Indian Primary Hyperparathyroidism Patients with Parathyroid Carcinoma do not Differ in...

Indian Primary Hyperparathyroidism Patientswith Parathyroid Carcinoma do not Differ inClinicoinvestigative Characteristics from Thosewith Benign Parathyroid PathologyGaurav Agarwal, MS, DNB, PDC,1 Kaushal K. Prasad, MD, PDC,2 Dilip K Kar, MS, PDC,1

Narendra Krishnani, MD,2 Rakesh Pandey, MD,2 Saroj K. Mishra, MS, FACS1

1Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow

226014, India2Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014,

India

Abstract

Introduction: No foolproof preoperative diagnostic indicators of parathyroid carcinoma (PC) exist in

absence of nonskeletal metastases. Palpable parathyroid tumor, advanced skeletal and renal

manifestations, and very high serum calcium and parathyroid hormone levels are considered

strong predictors. Most of these features are common in Indian primary hyperparathyroidism

(PHPT) patients although only few have PC. The aim of this study was to identify dependable

clinicoinvestigative predictors of PC in Indian PHPT patients.

Materials and Methods: Clinical, biochemical, radiological, and densitometric attributes of 100

PHPT patients who underwent successful parathyroidectomy (1990–2004) were studied. Various

parameters of patient groups with parathyroid adenoma (n = 84), primary hyperplasia (n = 12),

and carcinoma (n = 4) were compared using ANOVA, with P value < 0.05 considered significant.

Results: Mean age of patients was 37.4 years, with no difference in the 3 groups (P = 0.92).

Patients in 3 groups had comparably severe bone disease; 36 had coexistent renal disease. Two

patients with PC and 27 (32%) with adenoma had palpable parathyroid tumor. None of the bio-

chemical parameters predicted malignant pathology. Mean tumor weight (milligram) in carcinoma

patients (15,080 – 5,638.02) was significantly higher than those with adenoma (5,724 – 1,257.9)

(P = 0.002). Postoperative course and recovery in carcinoma patients were similar to those with

adenoma. In follow-up (mean: 33 months), none of the adenoma patients were found to have

persistent/recurrent PHPT attributable to missed PC.

Conclusion: Indian patients with parathyroid adenoma, hyperplasia, and carcinoma were not found

to differ in their clinical, biochemical, and pathological characteristics except for significantly higher

tumor weight in the carcinoma group.

Parathyroid carcinoma (PC) is a rare cause for pri-

mary hyperparathyroidism (PHPT), accounting for

less than 2% of all PHPT cases,1–3 although the rela-

tive incidence is reported at 4%–8% from developing

Correspondence to: Gaurav Agarwal, MS, DNB, PDC, AssociateProfessor Department of Endocrine Surgery, Sanjay Gandhi Post-graduate Institute of Medical Sciences, Raebareli Road, Lucknow226014, India, e-mail: gaurav@ sgpgi.ac.in

� 2006 by the Societe Internationale de Chirurgie World J Surg (2006) 30: 732–742

Published Online: 17 April 2006 DOI: 10.1007/s00268-005-0366-5

countries, as also in early reports from the developed

world.4–7 In absence of apparent nonskeletal metastatic

disease, it is difficult to establish the diagnosis of PC, and

the diagnosis is rarely evident preoperatively.8 Radical

surgical excision of a PC along with any infiltrated struc-

tures and metastatic lymph nodes provides the best, and

perhaps the only chance of long-term cure in these pa-

tients.9 In order to cure hyperparathyroidism and achieve

adequate oncological control of this disease, it is imper-

ative that the condition be identified before or during the

operation and dealt with appropriately at the time of the

primary surgery.1,9,10

Various clinical and investigative features, such as

palpable parathyroid tumor, symptomatic skeletal mani-

festations, osteitis fibrosa cystica (OFC) (especially when

these coexist with renal manifestations), very high serum

calcium (s-Ca) and parathyroid hormone (s-PTH) levels,

and large tumors are considered predictive of the pres-

ence of PC.1,9,10 However, no foolproof preoperative

diagnostic criteria are known. Even on histology, diag-

nosis may at times be difficult although a set of criteria

proposed by Shantz and Castleman 11are widely

followed.

Indian PHPT patients present at a relatively young

age with symptomatic disease. The majority of patients

have OFC, extreme osteopenia (syndrome of disap-

pearing bones), and some are crippled due to fractures,

brown tumors, and muscle weakness (parathyroid crip-

ples). Renal manifestations are common and are often

present simultaneously with bone disease. Many have a

palpable parathyroid tumor and extremely high s-PTH

levels.4,5 In spite of these clinical, biochemical, radiolog-

ical, and pathological features commonly used to indicate

possible presence of malignant parathyroid tumors, fewer

than 5% of Indian PHPT patients are diagnosed with PC.

Doubts may thus be raised about the applicability of these

criteria for prediction of parathyroid malignancy. The

current study aimed at comparing clinical and laboratory

parameters of Indian PHPT patients with benign and

malignant parathyroid tumors in order to identify predic-

tive features of PC.

MATERIALS AND METHODS

Primary hyperparathyroidism patients managed at the

Department of Endocrine Surgery, Sanjay Gandhi Post-

graduate Institute of Medical Sciences (SGPGIMS),

Lucknow, India from 1990 to 2004 were the subjects of

this study. The patients were divided into groups A

(parathyroid adenoma, n = 84), B (primary parathyroid

hyperplasia, n = 12), and C (parathyroid carcinoma,

n = 4). The diagnosis of parathyroid adenoma, hyper-

plasia, or carcinoma were made on the basis of para-

thyroid imaging, operative findings, and gross and

microscopic pathology reported by two pathologists

independently using established criteria,12–14 and follow-

up.

Parathyroid adenoma diagnosis was based on locali-

zation of a single pathological parathyroid gland (PTG) on99mTc-MIBI scanning (or Tl-Tc subtraction scans before

1999) and high-resolution ultrasonography and finding of

a parathyroid tumor in the predicted location during fo-

cused or minimally invasive parathyroidectomy, with

gross and microscopic pathology consistent with an

adenoma. In earlier years of the study, when preoperative

parathyroid imaging was not routinely employed, and in a

few recent patients with inconclusive parathyroid imaging,

diagnosis of parathyroid adenoma was based on the

finding of a single pathological and three normal PTGs at

bilateral neck exploration and if the removed pathological

PTG had gross and microscopic features consistent with

an adenoma. The diagnosis of double adenoma and

primary parathyroid hyperplasia were based on findings

at bilateral neck exploration and gross and microscopic

pathology. Operative findings of large, grayish-white,

firm-to-hard tumor with infiltration into surrounding mus-

cles and visceral structures were considered indicative of

PC, and such patients were treated with an en bloc

resection of parathyroid tumor together with infiltrated

structures.

Histopathological diagnosis was based on weight and

histological findings of the excised parathyroid tissues.

Hyperplasia was diagnosed when histopathological cri-

teria of adenoma were absent and multiple glands were

enlarged (weight: >59 mg) and had abnormal microscopic

appearance with decreased fat-cell content together with

pathologic arrangement and reduced cytoplasmic fat

content of the parenchymal cells.12,13 Diagnosis of PC

was made on the basis of gross and microscopic

pathology.11,14 Following parathyroidectomy, patients

were followed up for a minimum of 1 year with periodic s-

Ca and intact PTH estimations and appropriate imaging

so as to ensure they did not have metastatic disease,

which would have changed the diagnosis from adenoma

or hyperplasia to carcinoma.

Information on clinical, biochemical, radiological, den-

sitometric, and pathological features of patients in groups

A, B, and C were derived from a prospectively main-

tained parathyroid data base at the Department of

Endocrine Surgery. Biochemical evaluation included se-

rial estimation of s-Ca, inorganic phosphorus (s-iP),

Agarwal et al.: Hyperparathyroidism in Indians 733

alkaline phosphatase (s-ALP), creatinine, s-iPTH, and

25-hydroxy vitamin D (s-25-OH-D). Calcium and creati-

nine excretions in 24-hour urine collections were also

sampled. X-rays of the hands, skull, pelvis, spine, and

any fracture or brown tumor sites of patients in groups A,

B, and C were compared. Bone mineral densitometry

(BMD) using dual-energy X-ray absorptiometry (DEXA)

was carried out before and after parathyroidectomy and

during follow-up. Weight of pathological parathyroid tis-

sue in the 3 groups was compared. Values are presented

as mean – standard error (SE). Values of various bio-

chemical indices, clinical symptoms, and PTG weight

were compared using one-way analysis of variance

(ANOVA), with P value <0.05 considered significant.

RESULTS

Mean patient age was 37.4 – 7.04 years (range: 13–66

years), with no significant difference between the 3

groups (P = 0.92). There were 73 females and 27 males

(male/female ratio: 1:3). Comparison of the clinical attri-

butes of patients in the 3 groups is provided in Table 1.

None of the patients were truly asymptomatic; all but 3

presented with symptoms attributable to PHPT and its

complications. Hypercalcemia was detected in 3 patients

during evaluation for unrelated symptoms in 1 and on

periodic health check-ups in 2. On careful scrutiny,

however, all 3 were found to have musculoskeletal

symptoms attributable to PHPT together with osteopenia

and low BMD. Six patients presented with hypercalcemic

crisis, of whom 4 were found to have a parathyroid ade-

noma and 1 each PC and hyperplasia. The average

duration of symptoms in all 100 patients was 4.0 years

(range: 6 months–26 years), with no significant difference

between the 3 groups.

Skeletal manifestations were the commonest clinical

presentation, with all patients having bone pains, and 60

proximal muscle weakness. As a result of osteopenia,

pathological fractures, and proximal muscle weakness, 27

patients were confined to bed. Though the proportion of

such ‘‘parathyroid cripples’’ in the PC group was higher,

this difference was not statistically significant (P value

0.078). Renal involvement was present in 36 patients: 14

had nephrocalcinosis, 27 nephrolithiasis, and 5 had both.

Concomitant skeletal and renal manifestations occurred

with comparable frequency in the 3 patient groups. Psy-

chiatric manifestations in 38 and gastrointestinal symp-

toms in 14 occurred with comparable frequency in the 3

groups. Parathyroid tumors were palpable in the neck in

29 of the 88 patients with PHPT due to parathyroid tu-

mors. These included, besides two (50%) patients with

PC, 27 (32%) parathyroid adenoma patients as well, (no

significant difference, P-value = 0.238).

Table 2 depicts biochemical features in PHPT patients

in the 3 groups. The mean s-Ca and s-iP were not sig-

nificantly different in the 3 groups (P = 0.634 and 0.329,

respectively), nor were the mean s-ALP and s-iPTH lev-

els (P = 0.083 and 0.154, respectively). The s-25-OH-D

levels were also not significantly different in the 3 groups

(P = 0.662). PHPT patients with adenoma, hyperplasia,

and carcinoma had equally severe bone disease, as

evidenced by comparable BMDs and z-scores assessed

by DEXA (Table 3). Forty-nine patients had brown tu-

mors, and 56 had pathological fractures, and these were

not predictive of type of parathyroid pathology. Compar-

ison of qualitative radiological features did not reveal

significant difference between the 3 groups (Figs. 1 and

Table 1.Clinical features of primary hyperparathyroidism patients with parathyroid adenoma, hyperplasia, and carcinoma

Group Aa Group Bb Group Cc P-value

Age (years): mean (range) 36.8 (14–66) 38.9 (13–50) 37.0 (22–56) 0.92Male: female ratio 1:4 1:3 1:3 0.311Duration of symptoms (years) 3.5 (0.5–26) 8.0 (3–20) 2.5 (0.5–6) 0.154Bone pain 84 (100%) 12 (100%) 4 (100%) 0.590Proximal muscle weakness 49 (58.3%) 7 (58.3%) 4 (100%) 0.065Crippling 20 (23.8%) 4 (33.3%) 3 (75%) 0.078Concomitant skeletal and renal manifestations

(renal stone/nephrocalcinosis)30 (35.7%) 4 (33.3%) 2 (50%) 0.076

Behavioral disorders 33 (39.2%) 5 (41.6%) 2 (50%) 0.192Gastrointestinal symptoms 11 (13.1%) 2 (16.7%) 1 (25%) 0.188Palpable parathyroid tumor/ gland 27 (32.1%) None 2 (50%) 0.238

aParathyroid adenoma (n = 84).bPrimary parathyroid hyperplasia (n = 12).cParathyroid carcinoma (n = 4).dSignificant P value < 0.05.

734 Agarwal et al.: Hyperparathyroidism in Indians

2). Of the 7 patients with ‘‘disappearing bones’’ syndrome

(Figure 3), 5 had adenoma and 2 had carcinoma.

Forty-two patients were scheduled to have a minimally

invasive or focused parathyroidectomy and the rest a

bilateral neck exploration. Of the 42 undergoing minimally

invasive parathyroidectomy, 4 had the procedure con-

verted to bilateral exploration due to suspicion of multi-

gland disease in 3 and failure to find a tumor in the

location predicted on preoperative parathyroid imaging in

1. During the operation, presence of a large, hard, gray-

ish-white tumor invading the thyroid lobe, strap muscles,

or other surrounding structures led to a suspicion of PC in

6 patients. These were subjected to en bloc resection of

parathyroid tumor along with infiltrated structures. Two of

these were, however, diagnosed as adenomas based on

histology. In follow-up of 3 and 4.5 years, both these

patients have remained free of tumor recurrence, thus

vindicating the diagnoses of adenoma.

Postoperative hypocalcemia occurred in 94 patients

and was managed with calcium carbonate and calcitriol

supplements, with 83 requiring intravenous calcium infu-

sion. One patient had persistent hyperparathyroidism

attributed to a missed parathyroid adenoma at the initial

operation. During follow-up (mean: 33 months; range: 6–

136 months), 2 patients with parathyroid adenoma pre-

sented with recurrent hyperparathyroidism, one due to a

missed second adenoma and the other due to asym-

metrical parathyroid hyperplasia. Three of the 4 PC pa-

tients had local recurrence and/or metastases during

follow-up. One had intracranial metastases and suc-

cumbed to neurological and metabolic consequences

after 39 months of follow-up. Another died after 24

months with end-stage renal disease a few months after

detection of recurrence in the contralateral thyroid lobe

and neck nodes confirmed on cytology. Two patients are

alive and free of disease at 16 months and 9 years of

follow-up although the latter had a recurrent but asymp-

tomatic subcutaneous nodule not resulting in recurrent

hyperparathyroidism along the fine-needle aspiration

cytology (FNAC) track of the primary tumor 64 months

Table 3.Radiological features and parathyroid weights of primary hyperparathyroidism patients with parathyroid adenoma, hyperplasia, and

carcinoma

Group Aa Group Bb Group Cc P-valued

Mean BMD at distal radius (gm/cm2)/ z-score 0.426 / )3.8 0.542 / )3.3 0.388 / )4.4 0.121Radiological features of osteitis fibrosa cystica 72 (85.7%) 9 (75%) 4 (100%) 0.34Pathological fractures 48 (57.1%) 5 (41.7%) 3 (75%) 0.183Brown tumors 39 (46.4%) 6 (50%) 4 (100%) 0.067Tumor/PTG weight (mg) mean – S.D. 5,724 – 1,257.9 3,108e – 1,129.3 15,080 – 5,638.02 0.02*

BMD: bone mineral density; PTG: parathyroid gland.aParathyroid adenoma (n = 84).bPrimary parathyroid hyperplasia (n = 12).cParathyroid carcinoma (n = 4).dSignificant P value < 0.05.eCombined. PTG weight of the excised, abnormal parathyroid tissue.*Statistically significant difference.

Table 2.Biochemical features in primary hyperparathyroidism patients with parathyroid adenoma, hyperplasia, and carcinoma

Group Aa Group Bb Group Cc P-valued

Serum calcium (mean, mg/dl) (Normal range: 8.2–10.5) 12.6 12.3 13.2 0.634Serum inorganic phosphorus (mean, mg/dl) (Normal range: 3.5–5.5) 2.8 2.3 2.1 0.329Serum alkaline phosphatase (mean, IU/l) (Normal <135) 1789.3 2872.4 673.8 0.083Serum parathyroid hormone (mean, pg/ml) (Normal range: 9–55) 683 728 922 0.154Serum 25-OH vitamin D (mean, ng/dl) (Normal range: 9–45) 11.6 7.5 12.1 0.662

aParathyroid adenoma (n = 84).bPrimary parathyroid hyperplasia (n = 12).cParathyroid carcinoma (n = 4).dSignificant P value <0.05.


after the initial operation. None of 3 adenoma patients

found to have persistent/recurrent PHPT have been

attributed to an overlooked PC.

Mean parathyroid tumor/PTG weight (milligram) in

patients with carcinoma (15,080 – 5,638.02) was signifi-

cantly higher when compared with adenoma (5,724 –

Figure 1. Radiograph of both hands of a patient with parathyroid adenoma showing subperiosteal bone resorption.

Figure 2. Radiograph of both knees of a young patient with primary parathyroid hyperplasia showing brown tumors at lower end ofright femur and upper end of left tibia.


1,257.9) and hyperplasia (3,310 – 655.84) (P = 0.002).

Histopathologically, in all cases of parathyroid hyperpla-

sia and carcinoma, the cells were predominantly dis-

posed in solid sheets with intervening thin sinusoidal

spaces. In 66 (78.6%) cases with parathyroid adenoma,

the cells were predominantly disposed in solid sheets with

intervening thin sinusoidal spaces. In 3 (3.6%) adenomas,

cells were disposed in sheets and tubular pattern while in

15 (17.8%), they were predominantly disposed in tubular

pattern. In one case of adenoma, the cells in a few foci

were disposed in follicular pattern with intrafollicular

amyloid deposition. Eighty-one (96.4%) adenomas were

composed of either chief cells or mixed chief and clear

cells. One adenoma was composed of water-clear cells

and 2 of oxyphilic cells. One case with functioning oxy-

philic parathyroid adenoma manifested with severe clini-

cal manifestation of PHPT but had a rather small (950

mg) and noninvasive parathyroid tumor. Three patients

had synchronous double adenomas with only 2 enlarged

glands, both of which fulfilled adenoma criteria. The

remaining 2 parathyroids were visually normal, and a

biopsy from one of those did not show features sugges-

tive of hyperplasia. All cases of parathyroid hyperplasia

and carcinoma were histologically composed of either

chief cells or mixed chief and clear cells. Vascular and

capsular invasion (Fig. 4), thick fibrous septae (Fig. 5),

and characteristic cellular features such as nuclear aty-

pia, vesicular nuclei, macro nucleoli, and frequent mitotic

figures (Fig. 6) were seen in all 4 cases of PC. In 2 cases,

local tumor infiltration was also present. Diagnosis of PC

was further substantiated by occurrence of metastatic

and locally or regionally recurrent disease in 3 patients

while diagnosis was quite apparent from gross contigu-

ous invasion of neck structures in the fourth. None of the

biochemical parameters correlated with either glandular

weight or cell morphology. Glandular weight and size

were markedly variable in chief cell hyperplasia.

DISCUSSION

The clinical, biochemical, radiological, and pathological

features of 84 Indian PHPT patients with parathyroid

adenoma, 12 with primary parathyroid hyperplasia, and 4

with PC were not significantly different. These findings are

contrary to a common belief that patients with parathyroid

cancer have different clinical and biochemical features

than those with a benign parathyroid pathology.3,9,10

Carcinoma of the parathyroid is a rare cause of PHPT,

constituting less than 2% of all PHPT cases.1–3 The

proportion of PHPT patients with PC is reported higher in

series from developing countries and in earlier studies

from certain developed countries.4–7 Most reports have

shown no gender predilection for PC,1,3,15 in contrast to a

definite female preponderance of adenomas. Our study,

as have a few others 16, found a similar preponderance of

Figure 3. Radiographs of pelvis and upper femurs of a patient with parathyroid carcinoma. Extreme bone destruction, browntumors, cysts, and fractures have caused much of the skeletal framework to become invisible: ‘‘disappearing bones’’ syndrome.


women even in patients with PC. PCs are reported to

occur about a decade earlier than adenomas, with a

mean age of approximately 45 years for PC compared to

55 years for adenomas.1,3,15 In our experience, the

average age of PHPT patients with benign or malignant

pathology were similar, reflecting an overall young age of

Indian PHPT patients.

Diagnosis of PC is often difficult to establish and is only

rarely evident preoperatively.8,17 This rare condition is

diagnosed by a combination of clinical, biochemical, and

pathological features attributed to this disease. Clinical

features such as symptomatic skeletal manifestations of

PHPT in young patients, especially when present simul-

taneously with renal manifestations, and a palpable

parathyroid mass are considered indicative of presence

of PC.9 Extreme hypercalcemia, with s-Ca levels >14 mg/

dl, and very high s-PTH levels have also been seen as

warning signs of malignant parathyroid pathology in

PHPT patients.8–10 In our patients, s-Ca levels were only

moderately elevated in a majority, including those with

PC, and s-PTH levels were extremely high irrespective of

the parathyroid pathology. Of the 6 patients who pre-

sented with hypercalcemic crisis, only one was found to

have PC. Presentation with hypercalcemic crisis in 25%,

i.e., 1 of 4 PC patients, in contrast to only 4/84 (5%)

parathyroid adenoma and 1/12 (8.3%) of hyperplasia

Figure 4. Photomicrograph showing nests of bland-looking cells traversed by delicate vasculature and a focus of capsular invasionin a case with parathyroid carcinoma. H & E, 200·.

Figure. 5. Photomicrograph of a parathyroid carcinoma showing thick fibrous band traversing the tumor. H & E, 200·.


patients, indicates a greater degree of hypercalcemia and

perhaps more rapidly rising serum calcium in patients

with PC. However, the small number of patients with

hypercalcemic crisis in the PC group limits a valuable

comparison.

Presence of severe osteopenia on BMD and radiolog-

ical features of OFC, brown tumors, or cysts and patho-

logical fractures are often considered to be associated

with parathyroid cancer. However, the extent of bone loss

and nature of skeletal disease in our patients with PC and

benign pathology was quite comparable. At operation,

presence of a large, gray-white parathyroid tumor with

invasion into the surrounding strap muscles, thyroid lobe,

and other structures and high tumor weight have often

been considered suggestive of a malignant parathyroid

neoplasm.1,9,10 Similar operative findings led to intraop-

erative suspicion and en bloc radical excision of the

parathyroid tumor in 6 patients, of which 2 were eventu-

ally found to be large adenomas. The benign nature of

disease in both these patients has been confirmed by

long-term relapse-free course during follow-up.

The basis of such clinical and investigative features

being considered diagnostic or indicative of PC and as

distinctive from parathyroid adenomas is observations in

a relatively small number of PC patients and a huge

number of asymptomatic PHPT patients with small ade-

nomas in industrially developed countries. The picture in

the Indian PHPT patients with PC closely resembles that

of PC patients reported from developed countries. How-

ever, the majority of Indian PHPT patients with benign

parathyroid pathology have similar symptoms, advanced

bone and renal disease, and large but clearly noninvasive

benign tumors, making preoperative reliable prediction of

parathyroid cancers almost impossible.

The reasons for little difference between Indian patients

with parathyroid adenoma, primary hyperplasia, and

carcinoma may be manifold. Firstly, unlike Western pa-

tients where most are diagnosed at asymptomatic stages,

often on basis of biochemical survey,18 almost all PHPT

patients in India are diagnosed at a relatively late symp-

tomatic stage and are rarely asymptomatic.4,5,19–21 Indian

PHPT patients present at a relatively young age with OFC

and extreme osteopenia (‘‘disappearing bones’’ syn-

drome). Some are crippled due to fractures, brown tu-

mors, and muscle weakness (parathyroid cripples). Renal

manifestations are common, and as skeletal manifesta-

tions are ubiquitous, the two are often present simulta-

neously. Many have palpable parathyroid tumor and

extremely high serum PTH levels.4,5 Reports from other

developing countries have indicated presence of similar

clinical picture of PHPT.6,22–28 Possibly, only severe

cases are diagnosed, after a relatively long duration of

illness due to relative lack of awareness of the disease in

India and other developing countries. In spite of such

clinical, biochemical, radiological, and pathological fea-

tures that are conventionally considered to indicate

presence of malignant tumors, fewer than 5% of Indian

PHPT patients are diagnosed with PC.

Secondly, nutritional and environmental factors may

play a role in pathogenesis and progression of parathy-

roid tumors.4,5,21,22,29 Vitamin D status influences the

clinical expression of PHPT, and patients with low vitamin

Figure 6. Photomicrograph showing nuclear atypia with vesicular nuclei, mitotic figures, presence of macronuclei, and moderateamount of pale cytoplasm in section from parathyroid carcinoma. H & E, 400·.


D levels are particularly prone to develop marked PTG

enlargement and severe skeletal manifestations.4,5,29

This was substantiated by our findings of low s-25-OH-D

levels in our symptomatic patients with OFC and large

parathyroid tumors. Nutritional deficiency of calcium and

vitamin D, which is common in the Indian population, may

lead to marked parathyroid cell proliferation as in patients

with chronic renal failure.18 This results in a more severe

primary hyperparathyroid state and development of large

tumors, which may be palpable even though benign. The

excessive serum levels of PTH in PHPT impose a greater

demand of vitamin D on the body and tend to result in

attenuated relative vitamin D deficiency.22,29 Therefore,

PHPT may manifest with secondary osteomalacia in

individuals with preexisting nutritional vitamin D defi-

ciency,22 making the skeletal manifestations of PHPT

more florid,4,5,22 as seen in Indian PHPT patients.

Diminished intake and dermal production of vitamin D,

and possibly increased activity of 25(OH)D-24-hydroxy-

lase, may be responsible for low serum 25-OH-D in

Indians.30

It is often difficult to distinguish PC from adenoma only

on the basis of histology. Histological criteria for PC

proposed by Schantz and Castleman3 are widely used,

including presence of: (a) broad fibrous capsule or tra-

beculae (Fig. 5), (b) trabecular or rosette-like cellular

architecture, (c) mitotic figures (Fig. 6), and (d) capsular

or vascular invasion (Fig. 4). Most of these features can

also be seen in isolation in adenomas, and thus the

overall histological picture is more important as presence

of several in the same tumor increases the possibility of

malignancy.31 All 4 of our PC patients were found to have

typical histological features. A histological classification of

PC�s into low-grade (those with limited local infiltration)

and high-grade (with widespread infiltration) carcinomas

has recently been proposed.31

In our patients with PC, the only significant distinctive

feature from patients with adenoma was higher tumor

weight, in agreement with observations by others.10 This

significant difference was seen in spite of the fact that the

diseased PTG mass even in benign pathologies was

appreciably higher in our study compared with reports

from the developed world. PTG size and weight were

markedly variable in our patients with chief cell hyper-

plasia, as also reported by others.32 The distinction be-

tween adenoma and chief cell hyperplasia is difficult. S-

Ca has been reported to be inversely correlated with chief

cell hyperplasia and positively correlated with the glan-

dular weight in both adenoma and hyperplasia.32 In our

series, none of the biochemical parameters correlated

with either glandular weight or cell morphology.

In the present series of 100 cases, parathyroid lesions

were composed predominantly of chief cells or mixed

chief and clear cells, similar to most Western reports,32,33

and were deposited in solid sheets with intervening thin

sinusoidal spaces. Trabecular arrangement of tumor cells

is an uncommon finding, and its presence favors the

diagnosis of PC.34 In our patients, foci of trabecular pat-

tern were found in both adenoma and carcinoma. In 1

patient, the parathyroid adenoma was composed of wa-

ter-clear cells and deposited in tubular pattern—a rare

histological type of adenoma with only 5 such cases,

including ours, reported in the medical literature.35 Oxy-

phil parathyroid adenomas are usually nonfunctional, and

fewer than 70 functional oxyphil adenomas are reported

in the medical literature.36 These need to be carefully

differentiated from oxyphil PC, which is a distinct though

rare histological variety of PC.37 One of our patients with

functioning oxyphil adenoma was a 25-year-old woman

with severe clinical and biochemical manifestations of

PHPT. The fact that after parathyroidectomy she has

remained normocalcemic and free of recurrence after 6

years of follow-up confirms that an oxyphil PC was not

missed. Three of our patients had double adenoma with

only 2 enlarged glands, both of which fulfilled adenoma

criteria.38

In view of numerous complexities and uncertainties

plaguing the histological diagnosis of PC, the most reli-

able way of diagnosing it is demonstration of distant or

lymph nodal metastases and/or gross contiguous inva-

sion of nearby structures. In all such patients who do not

fit these criteria and have a clinical or histological suspi-

cion of PC, only local or metastatic recurrence at follow-

up can provide foolproof evidence of malignancy.3,15,39

None of our patients with a benign pathology, including

the 3 with persistent or recurrent PHPT, were found to

have local recurrence of tumor or metastases during the

minimum follow-up period of 1 year, thus vindicating the

diagnosis of a benign lesion and suggesting that PC was

not missed. Furthermore, reversal of most symptoms and

musculoskeletal complications following successful

parathyroidectomy, as evidenced by spectacular rise in

BMD, healing of pathological fractures, and brown tu-

mors, albeit with persistent bony deformities, regaining of

muscle strength, and walking ability by parathyroid crip-

ples 5 provide additional evidence of cure.

In conclusion, contrary to conventional belief, Indian

patients with parathyroid adenoma, hyperplasia, and

carcinoma do not differ in their clinical, biochemical, and

pathological characteristics, except for significantly higher

tumor weight in the carcinoma group. It will be interesting

to see if similar overlap of clinical, biochemical, and


pathological features in parathyroid adenoma, primary

hyperplasia, and PC remains when a higher proportion of

asymptomatic PHPT patients are studied. At present,

lack of features for differentiation of various parathyroid

pathologies makes preoperative prediction of PC nearly

impossible.

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