ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 24, No. 5Copyright © 1994, Institute for Clinical Science, Inc.

Medullary Thyroid Carcinoma Metastatic to Breast Masquerading as Infiltrating Lobular Carcinoma*SYED Z. ALI, SAUL TEICHBERG, Ph.D.,tJOSEPH N. ATTIE, M.D.§ and MYRON SUSIN, M.D.t

Division o f Surgical Pathology, Department o f Laboratories,tDepartment o f Pediatrics,t

and Department o f Surgery,§ North Shore University H ospital-

Com eli University Medical College, Manhasset, NY 11030

ABSTRACTMetastatic tumors to the breast from an extramammary site are rare enti­

ties and may present diagnostic difficulties for the surgical pathologist because of frequent histological similarities to primary neoplasms in this location. A case is reported of medullary thyroid carcinoma metastatic to the breast in a 28-year-old woman with a family history of MEN IIA (Sip- ple’s) syndrome. Histological features resembled infiltrating lobular carci­noma and included the so-called “targetoid” and “Indian file” patterns. Immunostaining revealed the true nature of the lesion and was diffusely positive for calcitonin, chromogranin, and carcinoembryonic antigen. Elec­tron microscopy disclosed typical neurosecretory granules confirming the diagnosis. A brief review of the literature and differential diagnosis is also presented.

IntroductionMetastatic tumors to the breast account

for 0 .8% to 6 .6% of all breast malignan­cies.1,2 In almost one-third of the cases, the metastatic focus represents the initial clinical presentation of an occult primary, usually a carcinoma,3 although more fre­quently it is a sign of widespread dis­semination of the tumor.1 Metastatic car­cinoma from the opposite breast is the

* Address reprint requests to: Myron Susin, M.D., North Shore University Hospital—Cornell Univer­sity Medical College, 300 Community Drive, Man­hasset, NY 11030.

commonest secondary tumor to the breast in females as opposed to hematopoietic tumors (lymphomas and leukemias) and prostate carcinoma which are the com­monest metastatic tumors to the male breast.1,2,4 In addition to these, meta­static disease has been associated with malignant melanoma,1,5,6,7,8 lung carci­noma (oat cell type in particular),1,6,8,9 renal cell carcinoma, gastrointestinal car­cinoma,5,6 thyroid (papillary and follicu­lar carcinomas),6,10 carcinoids,11,12,13,14 ovarian carcinoma ,3,5,8,15 endom etrial carcinoma, pancreatic carcinom a ,5 as well as hepatoma and neuroblastoma.8 In children rhabdomyosarcoma,16 medullo-

4410091-7370/94/0900-0441 $01.20 © Institute for Clinical Science, Inc.

4 4 2 ALI, TEICHBERG, ATTIE, AND SUSIN

blastoma and glioblastoma17,18 have been reported. A case of metastatic medullary thyroid carcinoma to the breast diag­nosed in fine needle aspirate has been reported ;19 to our knowledge, the cur­rent study is the first report of medullary thyroid carcinom a m etastatic to the breast with a description of histological, immunohistochemical, and ultrastruc- tural features.

Case ReportA 28-year-old female was admitted to North Shore

University Hospital for the evaluation and treat­m ent of a right breast lump which was noted by her a few weeks prior to admission. Past medical history was significant for a diagnosis of MEN IIA (Sip- p le’s) syndrome and for m ultiple surgical proce­dures. In January, 1988, she presented with a thy­roid lump and underw ent a total thyroidectomy for a multifocal and bilateral medullary thyroid carci­noma with positive right paratracheal lymph nodes. H er postoperative calcitonin dropped but never reached normal limits, and a month later she was readmitted for a palpable node in the right neck. She underw ent a right modified neck dissection w ith m etasta tic m edu llary carcinom a in n ine regional lymph nodes. Again her postoperative cal­citonin levels remained elevated, and she was read­m itted six months later. Although no nodes were felt at this time, she underw ent an elective left modified neck dissection again with positive lymph nodes. Her calcitonin level returned to normal post- operatively. Fam ily history was significant for MEN IIA syndrome in the patient’s father, sister, and daughter.

During the current admission in June, 1993, a sonogram of the breast showed a w ell circum­scribed solid mass thought to be a fibroadenoma vs breast carcinoma. She underw ent a lumpectomy with removal of a 1 cm nodular mass. Frozen sec­tion showed a carcinoma with an infiltrating pat­tern. P ertinen t laboratory findings at that time included a mildly elevated calcitonin level. She had an uneventful postoperative recovery.

Materials and Methods L i g h t M ic r o s c o p y

Specimen was fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 4 microns, and stained with hematoxylin and eosin.

IMMUNOHISTOCHEMISTRY

Sections were cut at 3 microns, depar- affinized in xylene, rehydra ted and quenched in methanol with 4% hydrogen peroxide for twenty minutes. Slides were incubated with primary antibody over­night at 4°C. L abelled avidin biotin method was used, and immunostaining was demonstrated with diaminobenzi- dine-hydrogen peroxide reaction and counterstained with Gill’s III hematoxy­lin. All antibodies were used with appro­priate controls.

E l e c t r o n M i c r o s c o p y

Form alin-fixed paraffin em bedded tumor, in the breast, was rehydrated, post fixed in buffered 1% osmium tetroxide, buffered with 0.1 M cacodylate (pH 7.3), stained en bloc with uranyl acetate, dehy­drated in a graded series of ethanols, and embedded in effapoxy resin. One micron plastic sections were stained with tolu- idine blue. Thin sections were stained with uranyl acetate and lead citrate and examined on a JOEL JEM 100 CXII elec­tron microscope.

Results

M o r p h o l o g i c a n d I m m u n o h i s t o c h e m i c a l F i n d in g s

Grossly, the specimen was a tan-grey n odu le , w ell c ircu m scrib ed w ith a smooth pale white cut surface, and a maximum diameter of 1 cm. Light micro­scopic studies showed a well circum­scribed tumor with a histologic pattern resem bling infiltrating lobular carci­noma. The predominant feature was the typical “ ta rg e to id ” or “ b u ll’s ey e” arrangement of small to interm ediate

MEDULLARY THYROID CARCINOMA METASTATIC TO BREAST 4 4 3

sized uniform cells with hyperchromatic nuclei and scanty amount of amphophilic cytoplasm. This pattern was character­ized by the formation of the concentric rings around residual mammary ducts (figure 1).

In addition, the classical pattern of individual malignant cells arranged in single files or so called “Indian file” with intervening strands of thick collagenous stroma was also seen in areas (figure 2). Also noted were areas in which tumor cells formed distinct lobular structures as well as more solid nodules. No organoid architecture was noted, and none of the re s id u a l m am m ary ducts or lo b u les showed an in situ component. Spindle cells and extracellular amorphous mate­rial resembling amyloid were also absent from the lesion, and congo red stain was negative. Immunohistochemical studies were done (figure 3) and are summarized in table I.

Sections from the thyroidectomy spec­imen with the primary medullary carci­nom a w ere rev iew ed and show ed a variegated histological pattern consisting predominantly of nests of uniform angu- lated or spindly cells (figure 4) admixed with round or oval cells within a delicate fibrovascular stroma which, in places, c o n ta in e d m asses o f h o m o g en eo u s eosinophilic material which was strongly congophilic, consisten t w ith am yloid deposits. Multifocal capsular and vascu­lar invasion were present.U l t r a s t r u c t u r a l F i n d i n g s

By electron microscopy, the cytoplasm of the tumor cells contained variable numbers of relatively small, round, dense core granules (figure 5). There was also a w ell deve lop ed , rough endo p lasm ic reticulum, clusters of intermediate fila­ments, and lysosomes.

FIGURE 1. M e d u lla ry th y ro id c a rc in o m a m e ta s ta t ic to b re a s t . A c e n tra l m a m m a ry d u c t is s u r r o u n d e d c irc u m fe r e n t ia l ly b y in te r m e d ia te s iz e d tu m o r c e l ls g iv in g a ‘t a rg e to id ’ a p p e a ra n c e (h e m o to x y lin & e o s in xlOO).

444 ALI, TEICHBERG, ATTIE, AND SUSIN

FIGURE 2. Medullary thyroid carcinoma metastatic to breast. Collagenous mammary stroma with col­umns of tumor cells forming ‘Indian files’ (hemotoxylin & eosin x200).

F i g u r e 3. Medullary thyroid carcinoma metastatic to breast. Tumor cells with strong immunostaining for calcitonin. A mammary duct with negative staining is seen at the top of the picture (calcitonin X200).

MEDULLARY THYROID CARCINOMA METASTATIC TO BREAST 4 4 5

TABLE I

Summary of Immunohistochemical Findings

Antibody Source Dilution Staining Result

Calcitonin Dako, Carpinteria, CA 1:2,000 +++CEA (monoclonal) Biogenex, San Ramon, CA Prediluted ++Chromogranin Boehringer-Mannheim, Indianapolis, IN 1:10,000 +++

CEA = carcinoembryonic antigen.

DiscussionM etastatic tumors to the breast present

p erp le x in g d ia g n o stic p rob lem s both from the clin ical as w ell as h istological p oin ts o f v iew . A ccurate d iagn osis o f m etastatic lesions is important to avoid unnecessary, radical surgical procedures and to assu re appropriate ad ju n ctive therapy.1,14 There are no reliable clinical

criteria for d is t in g u ish in g a prim ary tumor from a secondary tum or in the breast. H ow ever, a superficial, sharply circum scribed solitary mass w h en noted in the upper-outer quadrant, esp ecia lly if attached to the overlying skin, or multi- nodular m asses in the superficial tissues o f the breast should raise the question of a m etastatic le s io n .1,2,14 M ammography may show nodular lesions w ith diffuse

F i g u r e 4 . M e d u lla ry th y ro id c a rc in o m a . P r im a ry tu m o r s h o w in g n e s ts o f u n ifo rm sp in d ly c e l ls w ith m u l t ip le a m y lo id d e p o s i ts in th e s tro m a (h e m o to x y lin & e o s in x 100).

4 4 6 ALI. TEICHBERG. ATTIE, AND SUSIN

F i g u r e 5. Electron micrograph of a portion of a metastatic tumor cell showing several round dense core granules (arrow). Nucleus is at N. Bar equals 1 micron x 28,500.

thickening o f the skin15 and absence of spiculations or m icrocalcification.3 H isto­logical features w hich may b e suggestive o f metastatic d isease include a periductal or perilobular distribution in the absence o f any in s itu ductal or lobular com po­nent. There is m inim al elastosis and des- m oplasia associated with these lesion s.4 F in a l co n firm a tio n u su a lly req u ires im m u n o h isto ch em ica l and ultrastruc- tural studies to establish the d iagnosis o f metastasis.

F ine n eed le aspiration b iopsy can also play an important role in identify ing a su sp ected m etastatic n eop lasm in the breast. E specia lly w hen com bined with im m u n ocytoch em istry , th e sen s it iv ity

and diagnostic capability o f this process is further enhanced and is extrem ely u se­ful in d ifferentiating secondary m alig­nancies o f the organ.8,19

The current case report exem p lifies som e of these difficulties because o f the h isto lo g ic sim ilarity o f the m etastatic medullary thyroid carcinoma to a primary infiltrating lobular carcinoma o f the breast, ow in g to a p rom inen t p erid u cta l and perilobular distribution o f the neoplastic cells. W hen faced with such a situation at the tim e o f intraoperative consultation, it is prudent to defer the final diagnosis, aw aitin g the resu lts o f im m u n oh isto ­chem ical or ultrastructural studies. The n eed for good com m unication b etw een the surgeon and the surgical pathologist in these cases cannot be over-emphasized.

Most o f the metastatic tumors in breast have been described in younger or mid- dle-aged w om en, perhaps b ecau se the better b lood supply in this age group encourages blood-borne m etastasis, the most frequent m ode o f cancer spread to this organ.9 Overall prognosis o f these ca ses is u su a lly grave w ith ap p rox i­mately 90% of the patients dying within

AcknowledgmentOur gratitude is expressed to Gladys Seiden for

her excellent secretarial assistance.

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