and pelvic washings were negative for carcinoma.

Postoperatively, a colonoscopy performedthrough the colostomy disclosed no mucosal le-sions. The serum CA-125 level was 88.8 U permilliliter (reference range, 0 to 35). Sigmoidoscopy,exploratory laparotomy, and removal (takedown)

of her colostomy were planned in the near future.She was referred to the Center for Cancer Risk Analysis.

Additional history was obtained. A laparoscopy and ovarian cystectomy had been performed inthe distant past; pathological examination of thetissue was said to have shown a benign condition.She had hypothyroidism for which she took levo-thyroxine sodium; she had no known allergies tomedications. She was married and worked in anoffice position; she occasionally smoked cigarettesand drank one alcoholic beverage in the evening.There was a maternal history of endometrial,breast, and colon cancers and colonic polyps(Fig. 1).

A diagnostic procedure was performed.

Differential Diagnosis

Dr. Michael V. Seiden: May we see the imaging stud-ies and the pathological findings?

Dr. Mary Jane O’Neill: On the abdominal pelvicCT scan, the cervix appears bulky (Fig. 2). The

proximal portion of the endometrial canal con-tains abnormal tissue. The ovaries appear normal.A hypervascular liver lesion has features on im-aging that suggest a benign lesion, and the lesion was later characterized on magnetic resonanceimaging as benign fibronodular hyperplasia.

Dr. Esther Oliva: The uterus was normal on grossexamination. Microscopical examination revealedan endometrioid adenocarcinoma centered in thelower uterine segment (Fig. 3). The carcinoma

invaded the inner half of the muscle wall, but no vascular invasion or extension into the endocervix was identified. The tumor cells were positive for vimentin, estrogen, and progesterone receptorsbut negative for carcinoembryonic antigen. Thetumor was classified as an endometrial adenocar-cinoma, endometrioid type with squamous dif-

ferentiation (grade 1 of 3), stage IB, according tothe staging system for uterine cancer of the Inter-national Federation of Gynecology and Obstet-rics. All lymph nodes were negative for tumor.

On gross examination, both ovaries were nor-mal in size and had several smooth, lined cysts, with the largest having a diameter of 1 cm, but noother abnormalities were identified. On micro-scopical examination, each ovary contained asingle, well-circumscribed tumor, 0.4 by 0.3 by 0.3 cm on the right ovary and 0.4 by 0.3 by 0.2 cmon the left ovary, composed of glands and stroma

(Fig. 4A). The glands were lined by flattened cells,most of which had scanty clear-to-pink cytoplasmand enlarged hyperchromatic nuclei; some cells were hobnail in shape, with the nuclei bulginginto the glandular lumens. The stromal compo-nent was relatively cellular and without cytologicatypia (Fig. 4B). No mitoses were identified ineither the glands or the stromal component. Thetumors were classified as clear-cell adenofibro-mas of borderline malignancy.

The segment of colon contained an irregularexophytic, partially ulcerated mass, 2.5 by 2.2 cm,that was 1.1 cm from the closest resection margin.The mass was 0.4 cm in thickness on gross exam-ination and appeared to infiltrate the lamina pro-pria. On microscopical examination (Fig. 4C), thetumor was a moderately differentiated adenocar-cinoma, associated with a prominent lymphocyticinfiltrate and occasional lymphoid aggregates,that had infiltrated the superficial muscularis pro-pria. There was an abrupt transition between theneoplastic glands and normal colonic glands, withno evidence of an associated adenoma. No lympho-

vascular invasion or lymph node metastases wereidentif ied. The tumor was classified as a stage IImoderately differentiated colonic carcinoma.

Dr. Seiden: This young woman had synchronoustumors, including an endometrioid carcinomaand adenocarcinoma of the colon. She also hadunusual tumors of the ovaries, clear-cell adeno-fibromas of borderline malignancy.

Endometrioid carcinoma is the most commoncancer in the uterine corpus. It is relatively com-




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mon in postmenopausal women, especially those with a history of exogenous estrogen use or co-existing conditions that increase endogenous es-trogen exposure. In younger women, this canceris often associated with a second cancer. In gen-eral, three different patterns are noted: tumors

of the ovary and endometrium, both of endome-trioid type; the combination of endometrioid tu-mors of the uterus and breast cancer; and thecombination of endometrioid tumors of the uterus with colon carcinoma.

Dual ovarian and endometrioid tumors are

l

Breastcancer

Miscella-neouscancer

Genito-

urinarycancer

Gastro-

intestinalcancer

Quadrant System

Unconfirmed colorectal cancer

70 Yr

61 Yr 70 YrRenal-cell cancer, 70 yr

Crohn’s disease

73 Yr 76 Yr 74 YrEndometrial or uterine

cancer, 50 yrAdenomatous colon polyp, 58 yr

Skin cancer, 70 yr

65 YrAdenomatous colonpolyp-A 10-100, 58 yr

30 Yr

5

40 Yr

4

45 Yr

3

21 Yr 13 Yr 12 Yr 6 Yr

48 Yr 47 YrOvarian cancer, 46 yr

Colorectal cancer, 46 yrEndometrial or uterine

cancer, 46 yr

40 Yr 15 YrLeukemia, 2 yr

40 Yr

91 Yr 62 YrColorectal

cancer, 55 yr

83 YrBreast cancer,

70 yr

Figure 1. Pedigree of the Patient’s Family.

Circles represent women, and squares represent men. Slashes indicate persons who died, and the numbers beneath

the circles or squares are age at death (if there is a slash) or, for those living, age at the time the pedigree was created.Yellow represents confirmed cancer. Black dots represent the presence of colon polyps. Diamonds indicate that sex is

unknown; the number inside the diamond indicates the number of persons represented by the diamond. The arrow

indicates the patient (proband) under discussion. The proband has colon, endometrial, and ovarian cancers, all diag-nosed when she was 46 years of age. The proband’s mother has a history of endometrial cancer diagnosed when

she was 50 years of age, basal-cell carcinoma diagnosed at the age of 70 years, and a colon polyp diagnosed at theage of 65 years. Her maternal aunt has a history of a colon polyp diagnosed at the age of 58 years. The proband’s

maternal cousin has a history of leukemia diagnosed at the age of 2 years. Her maternal grandfather had colon cancer

diagnosed at the age of 55 years. Her maternal grandmother had breast cancer diagnosed at the age of 70 years. Herpaternal uncle had kidney cancer diagnosed at the age of 70 years.




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frequently diagnosed in young women with a his-tory of infertility.1 Both tumors are often diag-

nosed at a low stage, with the ovarian tumor di-agnosed at an early stage because of abnormal vaginal bleeding caused by this tumor. To date,no underlying genetic abnormality has been iden-tified in these women and, indeed, many of themhave a history of endometriosis.

Uterine papillary serous carcinoma has beennoted in the presence of a BRCA1 mutation. Thus, women with this disease and a history of inva-sive ductal carcinoma of the breast should beconsidered for BRCA testing.2 BRCA1 carriers areprobably not at increased risk for colon cancer.

The combination of uterine cancer and a co-lonic cancer raises the possibility of other geneticsyndromes, most notably hereditary nonpolypo-sis colon cancer (HNPCC), also known as theLynch syndrome.3 The Lynch syndrome, which iscaused by mutations in the genes involved in theDNA mismatch-repair pathway, is the most com-mon hereditary colon cancer syndrome4-6 and isassociated with colon cancer, endometrioid car-cinoma of the uterus, and ovarian cancer, in that order of frequency, as well as with various other

kinds of cancer, including cancer of the smallbowel, the biliary tract, and perhaps the brain.The presentation of a synchronous or metachro-nous colon cancer and an endometrioid endome-trial cancer in a young woman, such as this pa-tient, especially if it occurs in the context of afamily history that includes multiple members with colon cancer or endometrial cancer, or both,is highly suggestive of HNPCC.

The pathological findings associated with this

woman’s synchronous gynecologic and colon tu-mors diagnosed at an early age, along with herfamily history of endometrial cancer in her moth-er and colon cancer in her maternal grandfather,

l

Figure 2. Abdominal Pelvic CT Scan.

Enhancement of the lower uterine segment (arrows)

is inhomogeneous, and the segment is prominent.

A

B

C

l

Figure 3. Specimen of the Lower Uterine Segment

Showing Endometrial Carcinoma.

Large endometrial-type glands with irregular outlines

(Panel A) are lined by tall cells with abundant cytoplasm,

focal squamous differentiation (arrow), and focal sub-nuclear vacuoles (Panel B, arrow), indicating secretory

change. The nuclei are oval with small nucleoli, mildcytologic atypia, and rare mitoses. The stroma around

the glands is desmoplastic and associated with a promi-nent lymphocytic reaction, with occasional lymphoid

aggregates (Panel C, arrow).




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build a strong case for genetic counseling andgenetic testing, to search for a germ-line muta-tion in a gene associated with HNPCC.

Ms. Devanshi Patel: Obtaining a complete fam-ily history of cancer in the form of a pedigree isthe most important step in determining whetherthere is a hereditary component to the canceroccurring in a family such as this one. We cre-ated a pedigree by identifying all persons in thispatient’s family, along with the types and sites

of the cancer and the age of the family membersat the time of diagnosis of each cancer (Fig. 1).Other phenotypes that may provide additionalclues for delineating a familial pattern of cancercan also be collected. For example, in families with a history of colon cancer, the presence andnumber of adenomatous polyps can help ascer-tain a specific colon cancer syndrome.7

HNPCC is an autosomal dominant disorder, with a penetrance of approximately 80%.6,8,9 The

lifetime risk of colon cancer is up to 80%, that for endometrial cancer in women 40 to 60%, andthat for ovarian cancer approximately 12%.6,10,11 To help to determine whether a family history issuggestive of HNPCC, three sets of guidelineshave been developed: the Amsterdam I criteria,12 the Amsterdam II criteria,13 and the RevisedBethesda criteria (Table 1).14 Using the Amster-dam II criteria, we made a clinical diagnosis of HNPCC in this patient.

We then used genetic testing to help confirmthe diagnosis. Five genes, MLH1, MSH2, MSH6,

PMS1, and PMS2, are known to be involved. Mu-tations in MLH1 and MSH2 account for about 90% of the mutations detected in families withHNPCC; mutations in MSH6 account for 7 to10%, and mutations in PMS2 for less than5%.5,6,11,15,16 This patient was offered two optionsto confirm the diagnosis of HNPCC. The first was a two-part screening test, performed on a

A

B C

l

Figure 4. Specimens of the Ovary and Colon Showing Tumor.

A well-circumscribed nodule (Panel A, arrow) composed of glands lined by atypical cells with scanty clear-to-pinkcytoplasm, with some cells in a hobnail configuration (Panel B, arrow), is seen in the ovary. Between the glands

there is benign ovarian-type stroma. The colonic adenocarcinoma (Panel C) is composed of irregularly distributedcomplex glands invading the submucosa (arrow) associated with a prominent lymphoid infiltrate, including lym-

phoid aggregates (arrowhead).




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paraff in block of a specimen obtained from hercolon, that included microsatellite instability test-ing and immunohistochemical testing. Microsatel-lite instability is an accumulation of genetic altera-tions that are frequently found in tumor samplesobtained from patients with HNPCC. Immunohis-tochemical testing detects the protein products of the different genes in a tumor sample; the absenceof the protein implies that the gene is not func-tioning.15 However, since testing for microsatelliteinstability and immunohistochemical staining can-not identify the specific genetic alteration, whichis important to know in order to identify at-risk family members, we also offered the patient direct genetic analysis.

DR. MICHA EL V. SEIDEN’S

DIAGNOSIS

Multiple neoplasia in a woman with HNPCC (theLynch syndrome).

Pathological Discussion

Dr. Oliva: The endometrial, ovarian, and colonic car-cinomas were tested on immunohistochemicalstaining for the protein products of the mismatch-repair genes MLH1 and MSH2. All three tumorsshowed loss of MLH2 expression (Fig. 5A and 5B),

with preservation of MSH2 expression in normaltissue and normal expression of MLH1 in all tu-mors. Testing for microsatellite instability showedhigh instability in the samples of the endometrialand colonic tumors (Fig. 5C) obtained from thispatient.

Colonic adenocarcinomas associated withHNPCC are more commonly located in the as-cending colon than in the descending or sigmoidcolon, in contrast to the f indings in this patient.These tumors frequently have distinctive histo-pathologic features: they are often poorly differ-entiated, with cribriform, solid, or mucinous arch-itecture.17,18 There is a characteristic lymphoidreaction, resembling Crohn’s disease, character-ized by lymphoid aggregates with an increasednumber of infiltrating CD3+ T lymphocytes.19,20 The tumors are typically diploid,19 of low stage,and are associated with a better prognosis than

conventional colonic carcinomas.21-23

This pa-tient’s tumor had a prominent lymphocytic reac-tion but otherwise did not show the distinctivefeatures of HNPCC-associated cancers.

Similar to the colonic carcinomas, endometrialcarcinoma in patients with HNPCC is often of aggressive histologic subtypes or poorly differen-tiated, is associated with a Crohn’s disease–likelymphoid reaction, as seen in this case, andshows lymphovascular invasion more often than

Table 1. Clinical Criteria for the Diagnosis of Hereditary Nonpolyposis Colon Cancer.

Amsterdam I criteria Three or more relatives with colorectal cancer in the family.One is a first-degree relative of the other two patients.Two or more generations are involved.One colorectal cancer has to be diagnosed in the patient by the age of 50 years.Familial adenomatous polyposis has to be excluded.

Amsterdam II criteria Three or more relatives with colorectal cancer or HNPCC-related cancers in the family.*

One is a first-degree relative of the other two.Two or more generations are involved.One cancer related to colorectal cancer or HNPCC has to be diagnosed in a patient by the age of 50 years.Familial adenomatous polyposis has to be excluded.

Bethesda criteria Tumors should be tested for microsatellite instability in the following situations:Colorectal cancer diagnosed in a patient who is less than 50 years of age.Presence of synchronous, metachronous colorectal, or other HNPCC–associated tumors, regardless of the

patient’s age.Colorectal cancer with the histologic features of microsatellite instability† diagnosed in a patient who is less

than 60 years of age.Colorectal cancer or an HNPCC-associated tumor diagnosed in one or more first-degree relatives, with one

cancer diagnosed at less than 50 years of age.Colorectal cancer or HNPCC-associated tumor diagnosed at any age in two first-degree or second-degree

relatives.

* Cancers related to hereditary nonpolyposis colon cancer (HNPCC) include colorectal, endometrial, gastric, ovarian, ureter or renal, pelvic,biliary tract, small bowel, pancreatic, brain (gliomas), and skin cancers (sebaceous adenomas).† Histologic features associated with tumors showing high degrees of microsatellite instability include the presence of tumor-infiltrating lympho-

cytes, Crohn’s disease–like lymphocytic reaction, mucinous or signet-ring differentiation, or a medullary growth pattern.




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does endometrial carcinoma in patients without HNPCC.24-29 HNPCC-related endometrial carcino-ma is associated with mutations in both the MSH2 and MSH6 genes.30,31 Even hyperplastic endome-trium may show altered expression of MLH1 andMSH2 mismatch-repair genes, indicating that lossof the MMR genes may be an early event in tumor-igenesis in patients with HNPCC.32

Finally, the vast majority of HNPCC-relatedovarian tumors are carcinomas, with borderlinetumors representing only 4% of epithelial tu-

mors.33

Among the carcinomas, the more fre-quent histologic subtype is serous carcinoma,followed by the endometrioid, mucinous, andclear-cell subtypes, with a distribution of survival similar to that seen in the general popula-tion. To my knowledge, clear-cell adenofibromashave not been reported in this syndrome.

Ms. Patel: Additional immunohistochemicaltesting for MSH6 and PMS2, performed at the MayoMedical Laboratories, showed that the tumorsample from this patient also failed to express

l

A

C

MLH1 B MSH2

Microsatellite Instability Status

100020003000

090 110 130 150

40005000

100020003000

0

40005000

100020003000

0

40005000

Colon Adenocarcinoma DNA

Germline DNA

Endometrial Adenocarcinoma DNA

Size (in base pairs)

90 110 130 150

90 110 130 150

R e l a t i v e

F l u o r e s c e n c e

R e l a t i v e


R e l a t i v e


*

129 Base pairs

Figure 5. Testing of the Tumors for Evidence of Abnormalities in the DNA Mismatch-Repair Pathway.

The endometrial cancer shows preserved MLH1 immunohistochemical expression (Panel A) with loss of MSH2 IHCexpression (Panel B). Similar results were obtained with specimens of the ovarian and colonic malignant tumors (see

figure in the Supplementary Appendix, available with the full text of this article at www.nejm.org). The endometrialand colonic carcinomas show microsatellite instability (Panel C) for all five microsatellites tested (BAT25, BAT26,

D17S250, D5S346, and D2S123); the mononucleotide microsatellite locus BAT25 is shown. The upper electrophero-gram shows the peak size of the BAT25 germ-line allele (129 bp). Arrows indicate new BAT25 allele peaks in the colon

tumor DNA (middle panel) and endometrial tumor (lower panel). Even though the degree of microsatellite instabilityis higher in the colonic tumor, both tumors show patterns of BAT25 allele peaks that would qualify as unstable.

(Panel C images courtesy of Dr. Anthony John Iafrate, Department of Pathology, Massachusetts General Hospital.)




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MSH6. The results of these screening tests con-firmed that the patient had HNPCC. Direct genetictesting of peripheral-blood leukocytes revealed agerm-line mutation 942+3A→T in the MSH2 gene.

Dr. Seiden: Have other family members beentested?

Ms. Patel: The mother has been tested and does

have the mutation. The patient’s two sisters areinterested in pursuing genetic testing.

Discussion of Management

Dr. Seiden: The genetic testing confirms the diag-nosis of HNPCC. Several issues deserve consider-ation. First, what is the prognosis for this woman with three different neoplasms associated with agerm-line mutation in MSH2? Second, are thereany specific recommendations for her care? Andfinally, what recommendations can be made for

family members at risk for being carriers of themutation?

Recommendations for a Patient with HNPCC

First, the data suggest that the prognosis for pa-tients with HNPCC syndrome and uterine or coloncancer is at least as good as that for patients withsporadic colonic or uterine cancer.34,35 However, women with HNPCC mutations require close fol-low-up for new cancers. Thus, the short-term rec-ommendations for clinical care should be the sameas those for patients with sporadic tumors of similar stage. This woman had a bilateral stage IBovarian clear-cell adenofibroma of borderline ma-lignancy that was likely to be cured with resec-tion36; a stage IB, grade 1 endometrial carcinoma;and a Dukes’ stage B1, grade 2 colon cancer. Boththe endometrial tumor and the colon tumor havean estimated 10-year disease-free survival rate inexcess of 80 to 85% without adjuvant therapy;there are no compelling data that adjuvant therapy for either of these cancers will substantially im-prove her likelihood of long-term survival. Indeed,

the greatest risk for this woman is the develop-ment of a second colon cancer, and therefore sur- veillance colonoscopy, performed at least every other year, would be advisable.

Recommendations for Family Members

of Patients with HNPCC

The patient’s mother, two sisters, four nieces,maternal aunt, and maternal first-degree cousinare all at risk for carrying the MSH2 mutation.The fact that the proband has a precisely defined

germ-line mutation in MSH2 simplifies and reduc-es the cost of evaluating DNA from her relatives,if they should choose to undergo testing. Untilrecently, one of the barriers to testing was thelimited data supporting its value and that of pro-phylactic surgery. Some of these issues have beendefined in a retrospective study of a large cohort

of carriers of HNPCC recently published in the Journal.37

In that study, elective resection of the ovariesand uterus was 100% effective in eliminating therisk of cancer of the ovaries and uterus; uterinecancer developed in 33% of the women who wereobserved, and ovarian cancer developed in 5.5%.Both cancers began to appear in women as youngas 35 to 40 years of age, with the incidence of uterine cancer increasing with age. Whereas themajority of the uterine cancers were confined tothe uterine corpus (stage 1), about half the ovar-

ian cancers were at an advanced stage.37 This andother studies have found that the primary gyne-cologic cancer (either uterine or ovarian cancer)predated the primary tumor in the colon in about 50% of women in whom dual primary cancerseventually developed.38 In women choosing pro-phylactic removal of the uterus and ovaries, theincidence of death was 5%, with all deaths fromcancer, as compared with 9% among womenchoosing observation.37

In summary, this woman presented with threeneoplasms, all probably associated with a germ-line mutation in the MSH2 gene. The diagnosis of her MSH2 mutation has implications for her fam-ily members, who should be urged to undergogenetic testing or frequent colonoscopy. Affectedfemale members of the family who have com-pleted childbirth should be informed of the po-tential benefits of prophylactic hysterectomy andoophorectomy.

Dr. Nancy Lee Harris (Pathology): Dr. Goodman,do you have any follow-up?

Dr. Annekathryn Goodman (Gillette Center for

Women’s Cancers): Six weeks after the operation,the patient was taken back to the operating room.Sigmoidoscopy disclosed a polyp at 18 cm; intra-operative examination of a frozen section showedinvasive adenocarcinoma arising in an adenoma.A sigmoid colectomy was performed, and thecolon was reanastomosed. Repeated sigmoido-scopic examination 6 months later disclosed atubular adenoma. She has been advised to con-sider a prophylactic colectomy. She has not electedto proceed with this and is being followed with




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annual endoscopies. She was well 2 years afterthe initial operation, without evidence of recur-rence of any of the cancers or new colon polyps.She did not receive adjuvant therapy.

A Physician: Would you suggest that patients whodo not want to undergo hysterectomy have yearly ultrasound studies and endometrial biopsies?

Ms. Patel: For patients who do not elect prophy-lactic surgery, annual transvaginal ultrasonogra-phy and endometrial biopsies, alternating every 6 months, starting when the patients are 25 to 30 years of age is typically recommended. This patient was also referred to a dermatologist for regularfollow-up because of the association between MSH2 mutations and sebaceous adenomas of the skin.

Anatomical Diagnosis

The Lynch syndrome (HNPCC) with a mutation inthe MSH2 gene, endometrioid adenocarcinoma of the uterus, clear-cell adenofibromas of borderlinemalignancy of the ovaries, and two adenocarcino-mas of the colon.

Dr. Seiden reports receiving laboratory research support fromPharmamar and Fujirebio, clinical trial support from Berlex, Fre-senius Biotech, Novellos, and CuraGen, and consulting fees fromEli Lilly, EMD Pharmaceuticals, Genitrix, ImmunoGen, EMD Se-rono, Telik, and Reishi Pharmaceutical; and Dr. O’Neill, receivingconsulting fees from GE Medical Systems and lecture fees fromPhilips Ultrasound. No other potential conflict of interest relevant to this article was reported.

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Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences

Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or referencematerial is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of theimages from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of theCase Record.

The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail [email protected].



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